COMPOUNDS AND METHODS FOR PROMOTING STRESS RESISTANCE

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/239,244 filed October 8, 2015 and U.S. Provisional Application No. 62/245,812 filed October 23, 2015 which are incorporated herein by reference in their entirety and for all purposes.

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

[0002] This invention was made with government support under Grant No. R01 AG044515 awarded by The National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] Increased resistance to environmental stress at the cellular level is often correlated with organismal longevity, as seen for cells from long-lived mutants and wild animal species.

Likewise, in many experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. No compound, to our knowledge, has been shown to extend lifespan, or healthy lifespan, of humans. Only a few small molecules, including resveratrol, metformin and rapamycin, are known to extend lifespan of experimental animals. Provided herein are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

[0004] In an aspect is provided a method of increasing resistance to cellular stress in a subject, the method including administering an effective amount of a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments) to the subject.

[0005] In an aspect is provided a method of increasing lifespan in a subject in need, the method including administering a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments) to the subject.

[0006] In an aspect is provided a method of treating an age associated disease in a subject in need, the method comprising administering a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments) to the subject. [0007] In an aspect is provided a method of inhibiting proliferation of cancer cells, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

[0008] In an aspect is provided a method of inhibiting survival of cancer cells, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

[0009] In an aspect is provided a method of increasing the level of FOX03 activity in a cell, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments). [0010] In an aspect is provided a method of increasing the level of RF2 activity in a cell, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

[0011] In an aspect is provided a method of increasing the level of autophagy in a cell, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

[0012] In an aspect is provided a method of reducing the level of mTOR activity in a cell, the method including contacting the cell with a stress resistance increasing compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

[0013] In another aspect is provided a pharmaceutical composition including a

pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. in an aspect, embodiment, example, figure, table, or claim).

[0014] In another aspect is provided a method of treating aging in a subject in need of such treatment, the method including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject.

[0015] In another aspect is provided a compound as described herein for use as a medicament. In embodiments, the medicament may be useful for treating aging in a subject in need of such treatment. In embodiments, the use may include administering a compound, or a

pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1. Small molecules do not quench H ₂ O ₂ . Amplex Red assay indicated that none of the 54 repurchased molecules quenches H ₂ O ₂ (n = 4, technical replicates). Catalase (0.02U and 0.04U) MP (Biomedicals), as the control, substantially reduced the absorbance. Molecules tested in this assay (as identified on the x axis) are in order left to right: Control, 0.02 U catalase, 0.04U catalase, Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2E, Gr- 3A, Gr-3B, Gr-3C, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 03, 04, 05, 06, 07, 08, 09, O10, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, and 027, respectively. [0017] FIG. 2. Certain small molecules inhibit the activity of human PARPl . Two known PARP inhibitors, including PJ-34 (Tocris) (IC ₅₀ : ~20 nM) and MK-4827 (IC ₅₀ : ~3.8 nM), were used as the controls at 200 nM and 40 nM, respectively. 11 of the 54 repurchased molecules inhibited PARPl . Note that all the molecules from Group 2, plus the 4-amino-l,8-naphthalimide PARP inhibitor analogs 07 and 022, were confirmed as PARP inhibitors by this assay.

Molecules tested in this assay (as identified on the x axis) are in order left to right: Control, PJ34, MK-4827, Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr- 6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, O10, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, and 027, respectively.

[0018] FIