Nurr1 receptor modulators and uses thereof

Abstract

Nurr1 receptor modulators and uses thereof are described herein.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 015,302, filed April 24, 2020, which is incorporated herein by reference in its entirety and for all purposes.

[0003] References to "sequence lists", tables, or appendices to lists of computer programs submitted as ASCII files.

[0004] The sequence list written to file 048536-681001WO_Sequence_Listing_ST25, created on April 15, 2021, with 27,033 bytes, IBM-PC machine format, and MS Windows operating system, is incorporated by reference. Claims regarding inventions made under federally funded research and development

[0005] This invention was made with government support under Contract No. R01 NS108404 granted by the National Institutes of Health. The government enjoys certain rights to this invention. Background Technology

[0006] More than one million Americans currently suffer from Parkinson's disease (PD), with approximately 60,000 new cases diagnosed each year. PD is the second most common degenerative neurodegenerative disease after Alzheimer's. Current PD treatments only improve symptoms, do not address disease progression, and lose effectiveness over time. New treatment strategies are needed to combat this disease. The nuclear receptor Nurr1 plays a crucial role in the development, maintenance, and survival of midbrain dopaminergic neurons. PD is a neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons. Nurr1 modulators (e.g., agonists or inhibitors) can provide an orthogonal approach to increasing dopamine levels in the brain (managing symptoms), improving health, and preventing the degeneration of existing dopaminergic neurons (managing disease progression). Solutions to these and other problems in the art are specifically disclosed herein. Summary of the Invention

[0007] In one aspect, a compound having the following formula is provided:

[0008]

[0009] R 1 Independently 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, -SF5, -SSR 1D -SiR 1A R 1B R 1C -SP(O)(OH)2, 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.

[0010] R 1A R 1B R 1C and R 1DIndependently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SeH, -SO3H, -OSO3H, -SO2NH2, NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 1A and R 1B Substituents can be bonded to form a substituted or unsubstituted heterocyclic alkyl group or a substituted or unsubstituted heteroaryl group.

[0011] The variable n1 is an independent integer from 0 to 4.

[0012] Variables m1 and v1 are independently 1 or 2.

[0013] X 1 It can be independently –F, -Cl, -Br, or –I.

[0014] The variable z1 is an integer from 0 to 6.

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

[0016] In one aspect, a method is provided for treating a disease of the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons in a subject with such need, the method comprising administering to the subject with such need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0017] In one aspect, a method is provided for treating neurodegenerative diseases in subjects with such need, the method comprising administering to the subject with such need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject with this need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0019] In one aspect, a method for reducing inflammation in a subject with this need is provided, the method comprising administering to the subject with this need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0020] In one aspect, a method for reducing oxidative stress in subjects with this need is provided, the method comprising administering to the subject with this need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, a method is provided for modulating Nurr1 activity levels in subjects in need, the method comprising administering to the subject in need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0022] In one aspect, a method for differentiating stem cells is provided, the method comprising contacting the stem cells in vitro with a compound described herein or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0023] Figure 1 The DHI analogs 5-chloroindole and 5-bromoindole directly bind to and stimulate the transcriptional activity of Nurr1. The electrostatic potential surface (EPS) of each DHI analog was calculated using the 6-31G** matrix and the B3LYP-D3 functional in water (PBS solvent model). The binding affinity (K) of the Nurr1 ligand-binding domain was also calculated. D Microscale thermophoresis was used to determine the relative expression of Nurr1 target genes Th and Vmat2 using mRNA from MN9D cells after treatment with the compounds (10 μM) for 24 h. The transcriptional level of each target gene was normalized to the housekeeping gene Hprt and to the expression level of cells treated with the mediator (DMSO only). All experimental values ​​are results of three or more independent measurements ± SD. *Note: A subset of the indoles tested showed signs of instability and polymerization in solution, as well as cytotoxicity in MN9D cells. In particular, binding data were excluded by initial fluorescence quenching and photobleaching of the compounds (5 / 6-aminoindole) and by auto-oxidation and subsequent polymerization of the compounds in solution (5 / 6-hydroxy and 5 / 6-aminoindole).

[0024] Figure 2A-2DPoint mutations (Arg563, His516) within the DHI binding pocket significantly affect the binding of 5-chloroindole and 5-bromoindole, and point to the second indole binding site with Nurr1 LBD. Figure 2A-2B Single and double mutants increased the affinity of 5-substituted indole for the receptor and significantly altered the thermophoretic response amplitude. Figure 2C-2D Single and double mutants reduced the affinity of 5,6-disubstituted indole for Nurr1, but had a relatively small effect on the thermophoretic response amplitude.

[0025] Figures 3A-3B Network molecular interactions support the binding of IQ and DHI to Nurr1 LBD within the "566 site". A close-up image of Nurr1 covalently bound to indoquinone in the crystal structure (PDB:6DDA) is shown. Figure 3A ), and a close-up image of Nurr1 non-covalently bound to indolequinone in the computational model of DHI unoxidized indole ( Figure 3B In the QM / MM model, DHI is positioned further away from H10 / 11 than IQ, resulting in a new interaction with His516, and tilted at approximately 45 degrees relative to IQ along the plane of the indole ring, leading to a closer interaction with Glu445 and Arg563. In the apo LBD structure (PDB:1OVL), the guanidinium salt side chain of Arg563 rotates approximately 180 degrees and forms an intramolecular bond (not shown) with the carboxylic ester side chain of Glu445.

[0026] Figures 4A-4C . Figure 4A The binding of indole to Nurr1 LBD is stabilized by a network of hydrogen, halogen, cation-π, and ionic bonds. Top: Chemical structure showing the interaction between the amino acid side chains within Nurr1 LBD and the binding ligand; only distances ≤ [missing information] are shown. The interaction. Bottom: The table shows the physical distance between the amino acid side chain and the binding ligand (in words). (in units). Distance ≤ Shown in black and distance > Shown in gray. Figure 4B In the computational (QM / MM) model, substituted indoles are expected to bind to Nurr1 in almost the same manner. Top: Model of 5-chloroindoles binding to Nurr1. Bottom: Superposition of computational models for all halogenated and 5-substituted indoles evaluated in this study. Figure 4CThe binding of 5-bromoindole and 5-chloroindole to Nurr1 is expected to be stabilized by a halogen bond with His516. A side view of the molecular ESP surface of the 5-halogenated indole highlights the interaction between the lone pair electrons on His516 and the σ-holes within the bromine and chlorine substituents. The insufficient electron density in the outer lobes of the pz orbitals of 5-bromoindole and 5-chloroindole compared to 5-fluoroindole results in a relatively more positive electrostatic potential surface in this region. The relative pKa values, interaction energies, and measured binding affinities are consistent with the proposed halogen bond between His516 and subsets of haloindole. pKa values ​​were predicted using propKa3.1 after QM / MM optimization of the non-covalently bound indole. Single-point interaction energies were calculated using the LMP2 / cc-pVDZ** theoretical level in the gas phase. The coordinates of the complexes were taken from the QM / MM optimized structures at the DFT-D3 / LACVP* theoretical level. In this study, it ranked among all 5-substituted indoles.

[0027] Figure 5 The DHI analogs 5-chloroindole and 5-bromoindole directly bind to stimulate the transcriptional activity of Nurr1. The molecular electrostatic potential (ESP) surface of each DHI analog was calculated using the 6-31G** basis set and bromine atoms treated with LAV2P**. The binding affinity (Kb) of Nurr1 LBD was also calculated. D Microscale thermophoresis was used to determine the relative expression levels of the Nurr1 target genes Th and Vmat2. The transcriptional levels of each target gene were normalized to the housekeeping gene Hprt and reported as fold changes relative to cells treated with the medium alone (DMSO). All experimental values ​​are results of three or more independent measurements ± SD. Detailed experimental protocols are described in Example 3. Note: Data collection for a subset of these compounds was excluded due to their chemical instability. In particular, reliable binding data could not be obtained due to initial fluorescence quenching and photobleaching (5-aminoindole and 6-aminoindole), and spontaneous oxidation and polymerization in solution (5-hydroxyindole and 6-hydroxyindole, 5-aminoindole and 6-aminoindole). These compounds also exhibited significant cytotoxicity (see [link to documentation]). Figure 6C ).

[0028] Figures 6A-6C A subset of haloindoles binds to the Nurr1 ligand-binding domain. This is achieved by plotting thermophoresis (F... n -F n0 The change in concentration relative to the tested compound ([indole], M) is used to obtain ( Figure 6A )5-substituted indole, ( Figure 6B )6-substituted indole and ( Figure 6C Microscale thermophoresis (MST) combined isotherms of 5,6-dihaloindole and Nurr1 LBD. All experimental values ​​are results of three or more independent measurements ± SD. Except for 5-chloroindole and 5-bromoindole, which require the use of the Hill equation, all data are best-fitted for single sites. Note: Hill coefficients (n) for 5-chloroindole (1.9 ± 0.2) and 5-bromoindole (1.9 ± 0.3) are given. H All Hill coefficients were greater than 1, while the values ​​for all other compounds were uniform within the error range. A Hill coefficient greater than 1 generally indicates cooperative binding of the ligands, where the absolute value sets a lower limit on the number of interacting binding sites (see Weiss, JN, "The Hill equation revisited: uses and misuses," FASEB J. 11, 835-841, 1997). However, we observed a significant change in the Hill coefficient with increasing surfactant concentration in 5-chloroindole, which could be due to partial denaturation of the protein and the loss of one of the accompanying indole binding sites. Alternatively, increasing the surfactant concentration may have disrupted the compound nanoaggregates that incorrectly indicate cooperative binding of the two indoles.

[0029] Figures 7A-7D Only a subset of indoles that bind to Nurr1 also stimulates the transcription of Nurr1 target genes in MN9D cells. Figure 7A )5-substituted indole, ( Figure 7B )6-substituted indole and ( Figure 7C The effects of 5,6-dihaloindole (10 μM, 24 h) on the expression of Nurr1, Th and Vmat2 relative to mediator-only (DMSO) (dashed line) were quantified by qPCR as described in Example 3. Figure 7D The effect of 5-chloroindole on the expression of Th and Vmat2 was concentration-dependent. All data are results of three or more independent measurements and are expressed as mean ± standard deviation (SD), where *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by one-way ANOVA compared to the response to mediator treatment (DMSO).

[0030] Figures 8A-8B 5-Chloroindole is not cytotoxic. Figure 8A After treatment with 10 μM compound for 24 hours, approximately half of the tested indole reduced the survival percentage of MN9D cells. Figure 8B5-Chloroindole at concentrations ≤10 μM had no significant effect on cell viability after 24 hours of treatment. Cell viability was measured using the CytoTox-Glo Cytotoxicity Assay Kit (Promega) according to the manufacturer's instructions after treatment with the specified indole or DMSO (10,000 cells / well). All experimental values ​​are results of three independent measurements ± SD, with *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared to the response to the medium treatment (DMSO) by one-way ANOVA.

[0031] Figures 9A-9B Increasing the surfactant concentration reduced the formation of 5-chloroindole nanoaggregates and increased the affinity for Nurr1 LBD by less than two times. Figure 9A As the percentage of Pluronic F127 increases, the aggregate count of 5-chloroindole is measured (DLS normalized intensity). Figure 9B : Binding affinity of 5-chloroindole measured with increasing percentage of Pluronic F127; K D (0.1%)=15.0±1.2μM, (nH=2); K D (0.2%)=8.3±0.7μM, (nH=2); K D (0.5%)=10.9±0.3μM, (nH=1); K D (1.0%) = 9.1 ± 0.4 μM, (nH = 1). All experimental values ​​are results from three or more independent biological replicates ± standard deviation.

[0032] Figures 10A-10B The DHI analog 5-chloroindole stimulated Nurr1 activity in two different luciferase reporter gene assays. (In...) Figure 10A Nurr1-LBD_Gal4-DBD luciferase reporter gene assay and ( Figure 10B In the full-length Nurr1NBRE luciferase reporter gene assay, 5-chloroindole stimulated luciferase production. The control compounds 5-cyanoyindole (negative control) and amodiaquine (positive control) performed as expected. MN9D cells were individually treated with the specified concentration of the ligand for 6 hours prior to measuring the luciferase signal (RLU, relative photometric units; see Example 3 for additional details). All experimental values ​​are results from three or more independent biological replicates and are expressed as relative mean response ± standard deviation, where *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by one-way ANOV, compared to the response using only the mediator (DMSO).

[0033] Figure 11A-11C The effect of 5-chloroindole on the expression of Nurr1 target genes depends on Nurr1 expression. The expression of Nurr1, Th, and Vmat2 transcripts was determined in the presence of 5-chloroindole (10 μM, 24 h) under conditions of Nurr1 knockdown with or without Nurr1 siRNA. Gene expression levels in the presence of 5-chloroindole were associated only with the same treatment using the same medium (DMSO). Figure 11A Nurr1 expression was significantly reduced by Nurr1 siRNA, but not by control siRNA. As described in Example 3, Nurr1 expression in MN9D cells was knocked down using Nurr1 siRNA. Figure 11B-11C The effect of 5-chloroindole on the expression of Th and Vmat2 was significantly reduced in the presence of Nurr1 siRNA, but not significantly reduced in the presence of control siRNA. All experimental values ​​are results of three or more independent biological replicates and are expressed as relative mean response ± standard deviation, where *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by one-way ANOVA compared to the response using only the mediator (DMSO).

[0034] Figure 12A-12D Halogenated indoles specifically bind to Nurr1 LBD, but not to RXRα LBD. Figure 12A 5-Bromoindole, ( Figure 12B 5-Chloroindole, ( Figure 12C 5,6-Dibromoindole and ( Figure 12D Comparison of the MST binding isotherms of 5,6-dichloroindole revealed saturated binding with Nurr1 LBD (light gray circle), but not with RXRα LBD (dark gray circle). Binding determinations were performed as described in Example 3. All experimental values ​​are results from three or more independent biological replicates ± standard deviation.

[0035] Figure 13 The Arg563 mutation in Nurr1 LBD reduces the protein's thermal stability. Melting profiles were obtained using differential scanning fluorometry (DSF). Nurr1 LBD (4 μM) was dissolved in 25 mM HEPES buffer, pH 7.4, 150 mM NaCl, and 1x SYPRO. TMIn orange dyes, the fluorescence response was normalized to the maximum fluorescence value defined as 100% for each dataset. The reported Tm (the inflection point of the sigmoid curve) was calculated using the Boltzmann sigmoid equation: Y = bottom + (top - bottom) / (1 + exp((Tm - x / slope)), where bottom and top are the values ​​of minimum and maximum intensity, respectively. Each data point is the mean ± standard deviation of at least three independent measurements; the curve for each variant is the result of a global fit to all replicates.

[0036] Figure 14 The characteristics of the two different ligand binding sites within the Nurr1 LBD. Site 566 only accommodates 5-substituted indole, requires His516 and Arg563 for binding, and upregulates Th and Vmat2 transcription. The novel site binds both 5-substituted and 5,6-disubstituted indole, but does not drive Th or Vmat2 expression. Detailed Implementation

[0037] I. Definition

[0038] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0039] When describing substituents using their conventional chemical formulas written from left to right, the substituents equally encompass chemically identical substituents obtained from structures written from right to left, for example, -CH2O- is equivalent to -OCH2-.

[0040] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, and / or polyunsaturated, and may contain monovalent, divalent, and polyvalent groups. Alkyl groups may contain a specified number of carbons (e.g., C1-C1). 10(This refers to a chain with one to ten carbon atoms). An alkyl group is an uncyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 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 group is an alkyl group connected to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. The alkenyl group may include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. The alkynyl group may include more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. In the embodiments, the alkyl group is fully saturated. In the embodiments, the alkyl group is monounsaturated. In the embodiments, the alkyl group is polyunsaturated.

[0041] Unless otherwise stated, the term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group typically having eight or fewer carbon atoms. Unless otherwise stated, the term "alkenyl" itself, or as part of another substituent, refers to a divalent group derived from an alkene. Unless otherwise stated, the term "alkynyl" alone, or as part of another substituent, refers to a divalent radical derived from an alkyne. In the examples, the alkylene is fully saturated. In the examples, the alkylene is monounsaturated. In the examples, the alkylene is polyunsaturated. In the examples, the alkenyl group comprises one or more double bonds. In the examples, the alkynyl group comprises one or more triple bonds.

[0042] Unless otherwise stated, the term "heteroalkyl" alone or in combination with another term means a stable straight or branched chain, or a combination thereof, comprising 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). One or more heteroatoms (e.g., N, S, Si, or P) may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Heteroalkyl groups are uncyclic chains. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -SCH2CH2, -S(O)CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CHN(CH3)CH3, -OCH3, -OCH2CH3, and -CN. Up to two or three heteroatoms can be consecutive, 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). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" itself or in combination with another term means a heteroalkyl group containing at least one double bond. A heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Unless otherwise stated, the term "heteroyynyl" itself or in combination with another term means a heteroalkyl group containing at least one triple bond. A heteroyynyl group may optionally include more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. In embodiments, the heteroalkyl group is fully saturated. In embodiments, the heteroalkyl group is monounsaturated. In embodiments, the heteroalkyl group is polyunsaturated.

[0043] Similarly, unless otherwise stated, the term "heteroalkylene" refers, alone or as part of another substituent, to a divalent group derived from a heteroalkylene group, such as (but not limited to) -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further still, for alkylene and heteroalkyl linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups connected to the remainder of the molecule via heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. Where the term "heteroalkyl" is followed by a specific heteroalkyl group, such as -NR'R", etc., it should be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R", etc. Unless otherwise stated, the term "heteroalkenyl" alone or as part of another substituent refers to a divalent group derived from a heteroalkene. Unless otherwise stated, the term "heteroyneyl" alone or as part of another substituent refers to a divalent group derived from a heteroalkynylene. In the examples, the heteroalkylene group is fully saturated. In the examples, the heteroalkylene group is monounsaturated. In the examples, the heteroalkylene group is polyunsaturated. In some embodiments, the hesenoyl group comprises one or more double bonds. In some embodiments, the hesenoyne group comprises one or more triple bonds.

[0044] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl," alone or in combination with other terms, refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. 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, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" refer, alone or as part of another substituent, to divalent groups derived from cycloalkyl and heterocycloalkyl groups, respectively. In the examples, the cycloalkyl group is fully saturated. In the examples, the cycloalkyl group is monounsaturated. In the examples, the cycloalkyl group is polyunsaturated. In the examples, the heterocycloalkyl group is fully saturated. In the examples, the heterocycloalkyl group is monounsaturated. In the examples, the heterocycloalkyl group is polyunsaturated.

[0045] In the embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In the embodiments, a monocyclic system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such groups may be saturated or unsaturated, but are not aromatic. In the embodiments, the cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to a plurality of rings fused together, wherein at least one fused ring is a cycloalkyl ring, and wherein the plurality of rings are attached to the parent molecule moiety by any carbon atom contained within the cycloalkyl ring of the plurality of rings.

[0046] In the embodiments, the term "heterocyclic alkyl" refers to a monocyclic, bicyclic, or polycyclic heterocyclic alkyl ring system. In the embodiments, the heterocyclic alkyl is fully saturated. A bicyclic or polycyclic heterocyclic alkyl ring system refers to a plurality of rings fused together, wherein at least one fused ring is a heterocyclic alkyl ring, and wherein the plurality of rings are attached to the parent molecule moiety by any carbon atoms contained within the heterocyclic alkyl rings of the plurality of rings.

[0047] Unless otherwise stated, the term "halogen" or "halogen," either alone or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" refer to both monohaloalkyl and polyhaloalkyl groups. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0048] Unless otherwise stated, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0049] Unless otherwise stated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which may be a monocyclic or co-fused (i.e., fused-ring aryl) or covalently linked multiple rings (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together, wherein at least one of the fused rings is an aryl ring. In embodiments, fused-ring aryl refers to multiple rings fused together, wherein at least one fused ring is an aryl ring, and wherein the multiple rings are attached to the parent molecule moiety via any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (e.g., N, O, or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Therefore, the term "heteroaryl" includes fused-ring heteroaryl (i.e., multiple rings fused together, wherein at least one of the fused rings is a heteroaryl ring). In embodiments, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of rings fused together, wherein at least one of the fused rings is a heteroaryl ring, and wherein the plurality of rings are attached to a portion of the parent molecule via any atoms contained within the heteroaryl rings of the plurality of rings). 5,6-fused-ring heteroaryl refers to two fused rings, one ring having 5 members and the other having 6 members, and wherein at least one ring is a heteroaryl ring. Similarly, 6,6-fused-ring heteroaryl refers to two fused rings, one ring having 6 members and the other having 6 members, and wherein at least one ring is a heteroaryl ring. And 6,5-fused-ring heteroaryl refers to two fused rings, one ring having 6 members and the other having 5 members, and wherein at least one ring is a heteroaryl ring. Heteroaryl groups can be attached to the remainder of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indoleyl, isoindoleyl, benzothiapheneyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl The substituents in the aryl and heteroaryl ring systems mentioned above are selected from the acceptable substituent group described below. (The list includes substituents such as pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalolinyl, 5-quinoxalolinyl, 3-quinolinyl, and 6-quinolinyl.)Alone or as part of another substituent, "arylene" and "heteroarylene" refer to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can be -O- bonded to a nitrogen atom in a cyclic heteroatom.

[0050] A spirocycle is a group of two or more rings in which adjacent rings are connected by a single atom. Individual rings within a spirocycle can be identical or different. Individual rings within a spirocycle can be substituted or unsubstituted and can have substituents different from those of other individual rings in the spirocycle group. Possible substituents of the individual rings within a spirocycle are possible substituents of the same ring (when not part of the spirocycle) (e.g., substituents of cycloalkyl or heteroalkyl rings). A spirocycle can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual rings within the spirocycle group can be any ring in the preceding list, including all rings of one type (e.g., all rings are substituted heteroalkylene, where each ring can be the same or different substituted heteroalkylene). When referring to a spirocycle system, a heterocyclic spirocycle means a spirocycle in which at least one ring is heterocyclic and each ring can be a different ring. When referring to spirocyclic systems, a substituted spirocycle means that at least one ring is substituted and each substituent may optionally be different.

[0051] The symbol “” indicates the point where the chemical part connects to the rest of the molecule or chemical formula.

[0052] As used in this article, the term "oxo" refers to oxygen bonded to a carbon atom in a double bond.

[0053] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In the examples, the alkylarylene has the following formula:

[0054]

[0055] The alkylarylene moiety may be substituted (e.g., substituted with substituents) at the alkylene moiety or arylene junction (e.g., at carbon 2, 3, 4, or 6) with the following: halogen, oxo group, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl groups, or substituted or unsubstituted 2- to 5-membered heteroalkyl groups. In the examples, the alkylarylene group is unsubstituted.

[0056] Each of the terms above (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes the substituted or unsubstituted form of the indicated group. Preferred substituents for each type of group are provided below.

[0057] The substituents of alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more selected from, but not limited to, the following groups: -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R"', -OC (O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=N R"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", the number ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. 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., using 1-3 halogens). Substituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted alkyl groups, alkoxy or thioalkoxy or aralkyl groups. When the compounds described herein contain more than one R group, each of the R groups is selected independently, for example, as if each R' group, R" group, R"' group and R"" group were selected independently when more than one of these groups were present. When R' and R" are attached to the same nitrogen atom, they can combine with said nitrogen atom to form a 4-membered, 5-membered, 6-membered or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" means a group comprising a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0058] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are varied and are selected, for example, from the following: -OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R"', -OC(O)NR'R"', -NR"C(O)R', -NR'C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"', -NR-C(NR'R")=NR"' -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR" (quantity range from zero to open valence on the aromatic ring system) The total number of valences); and wherein R', R", R"' and R"" are preferably independently selected independently 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 compound described herein contains more than one R group, each of the R groups is selected independently, for example, as if each R' group, R" group, R"' group and R"" group were selected independently when more than one of these groups are present.

[0059] Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring rather than on a specific atom of the ring (often referred to as floating substituents). In this case, the substituent can be attached to any ring atom (following the valence rules), and in the case of fused or spirocyclic rings, the substituent described as associated with one member of the fused or spirocyclic ring (floating substituents on a single ring) can be a substituent on any of the fused or spirocyclic rings (floating substituents on multiple rings). When the substituent is attached to the ring rather than a specific atom (floating substituent) and the substituent's subscript is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent can optionally be different. Where the connection point between the ring and the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of fused or spirocyclic rings, it can be any atom of any of the fused or spirocyclic rings (following the valence rules). In the case where a ring, fused ring, or spirocyclic ring contains one or more cyclic heteroatoms and the ring, fused ring, or spirocyclic ring is shown having another floating substituent (including, but not limited to, a connection point with the rest of the molecule), the floating substituent may be connected to the heteroatom. When the cyclic heteroatom is shown to be bonded to one or more hydrogen atoms in a structure or formula having a floating substituent (e.g., a cyclic nitrogen with two bonds bonded to the ring atom and a third bond bonded to a hydrogen atom), the substituent is understood to replace the hydrogen atom when the heteroatom is connected to the floating substituent, while following the rules of chemical valence.

[0060] Two or more substituents may optionally join to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called cycloforming substituents are typically (though not mandatory) linked to a cyclic base structure. In one embodiment, the cycloforming substituent is linked to an adjacent member of the base structure. For example, two cycloforming substituents linked to an adjacent member of the cyclic base structure produce a fused-ring structure. In another embodiment, the cycloforming substituent is linked to a single member of the base structure. For example, two cycloforming substituents linked to a single member of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cycloforming substituent is attached to a non-adjacent member of the base structure.

[0061] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be configured as -TC(O)-(CRR'). q A -U- ring, where T and U are independently -NR-, -O-, -CRR'-, or single bonds, 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 be of the formula -A-(CH2). rThe substituents of -B- are used, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -(CRR'). s -X'-(C"R"R"') d The substituents are substituted, wherein 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.

[0062] As used herein, the term "heteroatom" or "cyclic heteroatom" means comprising oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In the embodiments, the term "heteroatom" or "cyclic heteroatom" means comprising oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0063] As used herein, "substituent" means a group selected from the following:

[0064] (A) Oxide groups, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2 -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0065] (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 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), wherein the group is substituted by at least one substituent selected from the following:

[0066] (i) Oxide groups, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2 -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0067] (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 The group is substituted with at least one substituent selected from the group consisting of aryl, or phenyl, heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0068] (a) Oxide groups, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2 -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0069] (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 10The group is substituted with at least one of the following: oxy-group, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3 H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, 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).

[0070] As used herein, “size-limited substituent” or “size-limited substituent group” means a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C. 20 Alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0071] As used herein, “lower substituent” or “lower substituent group” means a group selected from all the substituents described above for the term “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 9-membered heteroaryl group.

[0072] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-restricted substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0073] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 alkyl group. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group, is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C... 20 Alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 3- to 8-membered heteroalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 10 heteroaryl group.

[0074] In some embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 2- to 8-membered heteroaryl group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 3- to 7-membered heteroalkylene group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 alkylene group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, the compound is a chemical substance set forth in the Examples section, figures, or tables below.

[0075] In the embodiments, the substituted or unsubstituted portions (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 heteroaryl) are unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted arylene and / or unsubstituted heteroaryl). In the embodiments, the substituted or unsubstituted portions (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 heteroaryl) are substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted arylene and / or substituted heteroaryl, respectively).

[0076] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, wherein if the substituted portion is substituted with multiple substituents, each substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple substituents, each substituent is different.

[0077] In embodiments, the substituted portion (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-restricted substituent, wherein if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0078] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, wherein if the substituted portion is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple lower substituents, each lower substituent is different.

[0079] In embodiments, the substituted portion (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, a size-restricted substituent, or a lower substituent; wherein if the substituted portion is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower substituents, then each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In embodiments, the substituted portion is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent is different.

[0080] In the claims or chemical formula descriptions herein, each R substituent or L connector described as “substituted” does not refer to the characteristics of any chemical part constituting the “substituted” group (also referred to herein as “open substitution” or “open-substituted” R substituent or L connector), in which, in embodiments, the R substituent or L connector may be substituted by one or more first substituents as defined below.

[0081] The first substituent is represented by the corresponding first decimal point numbering system, such that, for example, R 1 One or more can be used with R 1.1 The first substituent substitution, R 2 One or more can be used with R 2.1 The first substituent substitution, R 3 One or more can be used with R 3.1 The first substituent substitution, R 4 One or more can be used with R 4.1 The first substituent substitution, R 5 One or more can be used with R 5.1 The first substituent indicates substitution, and so on until or more can be replaced by one or more R. 100.1The first substituent represents the R that is substituted. 100 As another example, R 1A One or more can be used with R 1A.1 The first substituent substitution, R 2A One or more can be used with R 2A.1 The first substituent substitution, R 3A One or more can be used with R 3A.1 The first substituent substitution, R 4A One or more can be used with R 4A.1 The first substituent substitution, R 5A One or more can be used with R 5A.1 The first substituent is indicated by substitution, and so on up to or beyond R. 100A One or more can be used with R 100A.1 The first substituent is indicated by substitution. As another example, L... 1 One or more can be used with R L1.1 The first substituent is represented by L. 2 One or more can be used with R L2.1 The first substituent is represented by L. 3 One or more can be used with R L3.1 The first substituent is represented by L. 4 One or more can be used with R L4.1 The first substituent is represented by L. 5 One or more can be used with R L5.1 The first substituent indicates substitution, and so on up to or beyond L. 100 One or more can be used with R L100.1 The first substituent is indicated by substitution. Therefore, each numbered R group or L group (or referred to herein as R...) WW or L WW Where “WW” represents the superscript number of the subject matter R group or L group, it can be represented by one or more groups commonly referred to herein as R WW.1 Or R LWW.1 The first substituent is replaced. In turn, each first substituent (e.g., R) is replaced. 1.1 R 2.1 R 3.1 R 4.1 R 5.1 …R 100.1 ;R 1A.1 R 2A.1 R 3A.1 R 4A.1 R 5A.1 ...R 100A.1 ;R L1.1 R L2.1 R L3.1 RL4.1 R L5.1 ...R L100.1 It can be further substituented by one or more second substituents (e.g., by R respectively). 1.2 R 2.2 R 3.2 R 4.2 R 5.2 …R 100.2 ;R 1A.2 R 2A.2 R 3A.2 R 4A.2 R 5A.2 ...R 100A.2 ;R L1.2 R L2.2 R L3.2 R L4.2 R L5.2 …R L100.2 Substitution. Therefore, each first substituent, which can be alternatively represented herein as R as described above. WW.1 It can be further substituted by one or more second substituents, which can be alternatively represented herein as R. WW.2 .

[0082] Finally, each second substituent (e.g., R) 1.2 R 2.2 R 3.2 R 4.2 R 5.2 ...R 100.2 ;R 1A.2 R 2A.2 R 3A.2 R 4A.2 R 5A.2 …R 100A.2 ;R L1.2 R L2.2 R L3.2 R L4.2 R L5.2 ...R L100.2 It can be further substituented by one or more third substituents (e.g., R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R< 1.3 R 2.3 R 3.3 R 4.3 R 5.3 ...R 100.3 ;R 1A.3 R 2A.3 R 3A.3 R 4A.3 R 5A.3 ...R 100A.3 ;R L1.3 R L2.3 R L3.3 RL4.3 R L5.3 ...R L100.3 Substitution. Therefore, each second substituent, which can be alternatively represented herein as R as described above. WW.2 It can be further substituted by one or more third substituents, which can be alternatively represented as R in this document. WW.3 Each of the first substituents may be optionally different. Each of the second substituents may be optionally different. Each of the third substituents may be optionally different.

[0083] Therefore, as used in this article, R WW The substituent indicates an open substitution as described in the claims or the chemical formula description herein. “WW” indicates the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject R group. Similarly, L… WW It is the open-substitution linker as described in the claims or the chemical formula description herein. Similarly, "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group. As described above, in several embodiments, each R... WW It can be unsubstituted or independently represented by one or more of the terms referred to herein as R. WW.1 The first substituent is substituted; each first substituent R WW.1 It can be unsubstituted or independently represented by one or more of the terms referred to herein as R. WW.2 The second substituent is substituted; and each second substituent may be unsubstituted or independently substituted by one or more referred to herein as R. WW.3 The third substituent is substituted. Similarly, each L WW The connector can be unreplaced or independently formed by one or more referred to herein as R. LWW.1 The first substituent is substituted; each first substituent R LWW.1 It can be unsubstituted or independently represented by one or more of the terms referred to herein as R. LWW.2 The second substituent is substituted; and each second substituent may be unsubstituted or independently substituted by one or more referred to herein as R. LWW.3 The third substituent is substituted. Each first substituent is optionally different. Each second substituent is optionally different. Each third substituent is optionally different. For example, if R WW If it is a phenyl group, then the phenyl group is optionally defined by one or more R groups as follows. WW.1 Group substitution, for example when R WW.1 For R WW.2 When the alkyl group is substituted or unsubstituted, examples of such groups include, but are not limited to, the group itself optionally being surrounded by one or more R... WW.2 Instead, the R WW.2Optionally by one or more R WW.3 Replacement. For example, when R WW The group is R WW.1 When substituted phenyl, R WW.1 It is a methyl group, which can be further substituted to form a group, including but not limited to:

[0084]

[0085] R WW.1 Independent of oxo groups, halogens, and -CX groups WW.1 3. -CHX WW.1 2. -CH2X WW.1 -OCX WW.1 3. -OCH2X WW.1 -OCHX WW.1 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.2 - substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.2 -substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R WW.2 - substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.2 -substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R WW.2 -Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10 (or phenyl) or R WW.2 - Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R WW.1 Independent of oxo groups, halogens, and -CX groups WW.1 3. -CHX WW.1 2. -CH2X WW.1 -OCX WW.1 3. -OCH2X WW.1 -OCHX WW.12. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X WW.1 It can be -F, -Cl, -Br, or -I independently.

[0086] R WW.2 Independent of oxo groups, halogens, and -CX groups WW.2 3. -CHX WW.2 2. -CH2X WW.2 -OCX WW.2 3. -OCH2X WW.2 -OCHX WW.2 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.3 - substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.3 -substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R WW.3 - substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.3 -substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R WW.3 -Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10 (or phenyl) or R WW.3- Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R WW.2 Independent of oxo groups, halogens, and -CX groups WW.2 3. -CHX WW.2 2. -CH2X WW.2 -OCX WW.2 3. -OCH2X WW.2 -OCHX WW.2 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X WW.2 It can be -F, -Cl, -Br, or -I independently.

[0087] R WW.3 Independent of oxo groups, halogens, and -CX groups WW.3 3. -CHX WW.3 2. -CH2X WW.3 -OCX WW.3 3. -OCH2X WW.3 -OCHX WW.32. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X WW.3 It can be -F, -Cl, -Br, or -I independently.

[0088] In two different R WW In cases where substituents are joined together to form an open-substituted ring (e.g., a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, or a substituted heteroaryl), in the embodiments, the open-substituted ring may be independently formed by one or more rings referred to herein as R. WW.1 The first substituent is substituted; each first substituent R WW.1 It can be unsubstituted or independently referred to as R in this document by one or more. WW.2 The second substituent is substituted; and each second substituent R WW.2 It can be unsubstituted or independently referred to as R in this document by one or more. WW.3 The third substituent is substituted; and each third substituent R WW.3 Unsubstituted. Each first substituent is optionally different. Each second substituent is optionally different. Each third substituent is optionally different. In two different R WW When substituents join together to form an open-substituted ring, R WW.1 R WW.2 and R WW.3 The "WW" symbol in the text refers to two different R symbols. WW The specified number of one of the substituents. For example, in R 100A and R 100B In embodiments where the rings are optionally joined to form an open-substitute ring, R WW.1 For R 100A.1 R WW.2 For R 100A.2 And RWW.3 For R 100A.3 Alternatively, in R 100A and R 100B In embodiments where the rings are optionally joined to form an open-substitute ring, R WW.1 For R 100B.1 R WW.2 For R 100B.2 And R WW.3 For R 100B.3 The R in this paragraph WW.1 R WW.2 and R WW.3 As defined in the preceding paragraphs.

[0089] R LWW.1 Independent of oxo groups, halogens, and -CX groups LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 -OCX LWW.1 3. -OCH2X LWW.1 -OCHX LWW.1 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.2 - substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.2 -substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R LWW.2 - substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.2 -substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R LWW.2 -Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10 (or phenyl) or R LWW.2 - Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R LWW.1 Independent of oxo groups, halogens, and -CX groups LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 -OCX LWW.1 3. -OCH2X LWW.1 -OCHXLWW.1 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 1, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X LWW.1 It can be -F, -Cl, -Br, or -I independently.

[0090] R LWW.2 Independent of oxo groups, halogens, and -CX groups LWW.2 3. -CHX LWW.2 2. -CH2X LWW.2 -OCX LWW.2 3. -OCH2X LWW 2. -OCHX LWW .22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW .3-substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW .3-substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R WW .3-substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.3 -substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R LWW.3 -Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10(or phenyl) or R LWW.3 - Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R LWW .2 can be independently an oxo group, halogen, or -CX group. LWW .23、-CHX LWW .22、-CH2X LWW.2 -OCX LWW.2 3. -OCH2X LWW.2 -OCHX LWW.2 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X LWW.2 It can be -F, -Cl, -Br, or -I independently.

[0091] R LWW.3 Independent of oxo groups, halogens, and -CX groups LWW.3 3. -CHX LWW.3 2. -CH2X LWW.3 -OCX LWW.3 3. -OCH2X LWW.3 -OCHX LWW.32. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl groups (e.g., C1-C) 8. C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), unsubstituted aryl (e.g., C6-C... 12 C6-C 10 (or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X LWW.3 It can be -F, -Cl, -Br, or -I independently.

[0092] Any R group (R) described in the claims or the chemical formula description herein WW If the substituent is not specifically defined in this disclosure, then the R group (R WW The radical group is defined herein as an oxo group, halogen, -CX group, or other radical group that is independently oxidized. WW 3. -CHX WW 2. -CH2X WW -OCX WW 3. -OCH2X WW -OCHX WW 2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.1 - substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.1 -substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R WW.1 - substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.1 -substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R WW.1-Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10 (or phenyl) or R WW.1 - Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X WW Independently -F, -Cl, -Br, or -I. Similarly, "WW" denotes the superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). WW 1. R WW.2 and R WW 3. As defined above.

[0093] Any L-linking group (i.e., L-linking group) described in the claims or the chemical formula description herein WW If the substituent is not explicitly defined, then the L group (L WW The group is defined herein as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O-), -S-, -SO2-, -SO2NH-, R LWW .1-substituted or unsubstituted alkylene groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.1 -substituted or unsubstituted heteroalkylene compounds (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), R LWW.1 - substituted or unsubstituted cycloalkylene compounds (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.1 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8 quinones, 3 to 6 quinones, 4 to 6 quinones, 4 to 5 quinones, or 5 to 6 quinones), R LWW.1 -Substituted or unsubstituted aryl groups (e.g., C6-C) 12 C6-C 10 (or phenyl) or R LWW.1 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). Similarly, "WW" denotes the superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R LWW.1 and R LWW.2 and R LWW.3 As defined above.

[0094] Certain compounds disclosed herein have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers, and individual isomers of amino acids, which can be defined according to absolute stereochemistry as (R)-, (S)-, (D)-, or (L)-, are all covered within the scope of this disclosure. The compounds disclosed herein do not include compounds known in the art that are too unstable to be synthesized and / or isolated. This disclosure is intended to include compounds in both racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, it is intended that these compounds comprise both E and Z geometric isomers.

[0095] As used herein, the term "isomer" refers to a compound having the same number and type of atoms and therefore the same molecular weight but differing in the structural arrangement or configuration of the atoms.

[0096] As used in this article, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily transformed from one isomer to another.

[0097] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure.

[0098] Unless otherwise stated, the structures described herein also refer to all stereochemical forms that include that structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomeric mixtures and diastereomeric mixtures, are all within the scope of this disclosure.

[0099] Unless otherwise stated, the structures described herein also refer to compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having atoms other than those with hydrogen replaced by deuterium or tritium, or those with... 13 C-enriched or 14 Compounds of the present invention with C-enriched carbon replacing carbon other than carbon are within the scope of this disclosure.

[0100] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may contain, for instance, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14C) Radiolabeling with radioactive isotopes. All isotopic variations (whether radioactive or non-radioactive) of the compounds disclosed herein are covered within the scope of this disclosure.

[0101] It should be noted that throughout the application, alternatives are written in the Markush group, for example, each amino acid position containing more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered individually, thereby including another embodiment, and the Markush group should not be understood as a single unit.

[0102] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to associations that occur between atoms or molecules of a bioconjugate reactive group or a bioconjugate reactive moiety. Associations can be direct or indirect. For example, the association between a first bioconjugate reactive group (e.g., -NH₂, -COOH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., thiol, sulfur-containing amino acid, amine, amine side chain containing an amino acid, or carboxylate) can occur directly, for example, via a covalent bond or linker (e.g., the first linker of the second linker), or indirectly, for example, via non-covalent bonds (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 (π effect), hydrophobic interactions, etc.). In the embodiments, the 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., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitution (e.g., enamine reactions), and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reactions, Diels-Alder additions). These and other useful reactions are discussed in the following references: e.g., March, *Advanced Organic Chemistry*, 3rd ed., John Wiley & Sons, New York, 1985; Hermanson, *Bioconjugate Techniques*, Academic Press, San Diego, 1996; and Feeney et al., *Modification of Proteins*; Progress in Chemistry Series, Vol. 1, 198, American Chemical Society, Washington, DC, 1982. In examples, a first bioconjugate reactive group (e.g., maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., thiol). In examples, a first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., thiol). In one embodiment, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol group). In another embodiment, a first bioconjugate reactive group (e.g., an N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol group).In one embodiment, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol group). In another embodiment, a first bioconjugate reactive group (e.g., a sulfonyl-N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amino group).

[0103] Useful bioconjugate reactivity portions of the bioconjugate chemistry used herein include, for example: (a) carboxyl groups and their various derivatives, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters; (b) hydroxyl groups that can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups, wherein the halide can be subsequently treated with nucleophilic groups (such as, for example, amines, carboxylate anions, thiolate anions, carbanions, or alcohols). (d) a salt ion substitution, resulting in a new group covalently attached to the halogen atom site; (e) a dienophilic group capable of participating in a Diels-Alder reaction, such as a maleimide group or maleimide group; (f) an aldehyde or ketone group, such that subsequent derivatization can be achieved through the formation of a carbonyl derivative (e.g., an imine, hydrazone, hemicarbazone, or oxime) or through mechanisms such as Grignard addition or alkyllithium addition; and (c) a sulfonyl halide group, wherein... The sulfonyl halide group is used for subsequent reaction with an amine, for example, to form a sulfonamide; (g) a thiol group, which can be converted into a disulfide, react with an acyl halide, or bonded to a metal such as gold, or react with maleimide; (h) an amine group or a mercapto group (e.g., present in cysteine), which can be, for example, acylated, alkylated, or oxidized; (i) an olefin, which can undergo, for example, cycloaddition, acylation, Michael addition, etc.; (j) an epoxide, which can be reacted with, for example, an amine and hydroxylated. (k) phosphoramide and other standard functional groups that can be used in nucleic acid synthesis; (l) metal oxide bonding; (m) metal bonding with reactive phosphorus groups (e.g., phosphine) to form, for example, phosphodiester bonds; (n) linking azides to alkynes using copper-catalyzed cycloaddition click chemistry; and (o) biotin conjugates can react with avidin or strepavidin to form avidin-biotin complexes or strepavidin-biotin complexes.

[0104] The reactive groups in bioconjugates can be selected such that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be present to protect them from crosslinking reactions. In the examples, the bioconjugates comprise molecular entities derived from the reaction of unsaturated bonds (e.g., maleimide) with thiol groups.

[0105] The term "analog" or "derivative" is used according to its ordinary, general meaning in chemistry and biology, and refers to a compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound) for example, in the substitution of one atom with an atom of a different element, or in the presence of a particular functional group, or in the substitution of one functional group with another functional group, or in the absolute stereochemistry of one or more chiral centers of a reference compound. Therefore, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but dissimilar or not equivalent in structure or origin.

[0106] As used herein, the term "a / an" means one or more. Furthermore, as used herein, the phrase "replaced with [n]..." means that the specified group can be replaced by one or more of any or all of the substituents in the designated substituent. For example, in groups such as alkyl or heteroaryl groups, "replaced with unsubstituted C1-C..." 20 In the case of "alkyl or unsubstituted 2 to 20 heteroalkyl substitution", the group may contain one or more unsubstituted C1-C1 groups. 20 Alkyl groups, and / or one or more unsubstituted 2 to 20 heteroalkyl groups.

[0107] Furthermore, in cases where the group is partially substituted by an R substituent, the group can be referred to as "R-substituted". In cases of partial R substitution, the portion is substituted by at least one R substituent, and each R substituent is optionally different. When a specific R group is present in the description of a chemical class (e.g., formula (I)), Roman numeral symbols can be used to distinguish each appearance of that specific R group. For example, in the presence of multiple R groups... 13 In the case of substituents, each R 13 Substituents can be classified as R 13A R 13B R 13C R 13D etc., where R 13A R 13B R 13C R 13D Each of them is in R 13 Defined within the scope of the definition and optionally different.

[0108] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted with one or more of a plurality of substituents, such substitutions are chosen to conform to the principles of chemical bonding and to obtain compounds that are not inherently unstable and / or, as known to those skilled in the art, may be unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, heterocyclic alkyl or heteroaryl groups, according to the principles of chemical bonding known to those skilled in the art, are linked to the rest of the molecule via cyclic heteroatoms, thereby avoiding inherently unstable compounds.

[0109] The term "pharmaceutically acceptable salt" means a salt containing an active compound prepared with a relatively non-toxic acid or base, depending on a specific substituent found on the compound described herein. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this disclosure contain relatively basic functional groups, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids (such as arginine salts) and salts of organic acids (such as glucuronic acid or galacturonic acid) (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functional groups that enable these compounds to be converted into base addition salts or acid addition salts.

[0110] Therefore, the compounds of this disclosure can exist in the form of salts of pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof comprising racemic mixtures), succinates, benzoates, and salts with amino acids (such as glutamic acid) and quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0111] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties (e.g., solubility in polar solvents).

[0112] In addition to salt forms, this disclosure also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. The prodrugs of the compounds described herein can be converted in vivo after administration. Alternatively, the prodrugs can be converted into the compounds of this disclosure in an in vitro environment (e.g., upon contact with suitable enzymes or chemical reagents) by chemical or biochemical methods.

[0113] Some compounds of this disclosure may exist in both unsolvable and solvable forms (including hydrated forms). Generally, solvable forms are equivalent to unsolvable forms and are covered within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

[0114] A polypeptide or cell is "recombinant" when it is artificially or engineered, or derived from artificially or engineered proteins or nucleic acids, or contains artificially or engineered proteins or nucleic acids (e.g., non-natural or non-wild-type). For example, a polynucleotide inserted into a vector or any other heterologous location, such as the genome of a recombinant organism, such that it does not associate with a nucleotide sequence that is normally side-linked to a polynucleotide found in nature, is a recombinant polynucleotide. Proteins expressed by recombinant polynucleotides in vitro or in vivo are examples of recombinant polypeptides. Similarly, polynucleotide sequences not found in nature (e.g., variants of naturally occurring genes) are recombinant.

[0115] "Co-administration" means administering the composition described herein simultaneously, immediately before, or immediately after the administration of one or more additional therapies. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration means administering compounds (more than one compound) individually or in combination, simultaneously or sequentially. Therefore, the formulation can also be combined with other active substances when needed (e.g., to reduce metabolic degradation).

[0116] As used herein, “cell” means a cell that performs metabolic or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to reproduce, or, if gametes are present, the ability to combine with a second gamete to produce viable progeny. Cells can 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 (e.g., noctuid moth) cells, and human cells. Cells may be useful when they are naturally non-adhesive or are treated to be non-adhesive to surfaces, for example, by trypsin digestion.

[0117] The term "treating" or "treatment" refers to any indicator of successfully treating or improving an injury, disease, pathology, or symptom, including any objective or subjective parameters, such as elimination; relief; reduction of symptoms or making the injury, pathology, or symptom more tolerable for the patient; slowing the rate of degeneration or decline; or reducing the final point of degeneration; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, some methods presented herein have successfully treated cancer by reducing the incidence of cancer and / or inducing 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 "treatment" and its adjuncts include prevention of injury, pathology, symptom, or disease. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention. In embodiments, treatment is not preventative treatment.

[0118] "Effective amount" is the amount of a compound sufficient to achieve its stated purpose (e.g., to achieve the effect it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce signal transduction pathways, to reduce one or more symptoms of a disease or condition) relative to the absence of the compound. When referred to in this context, an example of "effective amount" is an amount sufficient to induce treatment, prevention, or reduction of one or more symptoms of a disease; this amount may also be referred to as "therapeutic effective amount." "Reduction" of one or more symptoms (and its grammatical equivalent) means a reduction in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms. A "preventive effective amount" of a drug is the amount of drug that, when administered to a subject, will have the intended preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete preventive effect does not necessarily occur with a single dose and can occur after only a series of doses. Therefore, a preventive effective amount can be administered in the form of a single or multiple doses. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, “functional disruption amount” refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of an antagonist. As used herein, “activity enhancement amount” refers to the amount of agonist required to increase the activity of an enzyme relative to the absence of an agonist. As used herein, “functional enhancement amount” refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of an agonist. The precise amount will depend on the purpose of treatment and will be determined by a person skilled in the art using known techniques (see, for example, 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 ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0119] "Control" or "controlled experiment" is used in its ordinary, general sense and refers to an experiment in which subjects or reagents are treated as in a parallel experiment, except that the procedures, reagents, or variables of the experiment are omitted. In some cases, controls are used as a standard of comparison when evaluating the effects of an experiment. In some embodiments, a control is a measure of protein activity (e.g., signaling pathways) in the absence of compounds as described herein (including examples, instances, figures, or tables).

[0120] "Contact" is used in its ordinary, general sense and refers to a process that allows at least two different species (e.g., chemical compounds containing biomolecules or cells) to come close enough to react, interact, or physically touch. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents, or from an intermediate of one or more added reagents that can be produced in the reaction mixture.

[0121] The term "contact" can encompass allowing two species to react, interact, or physically contact, wherein the two species can be a compound and a cellular component (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cellular compartments, microorganisms, viruses, lipid droplets, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules) as described herein. In some embodiments, contact includes allowing the compounds described herein to interact with cellular components involved in signal transduction pathways (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, viruses, lipid droplets, organelles, cellular compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules).

[0122] As defined herein, the term “activation (activate / activating, etc.)” for proteins refers to the transformation of a protein from an initially inactive or deactivated state into a biologically activated derivative. These terms refer to activation, or the activation, sensitization, or upregulation of signal transduction or enzyme activity, or the amount of protein reduced in disease.

[0123] The terms "agonist," "activator," and "upregulator" refer to substances that can detectably increase the expression or activity of a given gene or protein. Compared to a control in the absence of an agonist, an agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than that in the absence of an agonist.

[0124] As defined herein, the terms “inhibition,” “inhibit,” and “inhibiting” in relation to cell component-inhibitor interactions mean, in the absence of an inhibitor, a negative impact (e.g., reduction) on the activity or function of a cell component relative to its activity or function (e.g., a reduction in signaling pathways stimulated by the cell component (e.g., proteins, ions, lipids, viruses, lipid droplets, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cell compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules)). In embodiments, inhibition means a negative impact (e.g., a reduction) on the concentration or level of a cell component relative to its concentration or level in the absence of an inhibitor. In some embodiments, inhibition refers to a reduction in disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., a reduction in pathways involving cell components). Therefore, inhibition at least partially comprises partially or completely blocking, reducing, preventing, or delaying activation, desensitizing, or downregulating signaling pathways or enzyme activity or the amount of a cell component.

[0125] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” are interchangeable as substances that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control without an antagonist. In some cases, expression or activity may be 1.5, 2, 3, 4, 5, 10, or more times lower than in the absence of an antagonist.

[0126] The term "modulator" refers to the physical state of a target molecule or its function or the target molecule that increases or decreases the level of the target molecule or the function of the target molecule or the molecule in the absence of the composition (e.g., the target can be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cell compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate or macromolecule)).

[0127] The term "allosteric modulator" is used in its general sense and refers to a substance (e.g., a compound) that binds to a receptor to alter the receptor's response to a stimulus. The site to which an allosteric modulator binds (i.e., the allosteric site) differs from the site to which an endogenous agonist of the receptor would bind (i.e., the ortho-allosteric site). Allosteric modulators can alter (e.g., increase or decrease) the affinity and potency of other substances acting on the receptor. "Positive allosteric modulator" or "PAM" refers to an allosteric modulator that increases the affinity and / or potency of an agonist. "Negative allosteric modulator" or "NAM" refers to an allosteric modulator that decreases the affinity and / or potency of an agonist.

[0128] The term "allosteric site" is used in its ordinary, general sense and refers to a binding site on an enzyme that is not an active site. In examples, the binding of a substance (e.g., a compound) to an allosteric site results in a conformational change of the enzyme. In examples, the binding of a substance (e.g., a compound) to an allosteric site results in the regulation of enzyme activity (e.g., activation or inhibition).

[0129] The term "expression" encompasses any step involved in the production of a polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for protein detection, such as ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.

[0130] The term "modulate" is used in its general sense and refers to the action of changing or altering one or more properties. "Modulation" refers to the process of changing or altering one or more characteristics. For example, when applied to the effect of a modulator on a target protein, modulation means altering the properties or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0131] "Patient" or "subject in need" means a living organism that suffers from or is susceptible to a disease or symptom that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0132] "Disease" or "symptom" refers to a state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a condition associated with (or caused by) cellular components such as proteins, ions, lipids, nucleic acids, nucleotides, amino acids, particles, organelles, cellular compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules. In one embodiment, the disease is a neurodegenerative disease. In another embodiment, the disease is cancer.

[0133] As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, and Gerstmann syndrome. Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy's disease, Krabbe's disease, Kuru disease, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, spirochete disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, amyotrophic lateral sclerosis, prions, Refsum's disease, Sandhoff's disease, Schilder's disease Diseases, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0134] 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 group, such as a healthy person 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, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, and Graves' ophthalmopathy. 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.

[0135] As used herein, the term "eye disease" refers to a disease or condition characterized by eye problems (e.g., an increased level of eye problems compared to a control group, such as a healthy person without the disease). Examples of eye diseases include, but are not limited to, cataracts (e.g., congenital cataracts), optic nerve diseases (e.g., glaucoma), retinal diseases, macular degeneration, diabetic eye problems, and conjunctivitis.

[0136] As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Other examples include: Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, primary brain tumor, cancer, malignant pancreatic cancer, malignant carcinoid tumor, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, endocrine or exocrine pancreatic lesions, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0137] The term “leukemia” broadly refers to a progressive, malignant disease of the blood-forming organs, typically characterized by the disordered proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on the following: (1) the duration and characteristics of the acute or chronic course; (2) the type of cells involved; myeloid, lymphoid, or monocytic; and (3) an increase or non-increase in the number of abnormal cells in the blood – leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukopenic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, and hemoblastic leukemia. Leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegelile leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia Leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0138] As used in this article, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It begins with lymphocytes, blood cells primarily 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. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the cancer's growth rate and the cell types involved. Aggressive (high-grade) and indolent (low-grade) types of NHL exist. Based on the cell types 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, nodular (monocyte-like B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-cell lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T-cell lymphoblastic lymphoma.

[0139] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue, and typically consists of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds or methods provided in this article include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, and Kupffer cell sarcoma. Cell sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or capillary hemangiosarcoma.

[0140] The term "melanoma" should be considered to refer to tumors originating from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

[0141] The term "cancer" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basoid cell tumor, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine endometrial cancer, cribriform carcinoma, armored carcinoma, carcinoma cutaneum, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, sclerosing carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, and gelatinous carcinoma. Carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, naive embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, molluscum carcinoma, mucinous carcinoma, mucinous cell carcinoma Mucocellular carcinoma, mucoepidermoid carcinoma, mucosular carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis pilaris, pultaceous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scleroderma, scrotal carcinoma.Scroti), signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma (carcinoma spongiosum), squamous cell carcinoma, tufted carcinoma, angiodilated carcinoma (carcinomate langiectaticum), telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0142] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of the active agent to a subject and facilitate absorption by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, carboxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0143] The term "formulation" refers to a compound comprising an active compound and an encapsulating material in the form of a carrier, wherein the active component, with or without another carrier, is surrounded by the carrier, thereby associating the active component with the carrier. Similarly, capsules and tablets are also included. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0144] As used herein, the term "about" means a range of values ​​that include a specified value and that would be reasonably thought by one of ordinary skill in the art to be reasonably similar to the specified value. In embodiments, "about" means within the standard deviation of a measurement result generally acceptable in the art. In embodiments, "about" means a range extended to + / - 10% of the specified value. In embodiments, "about" includes the specified value.

[0145] As used herein, the term "administration" means oral administration to a subject, administration in suppository form, local contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or administration via implantation of a slow-release device (e.g., a micro-osmotic pump). Administration via any route includes parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery modalities include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc. "Co-administration" means that the composition described herein is administered simultaneously, immediately before, or immediately after the administration of one or more other therapies (e.g., cancer therapies such as chemotherapy, hormone therapy, radiation therapy, or immunotherapy). The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration means the simultaneous or sequential administration of compounds (more than one compound) alone or in combination. Therefore, the formulations can also be combined with other active substances when needed (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered via transdermal or topical routes and can be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0146] The compounds described herein may be used in combination with each other, with other active agents known to be effective in treating diseases associated with cells expressing disease-related cellular components, or with adjuvants that may be ineffective on their own but may contribute to the efficacy of the active agents.

[0147] In some embodiments, co-administration involves administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration comprises administering the two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially. In some embodiments, co-administration can be accomplished by co-concentration, i.e., preparing a single pharmaceutical composition comprising the two active agents. In other embodiments, the active agents may be formulated separately. In yet another embodiment, the active agent and / or adjuvant may be linked or conjugated to each other.

[0148] The compounds described herein can be used in conjunction with conventional treatments for neurodegenerative diseases, including but not limited to treatments for Parkinson's disease such as levodopa, carbidopa, selegiline, amantadine, donepezil, galanthamine, rivastigmine, tacrine, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole), anticholinergic drugs (e.g., trihexyphenidyl, benztropine, biperiden, procyclidine), and catechol-O-methyl-convertase inhibitors (e.g., tolcapone, entacapone).

[0149] The compounds described herein can also be used in conjunction with conventional anti-inflammatory 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 opioids (e.g., codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone).

[0150] "Anticancer agent" is used in its ordinary, general sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has antitumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, an anticancer agent is a chemotherapeutic agent. In some embodiments, an anticancer agent is a pharmaceutical agent identified herein as having efficacy in methods of treating cancer. In some embodiments, an anticancer agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of cancer. In embodiments, an anticancer agent is a pharmaceutical agent with antitumor properties that has not (e.g., has not yet) been approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of cancer. Examples of anticancer agents include, but are not limited to, 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, PD318088, AS703026, BAY).869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas), nitrogen mustards (e.g., dichloromethyldiethylamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine). ustine, streptozocin, decarbazine, antimetabolites (e.g., 5-thiozolidine, folate, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed), folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, fluorouracil, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc., plant alkaloids (e.g., streptozocin, dacarbazine), plant alkaloids (e.g., 5-thiozolidine, folate, capecitabine, dacarbazine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc. 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, doxorubicin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, procainoxine, etc.). This includes methylhydrazine derivatives (e.g., icamycin), platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical inhibitors (e.g., mitotane, aminoacetylimine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), and inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY).43-9006, wortmannin or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituximab), gossyphol, genasense, polyphenol E, Chlorofusin, all-trans retinoic acid (ATRA), lichenin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-Table-1, 25-Dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Aclarubicin; Acylfulvene; Adecypenol; Adozelesin; Aldesleukin; ALL-TK antagonists; Altretamine; Ambamustine; Amidox Amifostine; Aminolevulin; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-backturn morphogenetic protein-1; Anti-androgen, prostate cancer substance; Anti-estrogen; Anti-tumor ketone; Antisense oligonucleotide; Aphidicolin glycinate; Apoptosis gene regulator; Cell apoptosis regulator; Depurinated nucleic acid; ara-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamestane; Atrimustine; Axinastatin1); Marine cyclic peptide 2 (axinastatin2); Marine cyclic peptide 3 (axinastatin3); Azasetron; Azatoxin; Azatyrosine; Baccatin III derivative; Balanol; Batimastat; BCR / ABL antagonist; Benzochlorin; Benzoylstaurosporine; β-lactam derivative; β-alethine; β-clarithromycin B; Betulinic acid acid); bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; bushionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitors; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues(analogues); Clotrimazole; Collosmycin A; Clumethicone B; Combretastatin A4; Cobretastatin analogues; Conagenin; Crambescidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cytarabine ocfosfate; Cytolytic agents Factor); Hexestrol phosphate (cytostatin); Dacliximab; Decitabine; Dehydro-Daidanine B; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Diaziquone; Daidanine B; Dihydroxybenzoxoxic acid; Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Biphenylspirostinespiromustine; docosanol; dolasetron; doxifiuridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristamine Estradiol; Estrogen mustard analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Fludarabine; Fludaunorunicin hydrochloride hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitor; gemcitabine; glutathione inhibitor; hepsulfam; heregulin; hexamethylenediacetamide; hypericin; ibandronic acidacid); idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukin; iobenguane; iododoxorubicin; ipomeanol, 4- ); Iroplact; Irsogladine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N-triacetic acid; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate sulfate); Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprorelin + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium Tetraphyrin; Lysofylline; Cleavage peptide; Maitansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrixlysin inhibitorInhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; dibromoceroxyl (mitolactol); mitomycin analogues; mitonafide; mitotoxin; fibroblast growth factor-saponin; mitoantrone; mofarotene; molgramostim; human chorionic gonadotropin monoclonal antibody; monophospholipid A+ mycobacterial cell wall skeleton; mopidamol; multidrug-resistant gene inhibitors; multi-tumor inhibitor-1-based therapies; mustard anticancer agents; Indian Ocean sponge B (mycaperoxide) B); Mycobacterium cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamide; nafarelin; nagrestip; naloxone + pentazoline; napavin; napterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid acid); neutral endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitrous oxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; omaliplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acidacid); panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentostatin; pentozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetic acid; phosphatase inhibitor; picibanil; pilocarpine hydrochloride hydrochloride; pirarubicin; pirritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgal protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purpurins; pyrazoloacridine; pyridoxal-modified hemoglobin polyoxyethylene conjugates; RAF antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated retelliptine; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinoic acid (RII) Retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytolA); Sargramostim; Sdi 1 mimic; Semustine; Senescence-related inhibitor 1; Significant oligonucleotide; Signal transduction inhibitor; Signal transduction regulator; Single-chain antigen-binding protein; Sizofuran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solvent; Somatostatin-binding protein; Sonermin; Sparfosic acid; Spicamycin D D); Spiromustine; Splenopentin; Splenopentin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromeysin inhibitor; Sulfinosine; Super-active vasoactive intestinal peptide antagonist; Suradista; Suramin; Swainsonine; Synthetic glycosaminoglycans; Talimustine; Tamoxifenmethiodide; Tauromustine; Tazarotene; Tecogalan sodium Sodium); Tegafur; Tellurapyrylium; Telomerase inhibitor; Temoporfin; Temozolomide; Teniposide; Tetrachlorodeoxide; Tetrazomine; Thaliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimics; Thymalfasin; Thymopoietin receptor agonists; Thymotrinan; Thyroid stimulating hormone; Tin ethylporphyrinetiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vapreotide; variolin B B); Vector systems, red blood cell gene therapy; Velaresol; Veramine; Verdins; Verteporfin; Vinorelbine; Vinxaltine; Vitaxin; Vorozole; Zanoterone; Zeniplatin; Zilascorb; Zinostatin stimalamer; Doxorubicin; Dactinomycin; Bleomycin; Vinxaltine; Cisplatin; Acivicin; Arubicin; Acodazole hydrochloride; Acronine; Adolexin; Interleukin; Altretamine; Ambomycin; Ametantrone acetate acetate); aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; barmastastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bleomycin sulfate; brequina sodiumsodium); brompirimidine; busulfan; cactinomycin C; calusterone; caracemide; carbetimer; carplatin; carmustine; carrubicin hydrochloride; carzesol; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; acetone; doxorubicin; doxorubicin hydrochloride; droloxifen; droloxifen citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride hydrochloride; estramustine; estramustine sodium phosphate; estanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenivel Aamine; fluxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloridehydrochloride); ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masorofol; maytansine; nitrogen mustard hydrochloride; megestrol acetate Acetate); Melengestrol acetate; Melphalan; Minoril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Miogillin; Mitomalcin; Mitosper; Mitotane; Mitoxantrone hydrochloride Hydrochloride; Mycophenolic acid; Nocodazoie; Nogalamycin; Omaplatin; Oxisuran; Pegaspargase; Peliomycin; Pentamustine; Peplomycin sulfate; Pephosphonamide; Pipobroman; Piposulfan; Piroxantrone hydrochloridehydrochloride; plicamycin; plomestane; porphyrin sodium; methylmitomycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogulam; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride hydrochloride; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogallan sodium; fenfluridine; teloxantrone hydrochloride; temoporphyrin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiazofurin; tiazofurin; terazamine; toremifene citrate; trestolone acetate; triciribine phosphate phosphate); trimethyltroxane; trimethyltroxane glucuronide; triptorelin; tobaccochloride hydrochloride; uracil mustard; uredepa; vapeptide; verteporfen; vinblastine sulfate; vincristine sulfate; vincristine sulfate; vindixin; vindixin sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfatesulfate); vortexil; zinostatin; zinostatin; zorubicin hydrochloride; agents that arrest cells in the G2-M phase and / or regulate microtubule formation or stability (e.g., Taxol™, Taxotere™, compounds including the taxane skeleton, Erbulozole (i.e., R-55104), sulphurin 10 (i.e., DLS-10 and NSC-376128), mivobulinisethionate (i.e., CI-980), vincristine, NSC-639829, spongilium rotundum ( Discodermolide (e.g., NVP-XX-A-296), ABT-751 (Abbott, e.g., E-7010), Altorhyrtin (e.g., Altorhyrtin A and Altorhyrtin C), Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cemadotin hydrochloride hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilone (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-epotassium B, 21-aminoepotassium B (i.e., BMS-310705), 21-hydroxyepotassium D (i.e., deoxyepotassium F and dEpoF), 26-fluoroepotassium, Auristati PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 ( Pharmacia (LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences)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), Nostocin 52 (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 R PR-258062A), Vitiligovamide, 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) Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide 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 Pharmaceuticals). Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Icahn School of Medicine at Mount Sinai, i.e., MF-191), TMPN (Arizona State University), Vanadoceneacetylacetonate), T-138026 (Durarik), Monsatrol, Inanocine (i.e., NSC-698666), 3-IAABE (cytoskeleton / Icahn School of Medicine, Mount Sisinai), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Annette), Eleutherobin (e.g., denativization) Desmethyleleutherobin, Desaetyleleutherobin, Isoesterobin A and Z-Esterobin, Caribaeolin, Halichondrin B, D-64131 (Astar Pharmaceuticals), D-68144 (Astar Pharmaceuticals), Chlorinated Cyclopeptide (D iazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Annette), A-259754 (Abbott), Diozostatin, (-)-phenylastine (i.e., NSCL-96F037), D-68838 (Astar Pharmaceuticals), D-68836 (Astar Pharmaceuticals), muscle Matrix protein (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 Phosphate sodium), BPR-OY-007 (National Health Research 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), progesterone (e.g., hydroxyprogesterone caproate).Caproate, megestrol acetate, medroxyprogesterone acetate, estrogens (e.g., diethlystilbestrol, ethinyl estradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin, 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-gallic acid conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., with... 111 In、 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, triptolide, homoharringtonine, dextrin, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonoxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agents (e.g., gefitinib). TM ), Erlotinib (Tarceva) TM ), cetuximab (Erbitux) TM Lapatinib (Tykerb) TM Panitumumab (Vectibix) TM ), vandetanib (Caprelsa) TMAfatinib (BIBW2992), CI-1033 (canertinib), neratinib (HKI-272), CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib (PF299804), OSI-420 (desmethylerlotinib) Examples of anticancer agents include erlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626, sorafenib, imatinib, sunitinib, dasatinib, etc. A portion of anticancer agents are monovalent anticancer agents (e.g., the monovalent forms of the drugs listed above).

[0151] In therapeutic uses for treating diseases, the compounds used in the pharmaceutical compositions of the present invention may be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg daily. The daily dose range may be from about 0.01 mg / kg to about 500 mg / kg, or from about 0.1 mg / kg to about 200 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or from about 10 mg / kg to about 50 mg / kg. However, the dose may vary depending on the patient's needs, the severity of the condition being treated, and the compound or drug used. For example, the dose may be determined empirically based on the type and stage of cancer diagnosed in a particular patient. In the context of the present invention, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also depend on the presence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular patient. Determining the appropriate dose for a specific situation is within the skill of the practitioner. Generally, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved in several cases. For convenience, the total daily dose can be divided into several portions and administered in batches throughout the day as needed.

[0152] The compounds described herein can be used in combination with each other, with other active agents known to be used to treat cancer, or with adjuvants that may be ineffective on their own but may help the efficacy of the active agents.

[0153] In the context of a substance or its activity or function related to a disease (e.g., a protein-related disease, a disease related to cellular components), the term "related" or "associated with" means that the disease (e.g., a neurodegenerative disease, cancer) is (wholly or partially) caused by the substance or its activity or function, or that the symptoms of the disease are (wholly or partially) caused by the substance or its activity or function, or that the disease or its symptoms can be treated by modulating (e.g., inhibiting or activating) a substance (e.g., a cellular component). For example, a neurodegenerative disease associated with protein aggregates can be a neurodegenerative disease caused ( wholly or partially) by abnormal protein aggregates or a neurodegenerative disease in which specific symptoms of the disease are caused (wholly or partially) by abnormal protein aggregates. As used herein, a pathogen is described as being associated with a disease if it can be a target for treatment. For example, a neurodegenerative disease associated with abnormal protein aggregates or a neurodegenerative disease related to protein aggregates can be treated with a protein aggregate modulator.

[0154] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity, abnormality refers to an activity that is greater than or less than the average activity of a normal control or a normal, non-disease-associated control sample. Abnormal activity can refer to an amount of activity that causes disease, wherein an amount that returns abnormal activity to normal or non-disease-associated levels (e.g., by administering a compound or using methods as described herein) results in a reduction of disease or one or more disease symptoms.

[0155] As used herein, the term "electrophilic" refers to a chemical group capable of accepting electron density. "Electrophilic substituent," "electrophilic moiety," or "electrophilic portion" refers to an electron-deficient chemical group, substituent, or portion (monovalent chemical group) that can react with an electron-donating group, such as a nucleophile, to form a bond by accepting electron pairs or electron density. 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 "covalently modified cysteine ​​moiety" or "covalently modified cysteine ​​substituent." The covalent bond formed between the electrophilic substituent and the thiol group of cysteine ​​can be reversible or irreversible. 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.

[0156] As used in this article, "nucleophile" refers to a chemical group that can provide electron density.

[0157] When applied to nucleic acids or proteins, the term "isolated" means that the nucleic acid or protein is substantially free of other cellular components associated with it in its native state. It can be, for example, in a homogeneous state and can be in a dry state 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. The major protein present in the formulation is substantially purified.

[0158] The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, and those subsequently modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds whose basic chemical structure is the same as that of naturally occurring amino acids (i.e., the α-carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. These analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are compounds whose structure differs from the general chemical structure of amino acids but function in a manner similar to that of naturally occurring amino acids. The terms "non-naturally occurring amino acids" and "non-natural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimics that are not found in nature.

[0159] Amino acids may be referred to in this article by their commonly known three-letter symbols or by the single-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be represented by their generally accepted single-letter codes.

[0160] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers containing amino acid residues, wherein the polymer may be conjugated with portions not composed of amino acids in the examples. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers.

[0161] The "position" of an amino acid or nucleotide base is indicated by a number, which sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5' end). Because deletions, insertions, truncations, fusions, etc., must be considered when determining optimal alignment, the number of amino acid residues in the test sequence, determined by counting only from the N-terminus, is not necessarily the same as their corresponding number in the reference sequence. For example, in cases where a variant has a deletion relative to the reference sequence being aligned, the variant will lack the amino acid corresponding to the deletion site in the reference sequence. In cases where there is an insertion in the reference sequence being aligned, the insertion will not correspond to the numbered amino acid position in the reference sequence. In cases of truncation or fusion, there may be amino acid segments in the reference or aligned sequences that do not correspond to any amino acid in the corresponding sequence.

[0162] When used in the context of numbering a given amino acid or polynucleotide sequence, the terms "numbered relative to" or "corresponding to" mean that when comparing a given amino acid or polynucleotide sequence with a reference sequence, the residues of a specified reference sequence are numbered.

[0163] An amino acid residue in a protein is considered to "correspond" to a given residue when it occupies the same basic structural position within the protein as a given residue. Instead of primary sequence alignment, three-dimensional structural alignment can be used, for example, by performing a maximum homology alignment of the selected protein with a human protein and comparing the overall structures. In this case, the amino acid occupying the same basic position as a specific amino acid in the structural model is said to correspond to that specific residue. For example, when a selected residue occupies the same basic space or other structural relationship as Arg563 in the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO:1), the selected residue in the selected protein corresponds to Arg563 in the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO:1). In some embodiments, when a maximum homology alignment is performed between the selected protein and the Nurr1 protein, the position in the selected protein aligned to Arg563 is considered to correspond to Arg563 in the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO:1). Instead of primary sequence alignment, three-dimensional structure alignment can be used, for example, where the structure of the selected protein is aligned to the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO: 1) for maximum correspondence and the overall structure is compared. In this case, the amino acid occupying the same essential position as Arg563 in the structural model is referred to as corresponding to the Arg563 residue. Another example is where the selected residue (e.g., arginine residue) occupies a substantially identical sequence, spatial, or other structural position within the protein as Arg563 in the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO: 1), and the selected residue in the selected protein corresponds to Arg563 in the Nurr1 protein (e.g., human Nurr1 protein or SEQ ID NO: 1).

[0164] The term "protein complex" is used in its ordinary, general sense and refers to a protein associated with another substance (e.g., another protein, protein subunit, or compound). Protein complexes typically have a well-defined quaternary structure. Association between a protein and another substance can be covalent. In embodiments, association between a protein and another substance (e.g., a compound) occurs through non-covalent interactions. 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.

[0165] The term "protein aggregate" is used in its ordinary, general sense and refers to the abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are commonly associated with diseases (e.g., amyloidosis). Typically, unfolded / misfolded proteins may aggregate when they misfold due to changes in their amino acid sequence or alterations to their native environment that disrupt normal non-covalent interactions, and the misfolded proteins are not corrected or degraded. Three main types of protein aggregates can form: amorphous aggregates, oligomers, and amyloid fibrils. In the examples, protein aggregates are referred to as aggresomes.

[0166] The terms “Nurr1” or “NR4A2” refer to the protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays a crucial role in maintaining the brain's dopaminergic system. The term “Nurr1” can refer to the nucleotide sequence or protein sequence of human NR4A2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM_006186.3, or RefSeq NP_006177.1). In the examples, the Nurr1 ligand-binding domain has the following amino acid sequence: (SEQ ID NO: 1).

[0167] The term "tyrosine hydroxylase" or "tyrosine 3-monooxygenase" refers to the 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 or protein sequence of human TH (e.g., Entrez 7054, Uniprot P07101, RefSeq NM_000360.3, RefSeq NM_199292.2, RefSeq NM_199293.2, RefSeq NP_000351.2, RefSeq NP_954986.2, or RefSeq NP_954987.2). In the examples, TH has the following amino acid sequence: (SEQ ID NO:2).

[0168] The term "dopamine receptor D2" or "D2R" refers to a dopamine receptor whose activity is mediated by a G protein that inhibits adenylate cyclase. In humans, dopamine receptor D2 is encoded by the DRD2 gene. The term "DRD2" can refer to the nucleotide or protein sequence of human DRD2 (e.g., Entrez 1813, Uniprot P14416, RefSeq NM_016574.3, RefSeq NM_000795.3, RefSeq NP_000786.1, or RefSeq NP_057658.2). In the examples, DRD2 has the following amino acid sequence:

[0169] MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVSREKALQTTTNYLIVSLAVADLLVATLVMPWVVVYLEVVGEWKFSRIHCDIFVT LDVMMCTASILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQNECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVN TKRSSRAFRAHLRAPLKGNCTHPEDMKLCTVIMKSNGSFPVNRRRVEAARRAQELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPK IAKIFEIQTMPNGKTRTSLKTMSRRKLSQQKEKKATQMLAIVLGVFIICWLPFFITHILNIHCDCNIPPVLYSAFTWLGYVNSAVNPIIYTTFNIEFRKAFLKILHC(SEQID NO:3).

[0170] The term "vesicle monoamine transporter 2" or "VMAT2" refers to an intact membrane protein that transports neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from the cytosol to synaptic vesicles. The term "VMAT2" can refer to the nucleotide or protein sequence of human VMAT2 (e.g., Entrez 6571, Uniprot Q05940, RefSeq NM_003054.4, or RefSeq NP_003045.2). In the examples, VMAT2 has the following amino acid sequence:

[0171] MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEIQTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSEDKDLLNENVQVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSSSYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGSVLYEFVGKTAPFLVLAALVLLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGSICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLCALLGMIIVGVSILCIPFAKNIYGLIAPNFGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGSVYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIIDILFAPLCFFLRSPPAKEEKMAILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD(SEQ ID NO:4)。

[0172] The terms “dopa decarboxylase” and “DDC” refer to proteins (including their homologs, isotypes, and functional fragments) that catalyze the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine. The terms include any recombinant or naturally occurring variants of DDC that maintain DDC activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type DDC). In the embodiments, the DDC protein encoded by the DDC gene has an amino acid sequence described in or corresponding to UniProt P20711, RefSeq(protein)NP_000781.1, RefSeq(protein)NP_001076440.1, RefSeq(protein)NP_001229815.1, RefSeq(protein)NP_001229816.1, RefSeq(protein)NP_001229817.1, RefSeq(protein)NP_001229818.1 or RefSeq(protein)NP_001229819.1. In the embodiments, the DDC gene has the nucleic acid sequence described in RefSeq(mRNA)NM_000790.3, RefSeq(mRNA)NM_001082971.1, RefSeq(mRNA)NM_001242886.1, RefSeq(mRNA)NM_001242887.1, RefSeq(mRNA)NM_001242888.1, RefSeq(mRNA)NM_001242889.1, or RefSeq(mRNA)NM_001242890.1. In the embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application.

[0173] The terms “dopamine transporter” and “DAT” refer to proteins (including their homologs, isotypes, and functional fragments) that transport dopamine from the synaptic cleft back to the cytosol. The terms include any recombinant or naturally occurring DAT variant that maintains DAT activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type DAT). In the examples, the DAT protein encoded by the SLC6A3 gene has an amino acid sequence described in or corresponding to Entrez 6531, UniProt Q01959, or RefSeq (protein) NP_001035.1. In the examples, the SLC6A3 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_001044.4. In the examples, the amino acid or nucleic acid sequences are sequences known at the time of filing of this application.

[0174] The terms "brain-derived neurotrophic factor" and "BDNF" refer to proteins (including their homologs, isotypes, and functional fragments) of the neurotrophic factor family of growth factors. The terms include any recombinant or naturally occurring BDNF variant that maintains BDNF activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type BDNF). In the examples, the BDNF protein encoded by the BDNF gene has been described in or corresponds to Entrez 627, UniProt... P23560, RefSeq(protein) NP_001137277.1, RefSeq(protein) NP_001137278.1, RefSeq(protein) NP_001137279.1, RefSeq(protein) NP_001137280.1, RefSeq(protein) NP_001137281.1, RefSeq(protein) NP_001137282.1, RefSeq(protein) NP_001137283.1, RefSeq(protein) NP_001137284.1, Ref The amino acid sequences of Seq(protein) NP_001137285.1, RefSeq(protein) NP_001137286.1, RefSeq(protein) NP_001137288.1, RefSeq(protein) NP_001700.2, RefSeq(protein) NP_733927.1, RefSeq(protein) NP_733928.1, RefSeq(protein) NP_733929.1, RefSeq(protein) NP_733930.1, or RefSeq(protein) NP_733931.1.In the examples, the BDNF gene has the following parameters: RefSeq(mRNA)NM_001143805.1, RefSeq(mRNA)NM_001143806.1, RefSeq(mRNA)NM_001143807.1, RefSeq(mRNA)NM_00143808.1, RefSeq(mRNA)NM_001143809.1, RefSeq(mRNA)NM_001143810.1, RefSeq(mRNA)NM_001143811.1, RefSeq(mRNA)NM_001143812.1, R The nucleic acid sequences described in RefSeq(mRNA)NM_001143813.1, RefSeq(mRNA)NM_001143814.1, RefSeq(mRNA)NM_001143816.1, RefSeq(mRNA)NM_001709.4, RefSeq(mRNA)NM_170731.4, RefSeq(mRNA)NM_170732.4, RefSeq(mRNA)NM_170733.3, RefSeq(mRNA)NM_170734.3, or RefSeq(mRNA)NM_170735.5. In the embodiments, the amino acid sequences or nucleic acid sequences are sequences known at the time of filing of this application.

[0175] The terms "nerve growth factor" and "NGF" refer to proteins (including their homologs, isotypes, and functional fragments) involved in regulating the growth, maintenance, proliferation, and survival of certain target neurons. The term includes any recombinant or naturally occurring NGF variant that maintains NGF activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type NGF). In embodiments, the NGF protein encoded by the NGF gene has an amino acid sequence described in or corresponding to Entrez 4803, UniProt P01138, or RefSeq (protein) NP_002497.2. In embodiments, the NGF gene has a nucleic acid sequence described in RefSeq (mRNA) NM_002506.2. In embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0176] The terms “glial cell line-derived neurotrophic factor” and “GDNF” refer to proteins (including their homologs, isotypes, and functional fragments) that promote the survival of multiple neuronal types. The terms include any recombinant or naturally occurring GDNF variant that maintains GDNF activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type GDNF). In the embodiments, the GDNF protein encoded by the GDNF gene has an amino acid sequence described in or corresponding to Entrez 2668, UniProt P39905, RefSeq(protein)NP_000505.1, RefSeq(protein)NP_001177397.1, RefSeq(protein)NP_001177398.1, RefSeq(protein)NP_001265027.1 or RefSeq(protein)NP_954701.1. In the embodiments, the GDNF gene has the nucleic acid sequence described in RefSeq(mRNA)NM_000514.3, RefSeq(mRNA)NM_001190468.1, RefSeq(mRNA)NM_001190469.1, RefSeq(mRNA)NM_001278098.1, or RefSeq(mRNA)NM_199231.2. In the embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application.

[0177] The terms “RET proto-oncogene” and “c-RET” refer to proteins (including their homologs, isotypes, and functional fragments) involved in cell proliferation, neuronal navigation, cell migration, and cell differentiation. The terms include any recombinant or naturally occurring c-RET variant that maintains c-RET activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type c-RET). In the examples, the c-RET protein encoded by the RET gene has an amino acid sequence described in or corresponding to Entrez 5979, UniProt P07949, RefSeq (protein) NP_065681.1, or RefSeq (protein) NP_066124.1. In the embodiments, the RET gene has the nucleic acid sequence described in RefSeq(mRNA)NM_020630.4 or RefSeq(mRNA)NM_020975.4. In the embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application.

[0178] The terms “superoxide dismutase 1” and “SOD1” refer to proteins (including their homologs, isotypes, and functional fragments) involved in apoptosis. The terms include any recombinant or naturally occurring SOD1 variant that maintains SOD1 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type SOD1). In the embodiments, the SOD1 protein encoded by the SOD1 gene has an amino acid sequence described in or corresponding to Entrez6647, UniProt P00441, or RefSeq (protein) NP_000445.1. In the embodiments, the SOD1 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_000454.4. In the embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0179] The terms "tumor necrosis factor α" and "TNFα" refer to proteins (including their homologs, isotypes, and functional fragments) involved in cell signaling. The terms include any recombinant or naturally occurring variant of TNFα that maintains TNFα activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type TNFα). In the embodiments, the TNFα protein encoded by the TNF gene has an amino acid sequence described in or corresponding to Entrez 7124, UniProt P01375, or RefSeq (protein) NP_000585.2. In the embodiments, the TNF gene has a nucleic acid sequence described in RefSeq (mRNA) NM_000594.3. In the embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0180] The terms “inducible nitric oxide synthase” and “iNOS” refer to proteins that produce nitric oxide (including their homologs, isotypes, and functional fragments). The terms include any recombinant or naturally occurring iNOS variant that maintains iNOS activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type iNOS). In the examples, the iNOS protein encoded by the NOS2 gene has an amino acid sequence described in or corresponding to UniProtP35228 or RefSeq (protein) NP_000616.3. In the examples, the NOS2 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_000625.4. In the examples, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0181] The terms “interleukin-1β” and “IL-1β” refer to cytokine proteins (including their homologs, isotypes, and functional fragments). The terms encompass any recombinant or naturally occurring IL-1β variant that maintains IL-1β activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type IL-1β). In the embodiments, the IL-1β protein encoded by the IL1B gene has an amino acid sequence described in or corresponding to Entrez 3553, UniProtP01584, or RefSeq (protein) NP_000567.1. In the embodiments, the IL1B gene has a nucleic acid sequence described in RefSeq (mRNA) NM_000576.2. In the embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0182] The terms “pituitary homeobox 3” and “PITX3” refer to proteins (including their homologs, isotypes, and functional fragments) belonging to the RIEG / PITX homeobox family, which are bicoid proteins of the homeo domain and act as transcription factors. The terms include any recombinant or naturally occurring PITX3 variant that maintains PITX3 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type PITX3). In the embodiments, the PITX3 protein encoded by the Pitx3 gene has an amino acid sequence described in or corresponding to Entrez 5309, UniProt O75364, or RefSeq (protein) NP_005020.1. In the embodiments, the Pitx3 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_005029.3. In the embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application.

[0183] The term "response element" is used in its ordinary general sense in the art and refers to a short DNA sequence within a gene promoter or enhancer region that can bind to a specific transcription factor and regulate gene transcription.

[0184] The term "NGFI-B Response Element" or "NBRE" refers to a response element of nerve growth factor IB (NGFI-B). In this embodiment, the binding site has the nucleotide sequence 5'-AAAGGTCA.

[0185] The term "Nur response element" or "NuRE" refers to a homodimer or heterodimer response element of the NR4A family of nuclear receptors. In the examples, the NuRE has the nucleotide sequence 5'-TGATATTACCTCCAAATGCCA (SEQ ID NO: 5).

[0186] The term "DR-5 response element" refers to a retinoic acid response element. In the embodiments, the DR-5 response element has the nucleotide sequence 5'-GGTTCACCGAAAGGTCA (SEQ ID NO:6).

[0187] II.Compounds

[0188] In one aspect, a compound having the following formula is provided:

[0189]

[0190] R 1 Independently 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)OR 1C -NR 1A OR 1C -N3, -SF5, -SSR 1D -SiR 1A R 1B R 1C-SP(O)(OH)2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) is either substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C8, C3-C6, C4-C6, or C5-C6). 10 (or phenyl), or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0191] R 1A R 1B R 1C and R 1DIndependently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I. -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted ( For example, alkyl groups substituted with at least one substituent, a size-restricted substituent, or a lower substituent, or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituent-substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10 (or phenyl) or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary); R bonded to the same nitrogen atom 1A and R 1B Substituents may be joined to form substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0192] The variable n1 is an independent integer from 0 to 4.

[0193] Variables m1 and v1 are independently 1 or 2.

[0194] X 1 It can be -F, -Cl, -Br, or -I independently.

[0195] The variable z1 is an integer from 0 to 6;

[0196] In the embodiments, the compound has the following formula: Where R 1 And z1 as described herein (included in the examples). In the examples, the compounds have the following formula: Where R 1 And z1 as described herein (included in the examples). In the examples, the compounds have the following formula: Where R 1 z1 is as described herein (included in the embodiments).

[0197] In the embodiment, the replaced R 1 (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 1 The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 1 When substituted, it is replaced by at least one substituent. In an embodiment, when R 1 When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 1 When substituted, it is replaced by at least one lower substituent.

[0198] In the embodiment, the replaced R 1A (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 1A The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 1A When substituted, it is replaced by at least one substituent. In an embodiment, when R 1A When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 1A When substituted, it is replaced by at least one lower substituent.

[0199] In the embodiment, the replaced R1B (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 1B The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 1B When substituted, it is replaced by at least one substituent. In an embodiment, when R 1B When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 1B When substituted, it is replaced by at least one lower substituent.

[0200] In the embodiments, when R is bonded to the same nitrogen atom 1A and R 1B When substituents bond, the substituted ring (e.g., the substituted heterocyclic alkyl and / or the substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if R bonded to the same nitrogen atom 1A and R 1B The substituted ring formed upon substituent bonding is replaced by a plurality of groups selected from substituents, size-restricted substituents, or lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R is bonded to the same nitrogen atom... 1A and R 1B When a substituted ring is formed during substituent bonding, it is substituted by at least one substituent. In an example, when R is bonded to the same nitrogen atom... 1A and R 1B When a substituted ring is formed during substituent bonding, it is substituted by at least one size-restricted substituent. In an embodiment, when R is bonded to the same nitrogen atom... 1A and R 1B When the substituted ring formed during substituent bonding is substituted, it is substituted by at least one lower substituent.

[0201] In the embodiment, the replaced R 1C (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 1C The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 1CWhen substituted, it is replaced by at least one substituent. In an embodiment, when R 1C When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 1C When substituted, it is replaced by at least one lower substituent.

[0202] In the embodiment, the replaced R 1D (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 1D The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 1D When substituted, it is replaced by at least one substituent. In an embodiment, when R 1D When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 1D When substituted, it is replaced by at least one lower substituent.

[0203] In the embodiment, R 1Independently halogenated, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -O CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted (examples) For example, substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituent-substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10 (or phenyl) or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary).

[0204] In the embodiment, R 1 Independently, it is a halogen. In the embodiments, R 1 Independently -F. In the embodiments, R 1 Independently -Cl. In the embodiments, R 1 Independently -Br. In the embodiments, R 1 Independently -I. In the embodiment, R 1 Independently -CCl3. In the embodiment, R 1 Independently -CBr3. In the embodiments, R 1 Independently -CF3. In the embodiment, R 1Independently -CI3. In the embodiment, R 1 Independently -CHCl2. In the examples, R 1 Independently -CHBr2. In the embodiments, R 1 Independently -CHF2. In the embodiment, R 1 Independently -CHI2. In the embodiment, R 1 Independently -CH2Cl. In the examples, R 1 Independently -CH2Br. In the embodiments, R 1 Independently -CH2F. In the embodiments, R 1 Independently -CH2I. In the embodiments, R 1 Independently -OCCl3. In the embodiment, R 1 Independently -OCF3. In the embodiment, R 1 Independently -OCBr3. In the embodiments, R 1 Independently -OCI3. In the embodiment, R 1 Independently -OCHCl2. In the examples, R 1 Independently -OCHBr2. In the embodiments, R 1 Independently -OCHI2. In the embodiment, R 1 Independently -OCHF2. In the embodiment, R 1 Independently -OCH2Cl. In the examples, R 1 Independently -OCH2Br. In the embodiments, R 1 Independently -OCH2I. In the embodiments, R 1 Independently -OCH2F. In the embodiment, R 1 Independently designated as -CN. In the embodiment, R 1 Independently -OH. In the examples, R 1 Independently -NH2. In the examples, R 1 Independently -COOH. In the examples, R 1 Independently -CONH2. In the embodiment, R 1 Independently -NO2. In the embodiments, R 1 Independently designated as -SH. In the embodiment, R 1 Independently -SeH. In the embodiment, R 1 Independently -SO3H. In the embodiment, R 1 Independently, it is –OSO3H. In the embodiment, R 1 Independently, it is -SO2NH2. In the embodiments, R 1 Independently -NHNH2. In the examples, R 1Independently -ONH2. In the embodiment, R 1 Independently, it is -NHC(O)NHNH2. In the examples, R 1 Independently, it is -NHC(O)NH2. In the examples, R 1 Independently -NHSO2H. In the examples, R 1 Independently -NHC(O)H. In the examples, R 1 Independently, it is -NHC(O)OH. In the examples, R 1 Independently –NHOH. In the examples, R 1 Independently -N3. In the embodiment, R 1 Independently -SF5. In the embodiment, R 1 Independently, it is -SP(O)(OH)2. In the examples, R 1 Independently, it is a substituted or unsubstituted alkyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted C1-C4 alkyl group. In the examples, R 1 Independently, it is an unsubstituted methyl group. In the examples, R 1 Independently, it is an unsubstituted ethyl group. In the examples, R 1 Independently, it is unsubstituted propyl. In the examples, R 1 Independently, it is an unsubstituted n-propyl group. In the examples, R 1 Independently, it is an unsubstituted isopropyl group. In the examples, R 1 Independently, it is an unsubstituted butyl. In the examples, R 1 Independently, it is an unsubstituted n-butyl group. In the examples, R 1 Independently, it is unsubstituted tert-butyl. In the embodiments, R 1 Independently, it is a substituted or unsubstituted heteroalkyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted 2- to 5-membered heteroalkyl group. In the examples, R 1 Independently, it is an unsubstituted methoxy group. In the examples, R 1 Independently, it is an unsubstituted ethoxy group. In the examples, R 1 Independently, it is an unsubstituted propoxy group. In the examples, R 1 Independently, it is an unsubstituted propoxy group. In the examples, R 1 Independently, it is an unsubstituted isopropoxy group. In the examples, R 1 Independently, it is an unsubstituted butoxy group. In the examples, R 1 Independently, it is an unsubstituted n-butoxy group. In the examples, R 1 Independently, it is an unsubstituted tert-butoxy group. In the examples, R 1Independently, it is a substituted or unsubstituted cycloalkyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted C3-C8 cycloalkyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted heterocyclic alkyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, R 1 Independently, it is either a substituted or unsubstituted aryl group. In the examples, R 1 Independently substituted or unsubstituted C6-C 10 Aryl. In the embodiments, R 1 Independently, it is a substituted or unsubstituted phenyl group. In the examples, R 1 Independently, it is a substituted or unsubstituted heteroaryl group. In the examples, R 1 Independently substituted or unsubstituted 5 to 10 heteroaryl groups.

[0205] In one embodiment, z1 is 0. In one embodiment, z1 is 1. In one embodiment, z1 is 2. In one embodiment, z1 is 3. In one embodiment, z1 is 4. In one embodiment, z1 is 5. In one embodiment, z1 is 6.

[0206] In the embodiments, the compound has the following formula:

[0207]

[0208] R 2 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 -SC(O)R 2C -C(O)OR 2C -C(O)NR 2A R 2B -OR 2D -SR 2D -SeR 2D -NR2A SO2R 2D -NR 2A C(O)R 2C -NR 2A C(O)OR 2C -NR 2A OR 2C -N3, -SF5, -SSR 2D -SiR 2A R 2B R 2C -SP(O)(OH)2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) is either substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C8, C3-C6, C4-C6, or C5-C6). 10 (or phenyl), or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0209] R 3 Hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 -OCX 3 3. -OCH2X 3 -OCHX 3 2. -CN, -SO n3 R 3D -SO v3 NR 3A R 3B -NHC(O)NR 3A R 3B -N(O) m3 -NR 3A R 3B -C(O)R 3C -SC(O)R3C -C(O)OR 3C -C(O)NR 3A R 3B -OR 3D -SR 3D -SeR 3D -NR 3A SO2R 3D -NR 3A C(O)R 3C -NR 3A C(O)OR 3C -NR 3A OR 3C -N3, -SF5, -SSR 3D -SiR 3A R 3B R 3C -SP(O)(OH)2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) is either substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C8, C3-C6, C4-C6, or C5-C6). 10 (or phenyl), or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0210] R 4 Hydrogen, halogen, -CX 4 3. -CHX 4 2. -CH2X 4 -OCX 4 3. -OCH2X 4 -OCHX 4 2. -CN, -SO n4 R 4D -SO v4 NR 4A R4B -NHC(O)NR 4A R 4B -N(O) m4 -NR 4A R 4B -C(O)R 4C -SC(O)R 4C -C(O)OR 4C -C(O)NR 4A R 4B -OR 4D -SR 4D -SeR 4D -NR 4A SO2R 4D -NR 4A C(O)R 4C -NR 4A C(O)OR 4C -NR 4A OR 4C -N3, -SF5, -SSR 4D -SiR 4A R 4B R 4C -SP(O)(OH)2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) is either substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C8, C3-C6, C4-C6, or C5-C6). 10 (or phenyl), or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0211] R 5 Hydrogen, halogen, -CX 5 3. -CHX 5 2. -CH2X 5 -OCX5 3. -OCH2X 5 -OCHX 5 2. -CN, -SO n5 R 5D -SO v5 NR 5A R 5B -NHC(O)NR 5A R 5B -N(O) m5 -NR 5A R 5B -C(O)R 5C -SC(O)R 5C -C(O)OR 5C -C(O)NR 5A R 5B -OR 5D -SR 5D -SeR 5D -NR 5A SO2R 5D -NR 5A C(O)R 5C -NR 5A C(O)OR 5C -NR 5A OR 5C -N3, -SF5, -SSR 5D -SiR 5A R 5B R 5C -SP(O)(OH)2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) is either substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C8, C3-C6, C4-C6, or C5-C6). 10(or phenyl), or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0212] R 2A R 2B R 2C R 2D R 3A R 3B R 3C R 3D R 4A R 4B R 4C R 4D R 5A R 5B R 5C and R 5D Independently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I. -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted ( For example, alkyl groups substituted with at least one substituent, a size-restricted substituent, or a lower substituent, or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted alkyl groups (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituent-substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10(or phenyl) or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary); R bonded to the same nitrogen atom 2A and R 2B Substituents can be joined to form substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl groups (e.g., 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered); R bonded to the same nitrogen atom 3A and R 3B Substituents can be joined to form substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl groups (e.g., 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered); R bonded to the same nitrogen atom 4A and R 4B Substituents can be joined to form substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl groups (e.g., 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered); R bonded to the same nitrogen atom 5A and R 5B Substituents may be joined to form substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8, 3 to 6, 4 to 6, 4 to 5, or 5 to 6), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0213] The variables n2, n3, n4, and n5 are independent integers from 0 to 4.

[0214] The variables m2, m3, m4, m5, v2, v3, v4, and v5 are independently 1 or 2.

[0215] X 2 X 3 X 4 and X 5It can be -F, -Cl, -Br, or -I independently.

[0216] In the embodiments, the compound has the following formula: R 2 R 3 R 4 and R 5 As described herein (including in the examples). In the examples, the compounds have the following formula: R 2 R 3 R 4 and R 5 As described herein (including in the examples). In the examples, the compounds have the following formula: R 2 R 3 R 4 and R 5 As described herein (including in the embodiments).

[0217] In the embodiments, the compound has the following formula:

[0218] R 2 R 3 and R 5 As described herein (including in the examples). In the examples, the compounds have the following formula: R 2 R 3 and R 5 As described herein (including in the examples). In the examples, the compounds have the following formula: R 2 R 3 and R 5 As described herein (including in the examples). In the examples, the compounds have the following formula: R 2 R 3 and R 5 As described herein (including in the embodiments).

[0219] In the embodiment, the replaced R 2 (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 2 The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 2When substituted, it is replaced by at least one substituent. In an embodiment, when R 2 When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 2 When substituted, it is replaced by at least one lower substituent.

[0220] In the embodiment, the replaced R 2A (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 2A The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 2A When substituted, it is replaced by at least one substituent. In an embodiment, when R 2A When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 2A When substituted, it is replaced by at least one lower substituent.

[0221] In the embodiment, the replaced R 2B (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 2B The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 2B When substituted, it is replaced by at least one substituent. In an embodiment, when R 2B When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 2B When substituted, it is replaced by at least one lower substituent.

[0222] In the embodiments, when R is bonded to the same nitrogen atom 2A and R 2B When substituents bond, the substituted ring (e.g., the substituted heterocyclic alkyl and / or the substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if R bonded to the same nitrogen atom 2A and R 2BThe substituted ring formed upon substituent bonding is replaced by a plurality of groups selected from substituents, size-restricted substituents, or lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an example, R bonded to the same nitrogen atom 2A and R 2B When a substituted ring is formed during substituent bonding, it is substituted by at least one substituent. In an example, when R is bonded to the same nitrogen atom... 2A and R 2B When a substituted ring is formed during substituent bonding, it is substituted by at least one size-restricted substituent. In an embodiment, when R is bonded to the same nitrogen atom... 2A and R 2B When the substituted ring formed during substituent bonding is substituted, it is substituted by at least one lower substituent.

[0223] In the embodiment, the replaced R 2C (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 2C The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 2C When substituted, it is replaced by at least one substituent. In an embodiment, when R 2C When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 2C When substituted, it is replaced by at least one lower substituent.

[0224] In the embodiment, the replaced R 2D (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 2D The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 2D When substituted, it is replaced by at least one substituent. In an embodiment, when R 2D When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 2D When substituted, it is replaced by at least one lower substituent.

[0225] In the embodiment, R 2Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OC H2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted (e.g.) The alkyl group is either substituted with at least one substituent, a size-restricted substituent, or a lower substituent, or an unsubstituted alkyl group (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or an unsubstituted heteroalkyl group (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituted alkyl groups or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10 (or phenyl) or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary).

[0226] In the embodiment, R 2Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, - SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 2- to 8-membered heteroalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted 3- to 8-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5 to 10 heteroaryl groups.

[0227] In the embodiment, R 2 Hydrogen, halogen, -CF3, -CH2F, -CHF2, -CN, -OH, -NH2, -COOH, -CONH2, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5 to 10 heteroaryl groups.

[0228] In the embodiment, R 2 It is hydrogen. In the examples, R is... 2 It is a halogen. In the embodiment, R is a halogen. 2 For -F. In the embodiment, R 2 For –Cl. In the embodiment, R 2 It is -Br. In the embodiments, R 2 For -I. In the embodiment, R 2 It is -CCl3. In the embodiment, R 2 It is -CBr3. In the embodiments, R 2 It is -CF3. In the embodiment, R 2 It is -CI3. In the embodiment, R 2 It is -CHCl2. In the examples, R 2 It is -CHBr2. In the embodiments, R2 It is -CHF2. In the embodiment, R 2 For -CHI2. In the embodiment, R 2 It is -CH2Cl. In the examples, R 2 It is -CH2Br. In the examples, R 2 It is -CH2F. In the embodiment, R 2 It is -CH2I. In the embodiment, R 2 It is -OCCl3. In the embodiment, R 2 It is -OCF3. In the embodiment, R 2 It is -OCBr3. In the embodiment, R 2 It is -OCI3. In the embodiment, R 2 It is -OCHCl2. In the examples, R 2 It is -OCHBr2. In the embodiment, R 2 For -OCHI2. In the embodiment, R 2 It is -OCHF2. In the embodiment, R 2 It is -OCH2Cl. In the examples, R 2 It is -OCH2Br. In the embodiments, R 2 For -OCH2I. In the embodiment, R 2 It is -OCH2F. In the embodiment, R 2 For -CN. In the embodiment, R 2 It is -OH. In the examples, R 2 It is -NH2. In the examples, R 2 For –COOH. In the examples, R 2 For -CONH2. In the embodiment, R 2 It is -NO2. In the embodiment, R 2 For -SH. In the embodiment, R 2 For –SeH. In the embodiment, R 2 It is -SO3H. In the embodiment, R 2 It is –OSO3H. In the embodiment, R 2 It is -SO2NH2. In the embodiment, R 2 It is -NHNH2. In the examples, R 2 It is -ONH2. In the embodiment, R 2 The form is -NHC(O)NHNH2. In the examples, R... 2 It is -NHC(O)NH2. In the examples, R 2 It is -NHSO2H. In the embodiment, R 2 It is -NHC(O)H. In the embodiment, R 2It is -NHC(O)OH. In the examples, R... 2 For –NHOH. In the examples, R 2 It is -N3. In the embodiment, R 2 It is -SF5. In the embodiment, R 2 It is -SP(O)(OH)2. In the examples, R 2 It is a substituted or unsubstituted alkyl group. In the examples, R 2 It is a substituted or unsubstituted C1-C4 alkyl group. In the examples, R 2 R is an unsubstituted methyl group. In the examples, R... 2 It is an unsubstituted ethyl group. In the examples, R... 2 It is an unsubstituted propyl group. In the examples, R 2 It is an unsubstituted n-propyl group. In the examples, R 2 It is an unsubstituted isopropyl group. In the examples, R 2 It is an unsubstituted butyl. In the embodiment, R 2 It is an unsubstituted n-butyl. In the examples, R 2 It is an unsubstituted tert-butyl group. In the embodiment, R 2 It is a substituted or unsubstituted heteroalkyl group. In the examples, R 2 It is a substituted or unsubstituted 2- to 5-membered heteroalkyl group. In the examples, R 2 It is an unsubstituted methoxy group. In the examples, R 2 It is an unsubstituted ethoxy group. In the examples, R 2 It is an unsubstituted propoxy group. In the examples, R 2 It is an unsubstituted propoxy group. In the examples, R... 2 It is an unsubstituted isopropoxy group. In the examples, R 2 It is an unsubstituted butoxy group. In the examples, R 2 It is an unsubstituted n-butoxy group. In the examples, R 2 It is an unsubstituted tert-butoxy group. In the examples, R 2 It is a substituted or unsubstituted cycloalkyl group. In the examples, R 2 It is a substituted or unsubstituted C3-C8 cycloalkyl group. In the examples, R 2 It is a substituted or unsubstituted heterocyclic alkyl group. In the examples, R 2 It is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, R 2 The aryl group may be substituted or unsubstituted. In the examples, R 2 For substituted or unsubstituted C6-C 10 Aryl. In the embodiments, R 2 It can be a substituted or unsubstituted phenyl group. In the examples, R 2For substituted or unsubstituted heteroaryl groups. In the examples, R 2 It consists of substituted or unsubstituted 5 to 10 heteroaryl groups.

[0229] In the embodiment, the replaced R 3 (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 3 The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 3 When substituted, it is replaced by at least one substituent. In an embodiment, when R 3 When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 3 When substituted, it is replaced by at least one lower substituent.

[0230] In the embodiment, the replaced R 3A (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 3A The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 3A When substituted, it is replaced by at least one substituent. In an embodiment, when R 3A When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 3A When substituted, it is replaced by at least one lower substituent.

[0231] In the embodiment, the replaced R 3B For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 3B The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 3B When substituted, it is replaced by at least one substituent. In an embodiment, when R 3B When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 3BWhen substituted, it is replaced by at least one lower substituent.

[0232] In the embodiments, when R is bonded to the same nitrogen atom 3A and R 3B When substituents bond, the substituted ring (e.g., the substituted heterocyclic alkyl and / or the substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if R bonded to the same nitrogen atom 3A and R 3B The substituted ring formed upon substituent bonding is replaced by a plurality of groups selected from substituents, size-restricted substituents, or lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an example, R bonded to the same nitrogen atom 3A and R 3B When a substituted ring is formed during substituent bonding, it is substituted by at least one substituent. In an example, when R is bonded to the same nitrogen atom... 3A and R 3B When a substituted ring is formed during substituent bonding, it is substituted by at least one size-restricted substituent. In an embodiment, when R is bonded to the same nitrogen atom... 3A and R 3B When the substituted ring formed during substituent bonding is substituted, it is substituted by at least one lower substituent.

[0233] In the embodiment, the replaced R 3C (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 3C The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 3C When substituted, it is replaced by at least one substituent. In an embodiment, when R 3C When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 3C When substituted, it is replaced by at least one lower substituent.

[0234] In the embodiment, the replaced R 3D (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 3DThe substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 3D When substituted, it is replaced by at least one substituent. In an embodiment, when R 3D When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 3D When substituted, it is replaced by at least one lower substituent.

[0235] In the embodiment, R 3 Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OC H2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted (e.g.) The alkyl group is either substituted with at least one substituent, a size-restricted substituent, or a lower substituent, or an unsubstituted alkyl group (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or an unsubstituted heteroalkyl group (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituted alkyl groups or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10 (or phenyl) or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary).

[0236] In the embodiment, R 3It is hydrogen. In the examples, R is... 3 It is a halogen. In the embodiment, R is a halogen. 3 For -F. In the embodiment, R 3 For –Cl. In the embodiment, R 3 It is -Br. In the embodiments, R 3 For -I. In the embodiment, R 3 It is -Br or -Cl. In the examples, R... 3 It is -CCl3. In the embodiment, R 3 It is -CBr3. In the embodiments, R 3 It is -CF3. In the embodiment, R 3 It is -CI3. In the embodiment, R 3 It is -CHCl2. In the examples, R 3 It is -CHBr2. In the embodiments, R 3 It is -CHF2. In the embodiment, R 3 For -CHI2. In the embodiment, R 3 It is -CH2Cl. In the examples, R 3 It is -CH2Br. In the examples, R 3 It is -CH2F. In the embodiment, R 3 It is -CH2I. In the embodiment, R 3 It is -OCCl3. In the embodiment, R 3 It is -OCF3. In the embodiment, R 3 It is -OCBr3. In the embodiment, R 3 It is -OCI3. In the embodiment, R 3 It is -OCHCl2. In the examples, R 3 It is -OCHBr2. In the embodiment, R 3 For -OCHI2. In the embodiment, R 3 It is -OCHF2. In the embodiment, R 3 It is -OCH2Cl. In the examples, R 3 It is -OCH2Br. In the embodiments, R 3 For -OCH2I. In the embodiment, R 3 It is -OCH2F. In the embodiment, R 3 For -CN. In the embodiment, R 3 It is -OH. In the examples, R 3 It is -NH2. In the examples, R 3 For –COOH. In the examples, R 3 For -CONH2. In the embodiment, R 3 It is -NO2. In the embodiment, R 3For -SH. In the embodiment, R 3 For –SeH. In the embodiment, R 3 It is -SO3H. In the embodiment, R 3 It is –OSO3H. In the embodiment, R 3 It is -SO2NH2. In the embodiment, R 3 It is -NHNH2. In the examples, R 3 It is -ONH2. In the embodiment, R 3 The form is -NHC(O)NHNH2. In the examples, R... 3 It is -NHC(O)NH2. In the examples, R 3 It is -NHSO2H. In the embodiment, R 3 It is -NHC(O)H. In the embodiment, R 3 It is -NHC(O)OH. In the examples, R... 3 For –NHOH. In the examples, R 3 It is -N3. In the embodiment, R 3 It is -SF5. In the embodiment, R 3 It is -SP(O)(OH)2. In the examples, R 3 It is a substituted or unsubstituted alkyl group. In the examples, R 3 It is a substituted or unsubstituted C1-C4 alkyl group. In the examples, R 3 R is an unsubstituted methyl group. In the examples, R... 3 It is an unsubstituted ethyl group. In the examples, R... 3 It is an unsubstituted propyl group. In the examples, R 3 It is an unsubstituted n-propyl group. In the examples, R 3 It is an unsubstituted isopropyl group. In the examples, R 3 It is an unsubstituted butyl. In the embodiment, R 3 It is an unsubstituted n-butyl. In the examples, R 3 It is an unsubstituted tert-butyl group. In the embodiment, R 3 It is a substituted or unsubstituted heteroalkyl group. In the examples, R 3 It is a substituted or unsubstituted 2- to 5-membered heteroalkyl group. In the examples, R 3 It is an unsubstituted methoxy group. In the examples, R 3 It is an unsubstituted ethoxy group. In the examples, R 3 It is an unsubstituted propoxy group. In the examples, R 3 It is an unsubstituted propoxy group. In the examples, R... 3 It is an unsubstituted isopropoxy group. In the examples, R 3 It is an unsubstituted butoxy group. In the examples, R 3It is an unsubstituted n-butoxy group. In the examples, R 3 It is an unsubstituted tert-butoxy group. In the examples, R 3 It is a substituted or unsubstituted cycloalkyl group. In the examples, R 3 It is a substituted or unsubstituted C3-C8 cycloalkyl group. In the examples, R 3 It is a substituted or unsubstituted heterocyclic alkyl group. In the examples, R 3 It is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, R 3 The aryl group may be substituted or unsubstituted. In the examples, R 3 For substituted or unsubstituted C6-C 10 Aryl. In the embodiments, R 3 It can be a substituted or unsubstituted phenyl group. In the examples, R 3 For substituted or unsubstituted heteroaryl groups. In the examples, R 3 It consists of substituted or unsubstituted 5 to 10 heteroaryl groups.

[0237] In the embodiment, the replaced R 4 (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 4 The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 4 When substituted, it is replaced by at least one substituent. In an embodiment, when R 4 When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 4 When substituted, it is replaced by at least one lower substituent.

[0238] In the embodiment, the replaced R 4A (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 4A The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 4A When substituted, it is replaced with at least one substituent. In an embodiment, when R 4A When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 4AWhen substituted, it is replaced by at least one lower substituent.

[0239] In the embodiment, the replaced R 4B (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 4B The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 4B When substituted, it is replaced with at least one substituent. In an embodiment, when R 4B When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 4B When substituted, it is replaced by at least one lower substituent.

[0240] In the embodiments, when R is bonded to the same nitrogen atom 4A and R 4B When substituents bond, the substituted ring (e.g., the substituted heterocyclic alkyl and / or the substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if R bonded to the same nitrogen atom 4A and R 4B The substituted ring formed upon substituent bonding is replaced by a plurality of groups selected from substituents, size-restricted substituents, or lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R is bonded to the same nitrogen atom... 4A and R 4B When a substituted ring is formed during substituent bonding, it is substituted by at least one substituent. In an example, when R is bonded to the same nitrogen atom... 4A and R 4B When a substituted ring is formed during substituent bonding, it is substituted by at least one size-restricted substituent. In an embodiment, when R is bonded to the same nitrogen atom... 4A and R 4B When a substituted ring is formed during substituent bonding, it is substituted by at least one lower substituent.

[0241] In the embodiment, the replaced R 4C (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 4CThe substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 4C When substituted, it is replaced with at least one substituent. In an embodiment, when R 4C When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 4C When substituted, it is replaced by at least one lower substituent.

[0242] In the embodiment, the replaced R 4D (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 4D The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 4D When substituted, it is replaced by at least one substituent. In an embodiment, when R 4D When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 4D When substituted, it is replaced by at least one lower substituent.

[0243] In the embodiment, R 4Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OC H2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted (e.g.) The alkyl group is either substituted with at least one substituent, a size-restricted substituent, or a lower substituent, or an unsubstituted alkyl group (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or an unsubstituted heteroalkyl group (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent). Substituted alkyl groups or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl groups (e.g., C6-C6). 10 (or phenyl) or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 ternary, 5 to 9 ternary, or 5 to 6 ternary).

[0244] In the embodiment, R 4 It is hydrogen. In the examples, R is... 4 It is a halogen. In the embodiment, R is a halogen. 4 For -F. In the embodiment, R 4 For –Cl. In the embodiment, R 4 It is -Br. In the embodiments, R 4 For -I. In the embodiment, R 4 It is -CCl3. In the embodiment, R 4 It is -CBr3. In the embodiments, R 4 It is -CF3. In the embodiment, R 4It is -CI3. In the embodiment, R 4 It is -CHCl2. In the examples, R 4 It is -CHBr2. In the embodiments, R 4 It is -CHF2. In the embodiment, R 4 For -CHI2. In the embodiment, R 4 It is -CH2Cl. In the examples, R 4 It is -CH2Br. In the examples, R 4 It is -CH2F. In the embodiment, R 4 It is -CH2I. In the embodiment, R 4 It is -OCCl3. In the embodiment, R 4 It is -OCF3. In the embodiment, R 4 It is -OCBr3. In the embodiment, R 4 It is -OCI3. In the embodiment, R 4 It is -OCHCl2. In the examples, R 4 It is -OCHBr2. In the embodiment, R 4 For -OCHI2. In the embodiment, R 4 It is -OCHF2. In the embodiment, R 4 It is -OCH2Cl. In the examples, R 4 It is -OCH2Br. In the embodiments, R 4 For -OCH2I. In the embodiment, R 4 It is -OCH2F. In the embodiment, R 4 For -CN. In the embodiment, R 4 It is -OH. In the examples, R 4 It is -NH2. In the examples, R 4 It is -COOH. In the examples, R 4 For -CONH2. In the embodiment, R 4 It is -NO2. In the embodiment, R 4 For -SH. In the embodiment, R 4 For –SeH. In the embodiment, R 4 It is -SO3H. In the embodiment, R 4 It is –OSO3H. In the embodiment, R 4 It is -SO2NH2. In the embodiment, R 4 It is -NHNH2. In the examples, R 4 It is -ONH2. In the embodiment, R 4 The form is -NHC(O)NHNH2. In the examples, R... 4 It is -NHC(O)NH2. In the examples, R 4It is -NHSO2H. In the embodiment, R 4 It is -NHC(O)H. In the embodiment, R 4 It is -NHC(O)OH. In the examples, R... 4 For –NHOH. In the examples, R 4 It is -N3. In the embodiment, R 4 It is -SF5. In the embodiment, R 4 It is -SP(O)(OH)2. In the examples, R 4 It is a substituted or unsubstituted alkyl group. In the examples, R 4 It is a substituted or unsubstituted C1-C4 alkyl group. In the examples, R 4 R is an unsubstituted methyl group. In the examples, R... 4 It is an unsubstituted ethyl group. In the examples, R... 4 It is an unsubstituted propyl group. In the examples, R 4 It is an unsubstituted n-propyl group. In the examples, R 4 It is an unsubstituted isopropyl group. In the examples, R 4 It is an unsubstituted butyl. In the embodiment, R 4 It is an unsubstituted n-butyl. In the examples, R 4 It is an unsubstituted tert-butyl group. In the embodiment, R 4 It is a substituted or unsubstituted heteroalkyl group. In the examples, R 4 It is a substituted or unsubstituted 2- to 5-membered heteroalkyl group. In the examples, R 4 It is an unsubstituted methoxy group. In the examples, R 4 It is an unsubstituted ethoxy group. In the examples, R 4 It is an unsubstituted propoxy group. In the examples, R 4 It is an unsubstituted propoxy group. In the examples, R... 4 It is an unsubstituted isopropoxy group. In the examples, R 4 It is an unsubstituted butoxy group. In the examples, R 4 It is an unsubstituted n-butoxy group. In the examples, R 4 It is an unsubstituted tert-butoxy group. In the examples, R 4 It is a substituted or unsubstituted cycloalkyl group. In the examples, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl group. In the examples, R 4 It is a substituted or unsubstituted heterocyclic alkyl group. In the examples, R 4 It is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, R 4 The aryl group may be substituted or unsubstituted. In the examples, R 4 For substituted or unsubstituted C6-C10 Aryl. In the embodiments, R 4 It can be a substituted or unsubstituted phenyl group. In the examples, R 4 For substituted or unsubstituted heteroaryl groups. In the examples, R 4 It consists of substituted or unsubstituted 5 to 10 heteroaryl groups.

[0245] In the embodiment, the replaced R 5 (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 5 The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 5 When substituted, it is replaced by at least one substituent. In an embodiment, when R 5 When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 5 When substituted, it is replaced by at least one lower substituent.

[0246] In the embodiment, the replaced R 5A (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 5A The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 5A When substituted, it is replaced with at least one substituent. In an embodiment, when R 5A When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 5A When substituted, it is replaced by at least one lower substituent.

[0247] In the embodiment, the replaced R 5B (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 5B The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 5BWhen substituted, it is replaced with at least one substituent. In an embodiment, when R 5B When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 5B When substituted, it is replaced by at least one lower substituent.

[0248] In the embodiments, when R is bonded to the same nitrogen atom 5A and R 5B When substituents bond, the substituted ring (e.g., the substituted heterocyclic alkyl and / or the substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if R bonded to the same nitrogen atom 5A and R 5B The substituted ring formed upon substituent bonding is replaced by a plurality of groups selected from substituents, size-restricted substituents, or lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R is bonded to the same nitrogen atom... 5A and R 5B When a substituted ring is formed during substituent bonding, it is substituted by at least one substituent. In an example, when R is bonded to the same nitrogen atom... 5A and R 5B When a substituted ring is formed during substituent bonding, it is substituted by at least one size-restricted substituent. In an embodiment, when R is bonded to the same nitrogen atom... 5A and R 5B When a substituted ring is formed during substituent bonding, it is substituted by at least one lower substituent.

[0249] In the embodiment, the replaced R 5C (For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 5C The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 5C When substituted, it is replaced with at least one substituent. In an embodiment, when R 5C When substituted, it is replaced with at least one size-restricted substituent. In an embodiment, when R 5C When substituted, it is replaced by at least one lower substituent.

[0250] In the embodiment, the replaced R 5D(For example, a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted R 5D The substituent is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when R 5D When substituted, it is replaced by at least one substituent. In an embodiment, when R 5D When substituted, it is replaced by at least one size-restricted substituent. In an embodiment, when R 5D When substituted, it is replaced by at least one lower substituent.

[0251] In the embodiment, R 5 Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -N O2, -SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0252] In the embodiment, R 5Hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, - SH, -SeH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, -SP(O)(OH)2, substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 2- to 8-membered heteroalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted 3- to 8-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5 to 10 heteroaryl groups.

[0253] In the embodiment, R 5 Hydrogen, halogen, -CF3, -CH2F, -CHF2, -CN, -OH, -NH2, -COOH, -CONH2, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5 to 10 heteroaryl groups.

[0254] In the embodiment, R 5 It is hydrogen. In the examples, R is... 5 It is a halogen. In the embodiment, R is a halogen. 5 For -F. In the embodiment, R 5 For –Cl. In the embodiment, R 5 It is -Br. In the examples, R 5 For -I. In the embodiment, R 5 It is -CCl3. In the embodiment, R 5 It is -CBr3. In the embodiments, R 5 It is -CF3. In the embodiment, R 5 It is -CI3. In the embodiment, R 5 It is -CHCl2. In the examples, R 5 It is -CHBr2. In the embodiments, R5 It is -CHF2. In the embodiment, R 5 For -CHI2. In the embodiment, R 5 It is -CH2Cl. In the examples, R 5 It is -CH2Br. In the examples, R 5 It is -CH2F. In the embodiment, R 5 It is -CH2I. In the embodiment, R 5 It is -OCCl3. In the embodiment, R 5 It is -OCF3. In the embodiment, R 5 It is -OCBr3. In the embodiment, R 5 It is -OCI3. In the embodiment, R 5 It is -OCHCl2. In the examples, R 5 It is -OCHBr2. In the embodiment, R 5 For -OCHI2. In the embodiment, R 5 It is -OCHF2. In the embodiment, R 5 It is -OCH2Cl. In the examples, R 5 It is -OCH2Br. In the embodiments, R 5 For -OCH2I. In the embodiment, R 5 It is -OCH2F. In the embodiment, R 5 For -CN. In the embodiment, R 5 It is -OH. In the examples, R 5 It is -NH2. In the examples, R 5 It is -COOH. In the examples, R 5 For -CONH2. In the embodiment, R 5 It is -NO2. In the embodiment, R 5 For -SH. In the embodiment, R 5 For –SeH. In the embodiment, R 5 It is -SO3H. In the embodiment, R 5 It is –OSO3H. In the embodiment, R 5 It is -SO2NH2. In the embodiment, R 5 It is -NHNH2. In the examples, R 5 It is -ONH2. In the embodiment, R 5 The form is -NHC(O)NHNH2. In the examples, R... 5 It is -NHC(O)NH2. In the examples, R 5 It is -NHSO2H. In the embodiment, R 5 It is -NHC(O)H. In the embodiment, R 5It is -NHC(O)OH. In several aspects, R 5 For –NHOH. In the examples, R 5 It is -N3. In the embodiment, R 5 It is -SF5. In the embodiment, R 5 It is -SP(O)(OH)2. In the examples, R 5 It is a substituted or unsubstituted alkyl group. In the examples, R 5 It is a substituted or unsubstituted C1-C4 alkyl group. In the examples, R 5 R is an unsubstituted methyl group. In the examples, R... 5 It is an unsubstituted ethyl group. In the examples, R... 5 It is an unsubstituted propyl group. In the examples, R 5 It is an unsubstituted n-propyl group. In the examples, R 5 It is an unsubstituted isopropyl group. In the examples, R 5 It is an unsubstituted butyl. In the embodiment, R 5 It is an unsubstituted n-butyl. In the examples, R 5 It is an unsubstituted tert-butyl group. In the embodiment, R 5 It is a substituted or unsubstituted heteroalkyl group. In the examples, R 5 It is a substituted or unsubstituted 2- to 5-membered heteroalkyl group. In the examples, R 5 It is an unsubstituted methoxy group. In the examples, R 5 It is an unsubstituted ethoxy group. In the examples, R 5 It is an unsubstituted propoxy group. In the examples, R 5 It is an unsubstituted propoxy group. In the examples, R... 5 It is an unsubstituted isopropoxy group. In the examples, R 5 It is an unsubstituted butoxy group. In the examples, R 5 It is an unsubstituted n-butoxy group. In the examples, R 5 It is an unsubstituted tert-butoxy group. In the examples, R 5 It is a substituted or unsubstituted cycloalkyl group. In the examples, R 5 It is a substituted or unsubstituted C3-C8 cycloalkyl group. In the examples, R 5 It is a substituted or unsubstituted heterocyclic alkyl group. In the examples, R 5 It is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, R 5 The aryl group may be substituted or unsubstituted. In the examples, R 5 For substituted or unsubstituted C6-C 10 Aryl. In the embodiments, R 5 It can be a substituted or unsubstituted phenyl group. In the examples, R 5For substituted or unsubstituted heteroaryl groups. In the examples, R 5 It consists of substituted or unsubstituted 5 to 10 heteroaryl groups.

[0255] In an embodiment, when R 1 When replaced, R 1 By one or more R 1.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1.1 When the substituent is substituted, R 1.1 Substituents are formed by one or more R 1.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1.2 When the substituent is substituted, R 1.2 Substituents are formed by one or more R 1.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1 R 1.1 R 1.2 and R 1.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1 R 1.1 R 1.2 and R 1.3 .

[0256] In an embodiment, when R 1A When replaced, R 1A By one or more R 1A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1A When the .1 substituent is substituted, R 1A.1 Substituents are formed by one or more R 1A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1A.2 When the substituent is substituted, R 1A.2 Substituents are formed by one or more R 1A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1AR 1A.1 R 1A.2 and R 1A.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1A R 1A.1 R 1A.2 R and R 1A.3 .

[0257] In an embodiment, when R 1B When replaced, R 1B By one or more R 1B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1B.1 When the substituent is substituted, R 1B.1 Substituents are formed by one or more R 1B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1B.2 When the substituent is substituted, R 1B .2 Substituents are formed by one or more R 1B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1B R 1B.1 R 1B.2 and R 1B.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1B R 1B.1 R 1B.2 and R 1B.3 .

[0258] In the embodiments, when R is bonded to the same nitrogen atom 1A and R 1B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is coupled by one or more of the following: R1A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1A.1 When the substituent is substituted, R 1A.1 Substituents are formed by one or more R 1A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1A.2 When the substituent is substituted, R 1A.2 Substituents are formed by one or more R 1A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1A.1 R 1A.2 and R 1A.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1A.1 R 1A.2 R and R 1A.3 .

[0259] In the embodiments, when R is bonded to the same nitrogen atom 1A and R 1B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 1B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1B.1 When the substituent is substituted, R 1B.1 Substituents are formed by one or more R 1B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1B.2 When the substituent is substituted, R 1B.2 Substituents are formed by one or more R 1B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1B.1 R 1B.2 and R 1B.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2and R WW.3 Corresponding to R respectively 1B.1 R 1B.2 and R 1B.3 .

[0260] In an embodiment, when R 1C When replaced, R 1C By one or more R 1C.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1C.1 When the substituent is substituted, R 1C .1 Substituents are formed by one or more R 1C.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1C.2 When the substituent is substituted, R 1C.2 Substituents are formed by one or more R 1C.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1C R 1C 1. R 1C.2 and R 1C.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1C R 1C.1 R 1C.2 and R 1C.3 .

[0261] In an embodiment, when R 1D When replaced, R 1D By one or more R 1D.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1D.1 When the substituent is substituted, R 1D.1 Substituents are formed by one or more R 1D.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 1D.2 When the substituent is substituted, R 1D.2 Substituents are formed by one or more R 1D.3The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 1D R 1D.1 R 1D.2 and R 1D.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 1D R 1D.1 R 1D.2 and R 1D.3 .

[0262] In an embodiment, when R 2 When replaced, R 2 By one or more R 2.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2.1 When the substituent is substituted, R 2.1 Substituents are formed by one or more R 2.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2.2 When the substituent is substituted, R 2.2 Substituents are formed by one or more R 2.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2 R 2.1 R 2.2 and R 2.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW The value of .3, as described in the definition section of the "First Substituent" description above, is where R WW R WW 1. R WW.2 and R WW.3 Corresponding to R respectively 2 R 2.1 R 2.2 and R 2.3 .

[0263] In an embodiment, when R 2A When replaced, R 2ABy one or more R 2A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2A.1 When the substituent is substituted, R 2A.1 Substituents are formed by one or more R 2A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2A.2 When the substituent is substituted, R 2A.2 Substituents are formed by one or more R 2A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2A R 2A.1 R 2A.2 and R 2A.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW .2 and R WW.3 Corresponding to R respectively 2A R 2A.1 R 2A.2 R and R 2A.3 .

[0264] In an embodiment, when R 2B When replaced, R 2B By one or more R 2B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2B.1 When the substituent is substituted, R 2B.1 Substituents are formed by one or more R 2B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2B.2 When the substituent is substituted, R 2B.2 Substituents are formed by one or more R 2B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2B R 2B.1 R 2B.2 and R 2B.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 2B R 2B.1 R 2B.2 and R 2B.3 .

[0265] In the embodiments, when R is bonded to the same nitrogen atom 2A and R 2B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 2A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2A.1 When the substituent is substituted, R 2A.1 Substituents are formed by one or more R 2A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2A.2 When the substituent is substituted, R 2A.2 Substituents are formed by one or more R 2A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2A.1 R 2A.2 and R 2A.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 2A.1 R 2A.2 R and R 2A.3 .

[0266] In the embodiments, when R is bonded to the same nitrogen atom 2A and R 2B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 2B.1 The first substituent is substituted, as defined above in the description of the "first substituent". In an embodiment, when R 2B.1 When the substituent is substituted, R 2B.1 Substituents are formed by one or more R 2B.2The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2B.2 When the substituent is substituted, R 2B.2 Substituents are formed by one or more R 2B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2B.1 R 2B.2 and R 2B.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 2B.1 R 2B.2 and R 2B.3 .

[0267] In an embodiment, when R 2C When replaced, R 2C By one or more R 2C.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2C.1 When the substituent is substituted, R 2C.1 Substituents are formed by one or more R 2C.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2C.2 When the substituent is substituted, R 2C.2 Substituents are formed by one or more R 2C.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2C R 2C.1 R 2C.2 and R 2C.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 2C R 2C.1 R 2C.2 and R 2C.3 .

[0268] In an embodiment, when R2D When replaced, R 2D By one or more R 2D.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2D.1 When the substituent is substituted, R 2D.1 Substituents are formed by one or more R 2D.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 2D.2 When the substituent is substituted, R 2D.2 Substituents are formed by one or more R 2D.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 2D R 2D.1 R 2D.2 and R 2D.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 2D R 2D.1 R 2D.2 and R 2D.3 .

[0269] In an embodiment, when R 3 When replaced, R 3 By one or more R 3.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3.1 When the substituent is substituted, R 3.1 Substituents are formed by one or more R 3.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3.2 When the substituent is substituted, R 3.2 Substituents are formed by one or more R 3.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 3 R 3.1 R 3.2 and R 3.3 The values ​​corresponding to R are respectively WW R WW.1 RWW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW .3 corresponds to R respectively 3 R 3.1 R 3.2 and R 3.3 .

[0270] In an embodiment, when R 3A When replaced, R 3A By one or more R 3A .1 indicates the first substituent substitution, as defined in the "First Substituent" section above. In an embodiment, when R 3A.1 When the substituent is substituted, R 3A.1 Substituents are formed by one or more R 3A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3A.2 When the substituent is substituted, R 3A.2 Substituents are formed by one or more R 3A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 3A R 3A.1 R 3A.2 and R 3A.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 3A R 3A.1 R 3A.2 R and R 3A.3 .

[0271] In an embodiment, when R 3B When replaced, R 3B By one or more R 3B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3B.1 When the substituent is substituted, R 3B.1 Substituents are formed by one or more R 3B.2The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3B.2 When the substituent is substituted, R 3B.2 Substituents are formed by one or more R 3B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 3B R 3B.1 R 3B.2 and R 3B.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 3B R 3B.1 R 3B.2 and R 3B.3 .

[0272] In the embodiments, when R is bonded to the same nitrogen atom 3A and R 3B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 3A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3A.1 When the substituent is substituted, R 3A.1 Substituents are formed by one or more R 3A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3A.2 When the substituent is substituted, R 3A.2 Substituents are formed by one or more R 3A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 3A.1 R 3A.2 and R 3A.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 3A.1 R 3A.2 and R3A.3 .

[0273] In the embodiments, when R is bonded to the same nitrogen atom 3A and R 3B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 3B.1 The first substituent is substituted, as defined above in the description of the "first substituent". In an embodiment, when R 3B.1 When the substituent is substituted, R 3B.1 Substituents are formed by one or more R 3B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3B.2 When the substituent is substituted, R 3B.2 Substituents are formed by one or more R 3B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 3B.1 R 3B.2 and R 3B.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW 1. R WW.2 and R WW.3 Corresponding to R respectively 3B.1 R 3B.2 and R 3B.3 .

[0274] In an embodiment, when R 3C When replaced, R 3C By one or more R 3C.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3C.1 When the substituent is substituted, R 3C.1 Substituents are formed by one or more R 3C.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3C.2 When the substituent is substituted, R 3C.2 Substituents are formed by one or more R 3C The .3 indicates a third substituent substitution, as defined in the "First Substituent" section above. In the above embodiments, R 3C R 3C 1. R 3C.2 and R 3C.3The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 3C R 3C.1 R 3C.2 and R 3C.3 .

[0275] In an embodiment, when R 3D When replaced, R 3D By one or more R 3D.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3D When the .1 substituent is substituted, R 3D .1 Substituents are formed by one or more R 3D.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 3D.2 When the substituent is substituted, R 3D .2 Substituents are formed by one or more R 3D The .3 indicates a third substituent substitution, as defined in the "First Substituent" section above. In the above embodiments, R 3D R 3D.1 R 3D .2 and R 3D The values ​​of .3 correspond to R respectively. WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 3D R 3D.1 R 3D.2 and R 3D.3 .

[0276] In an embodiment, when R 4 When replaced, R 4 By one or more R 4.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4.1 When the substituent is substituted, R 4.1Substituents are formed by one or more R 4.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4.2 When the substituent is substituted, R 4.2 Substituents are formed by one or more R 4.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4 R 4.1 R 4.2 and R 4.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4 R 4.1 R 4.2 and R 4.3 .

[0277] In an embodiment, when R 4A When replaced, R 4A By one or more R 4A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4A.1 When the substituent is substituted, R 4A.1 Substituents are formed by one or more R 4A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4A.2 When the substituent is substituted, R 4A.2 Substituents are formed by one or more R 4A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4A R 4A.1 R 4A.2 and R 4A.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4AR 4A.1 R 4A.2 and R 4A.3 .

[0278] In an embodiment, when R 4B When replaced, R 4B By one or more R 4B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4B.1 When the substituent is substituted, R 4B.1 Substituents are formed by one or more R 4B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4B.2 When the substituent is substituted, R 4B.2 Substituents are formed by one or more R 4B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4B R 4B.1 R 4B.2 and R 4B.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4B R 4B.1 R 4B.2 and R 4B.3 .

[0279] In the embodiments, when R is bonded to the same nitrogen atom 4A and R 4B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 4A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4A.1 When the substituent is substituted, R 4A.1 Substituents are formed by one or more R 4A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4A.2 When the substituent is substituted, R 4A.2 Substituents are formed by one or more R 4A.3The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4A.1 R 4A.2 and R 4A.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4A.1 R 4A.2 and R 4A.3 .

[0280] In the embodiments, when R is bonded to the same nitrogen atom 4A and R 4B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 4B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4B.1 When the substituent is substituted, R 4B.1 Substituents are formed by one or more R 4B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4B.2 When the substituent is substituted, R 4B.2 Substituents are formed by one or more R 4B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4B.1 R 4B.2 and R 4B.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4B.1 R 4B.2 and R 4B.3 .

[0281] In an embodiment, when R 4C When replaced, R 4C By one or more R 4C.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4C.1When the substituent is substituted, R 4C.1 Substituents are formed by one or more R 4C.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4C.2 When the substituent is substituted, R 4C.2 Substituents are formed by one or more R 4C.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4C R 4C.1 R 4C.2 and R 4C.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 4C R 4C.1 R 4C.2 and R 4C.3 .

[0282] In an embodiment, when R 4D When replaced, R 4D By one or more R 4D.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4D.1 When the substituent is substituted, R 4D.1 Substituents are formed by one or more of the following: 4D.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 4D.2 When the substituent is substituted, R 4D.2 Substituents are formed by one or more of the following: 4D.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 4D R 4D.1 R 4D.2 and R 4D.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and RWW.3 Corresponding to R respectively 4D R 4D.1 R 4D.2 and R 4D.3 .

[0283] In an embodiment, when R 5 When replaced, R 5 By one or more R 5.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5.1 When the substituent is substituted, R 5.1 Substituents are formed by one or more R 5.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5.2 When the substituent is substituted, R 5.2 Substituents are formed by one or more R 5.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5 R 5.1 R 5.2 and R 5.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5 R 5.1 R 5.2 and R 5.3 .

[0284] In an embodiment, when R 5A When replaced, R 5A By one or more R 5A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5A.1 When the substituent is substituted, R 5A.1 Substituents are formed by one or more R 5A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5A.2 When the substituent is substituted, R 5A.2 Substituents are formed by one or more R 5A.3The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5A R 5A.1 R 5A .2 and R 5A The values ​​of .3 correspond to R respectively. WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW .3 corresponds to R respectively 5A R 5A.1 R 5A.2 and R 5A.3 .

[0285] In an embodiment, when R 5B When replaced, R 5B by one or more 5B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5B.1 When the substituent is substituted, R 5B.1 Substituents are formed by one or more R 5B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5B.2 When the substituent is substituted, R 5B.2 Substituents are formed by one or more R 5B.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5B R 5B.1 R 5B.2 and R 5B.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5B R 5B.1 R 5B.2 and R 5B.3 .

[0286] In the embodiments, when R is bonded to the same nitrogen atom 5A and R 5BWhen substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 5A.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5A.1 When the substituent is substituted, R 5A.1 Substituents are formed by one or more R 5A.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5A.2 When the substituent is substituted, R 5A.2 Substituents are formed by one or more R 5A.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5A.1 R 5A.2 and R 5A.3 The values ​​corresponding to R are respectively WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5A.1 R 5A.2 and R 5A.3 .

[0287] In the embodiments, when R is bonded to the same nitrogen atom 5A and R 5B When substituents are optionally joined to form the substituted moiety (e.g., a substituted heterocyclic alkyl or a substituted heteroaryl), the moiety is formed by one or more R groups. 5B.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5B When the .1 substituent is substituted, R 5B .1 Substituents are formed by one or more R 5B.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5B.2 When the substituent is substituted, R 5B .2 Substituents are formed by one or more R 5B The .3 indicates a third substituent substitution, as defined in the "First Substituent" section above. In the above embodiments, R 5B.1 R 5B .2 and R 5B The values ​​of .3 correspond to R respectively. WW 1. R WW.2 and RWW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5B.1 R 5B.2 and R 5B.3 .

[0288] In an embodiment, when R 5C When replaced, R 5C By one or more R 5C.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5C.1 When the substituent is substituted, R 5C.1 Substituents are formed by one or more R 5C.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5C.2 When the substituent is substituted, R 5C.2 Substituents are formed by one or more R 5C.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5C R 5C.1 R 5C.2 and R 5C.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5C R 5C.1 R 5C.2 and R 5C.3 .

[0289] In an embodiment, when R 5D When replaced, R 5D By one or more R 5D.1 The first substituent substitution is indicated as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5D.1 When the substituent is substituted, R 5D.1 Substituents are formed by one or more R 5D.2 The second substituent is indicated by substitution as described in the definition section of the "First Substituent" description above. In an embodiment, when R 5D.2 When the substituent is substituted, R 5D.2Substituents are formed by one or more R 5D.3 The third substituent substitution is as defined in the "First Substituent" section above. In the above embodiments, R 5D R 5D.1 R 5D.2 and R 5D.3 The values ​​corresponding to R are respectively WW R WW.1 R WW.2 and R WW.3 The value of is as described in the definition section of the description of the "first substituent" above, where R WW R WW.1 R WW.2 and R WW.3 Corresponding to R respectively 5D R 5D.1 R 5D.2 and R 5D.3 .

[0290] In the embodiments, the compound is ( Figure 1 (First line, first compound). In the examples, the compound is... ( Figure 1 (First row, second compound). In the examples, the compound is... ( Figure 1 (First row, third compound). In the examples, the compound is... ( Figure 1 (First row, fourth compound). In the examples, the compound is... ( Figure 1 (First row, fifth compound). In the examples, the compound is... ( Figure 1 (First row, sixth compound). In the examples, the compound is... ( Figure 1 (First row, seventh compound). In the examples, the compound is... ( Figure 1 (First row, eighth compound). In the examples, the compound is... ( Figure 1 (Second line, first compound). In the examples, the compound is... ( Figure 1 (Second line, second compound). In the examples, the compound is... ( Figure 1 (Second row, third compound). In the examples, the compound is... ( Figure 1 (Second row, fourth compound). In the examples, the compound is... ( Figure 1 (Second row, fifth compound). In the examples, the compound is... ( Figure 1 (Second line, sixth compound). In the examples, the compound is... ( Figure 1 (Second line, seventh compound). In the examples, the compound is... ( Figure 1 (Second line, eighth compound). In the examples, the compound is... ( Figure 1 (Third line, first compound). In the examples, the compound is... ( Figure 1 (Third line, second compound). In the examples, the compound is... ( Figure 1 (Third line, third compound). In the examples, the compound is...

[0291] In the examples, the compound is not: In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not In the embodiments, the compound is not

[0292] In the embodiments, the compound binds (e.g., non-covalently) Nurr1 (e.g., human Nurr1). In the embodiments, the compound binds (e.g., non-covalently) the active site of Nurr1 (e.g., human Nurr1). In the embodiments, the compound binds (e.g., non-covalently) the allosteric site of Nurr1 (e.g., human Nurr1).

[0293] In the embodiments, the compound (e.g., described herein) is a positive allosteric modulator. In the embodiments, the compound (e.g., described herein) is a negative allosteric modulator.

[0294] In the embodiments, the compound contacts the amino acid corresponding to Arg515 of human Nurr1 (e.g., SEQ ID NO:1). In the embodiments, the compound contacts the amino acid corresponding to Arg563 of human Nurr1 (e.g., SEQ ID NO:1). In the embodiments, the compound contacts the amino acid corresponding to Glu445 of human Nurr1 (e.g., SEQ ID NO:1). In the embodiments, the compound contacts the amino acid corresponding to His516 of human Nurr1 (e.g., SEQ ID NO:1).

[0295] In the embodiments, the compound stabilizes the Nurr1 monomer. In the embodiments, the compound stabilizes the Nurr1 homodimer. In the embodiments, the compound stabilizes the head-to-tail Nurr1 homodimer. In the embodiments, the compound stabilizes the Nurr1 heterodimer. In the embodiments, the Nurr1 heterodimer is a heterodimer having RXRα.

[0296] In some embodiments, the compound contacts the Nurr1 monomer. In some embodiments, the compound contacts the Nurr1 homodimer. In some embodiments, the compound contacts the head-to-tail Nurr1 homodimer. In some embodiments, the compound contacts the Nurr1 heterodimer. In some embodiments, the Nurr1 heterodimer is a heterodimer having RXRα.

[0297] In some embodiments, the compound is linked to a Nurr1 monomer. In some embodiments, the compound is linked to a Nurr1 homodimer. In some embodiments, the compound is linked to a head-to-tail Nurr1 homodimer. In some embodiments, the compound is linked to a Nurr1 heterodimer. In some embodiments, the Nurr1 heterodimer is a heterodimer having RXRα.

[0298] In some embodiments, the compound prevents the formation of Nurr1:RXR heterodimers. In some embodiments, the compound inhibits the formation of Nurr1:RXR heterodimers. In some embodiments, the compound linked to Nurr1 inhibits the linking of the resulting compound:Nurr1 complex to RXR.

[0299] In some embodiments, the compound connects Nurr1 and induces Nurr1 to connect with an NBRE, NuRE, or DR-5 responsive element. In some embodiments, the compound connects Nurr1 and induces Nurr1 to connect with an NBRE. In some embodiments, the compound connects Nurr1 and induces Nurr1 to connect with a NuRE. In some embodiments, the compound connects Nurr1 and induces Nurr1 to connect with a DR-5 responsive element.

[0300] In the embodiments, the compound may be used as a comparative compound. In the embodiments, the comparative compound may be used to evaluate the activity of the test compound as described in the assays presented herein (e.g., in the Examples section, figures, or tables).

[0301] In the embodiments, the compound is a compound as described herein and is included in the embodiments. In the embodiments, the compound is a compound described herein (e.g., in the Examples section, Figures, Tables, or Claims).

[0302] III. Pharmaceutical Composition

[0303] In one aspect, a pharmaceutical composition is provided comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0304] In some embodiments, the pharmaceutical composition comprises an effective amount of the compound. In others, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0305] In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating neurodegenerative diseases. In an embodiment, the neurodegenerative disease is Parkinson's disease. In an embodiment, the second agent is a Parkinson's disease drug, such as levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromoergotide, pergolide, pramipexole, ropinirole, trihexyphenidyl, bentropin, biperiden, pracycline, tocapone, or entacapone. In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0306] In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating inflammatory diseases, such as acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac sodium, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0307] In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anticancer agent.

[0308] IV. Instructions for Use

[0309] In one aspect, a method is provided for treating a disease in the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons in a subject with this need, the method comprising administering to the subject with this need a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In embodiments, the method does not involve administering compounds other than those described herein for treating (e.g., effectively treating) a disease in the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons. In embodiments, the compound for treating (e.g., effectively treating) a disease in the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons is a compound for treating (e.g., effectively treating) Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In embodiments, the compound for treating (e.g., effectively treating) a disease in the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons is a compound for treating (e.g., effectively treating) cancer (e.g., an anticancer compound).

[0310] In the embodiments, the diseases associated with the dysregulation and / or degeneration of dopaminergic neurons are Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), schizophrenia, or drug addiction. In the embodiments, the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is Parkinson's disease. In the embodiments, the disease is Alzheimer's disease. In the embodiments, the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is multiple sclerosis. In the embodiments, the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is amyotrophic lateral sclerosis (ALS). In the embodiments, the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is schizophrenia. In the embodiments, the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is drug addiction.

[0311] In this embodiment, the disease associated with the dysfunction and / or degeneration of dopaminergic neurons is cancer. In this embodiment, the disease associated with the dysfunction and / or degeneration of dopaminergic neurons is an eye disease. In this embodiment, the eye disease is cataract. In this embodiment, the eye disease is congenital cataract.

[0312] In one aspect, a method is provided for treating neurodegenerative diseases in subjects with such need, the method comprising administering to the subject with such need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0313] In this embodiment, the disease is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), schizophrenia, or drug addiction. In this embodiment, the disease is Parkinson's disease. In this embodiment, the disease is Alzheimer's disease. In this embodiment, the disease is multiple sclerosis. In this embodiment, the disease is amyotrophic lateral sclerosis (ALS). In this embodiment, the disease is schizophrenia. In this embodiment, the disease is drug addiction.

[0314] In one aspect, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject with this need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0315] In the 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.

[0316] In one aspect, a method is provided for treating an eye disease in a subject with this need, the method comprising administering to the subject with this need a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In an embodiment, the eye disease is cataract. In an embodiment, the eye disease is congenital cataract.

[0317] In one aspect, a method for reducing inflammation in a subject with this need is provided, the method comprising administering to the subject with this n...

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease of the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons in a subject with this need, 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, and wherein the compound has the formula (Ia) or (IIa); in R 2 It is hydrogen; R 3 For halogens, hydrogen, -CN, -N(O) m3 -NR 3A R 3B -OR 3D or unsubstituted C1-C8 alkyl groups; R 4 It can be hydrogen, halogen, -CN, or -N(O). m4 -NR 4A R 4B -C(O)NR 4A R 4B -OR 4D or unsubstituted C1-C8 alkyl groups; R 5 It is hydrogen; R 3A R 3B R 3D R 4A and R 4D It is independently hydrogen or an unsubstituted C1-C8 alkyl group; R 4B Hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C6-C 10 Aryl, or substituted or unsubstituted 5-10 heteroaryl; and m3 and m4 are each 2.

2. The use according to claim 1, wherein the compound has the formula (Ib) or (IIb).

3. The use according to claim 1, wherein R 3 It can be hydrogen, halogen, -CN, -OH, -NH2, -NO2, unsubstituted methoxy, or unsubstituted C1-C8 alkyl.

4. The use according to claim 1, wherein R 3 It is a halogen.

5. The use according to claim 4, wherein R 3 It can be –Br or –Cl.

6. The use according to claim 1, wherein R 4 It is hydrogen, halogen, -CN, -OH, -NH2, -NO2, unsubstituted methoxy, or unsubstituted C1-C8 alkyl.

7. The use according to claim 1, wherein R 4 It is halogen.

8. The use according to claim 7, wherein R 4 It is –Br or –Cl.

9. The use according to any one of claims 1-8, wherein the disease associated with the dysregulation and / or degeneration of dopaminergic neurons is Parkinson's disease.

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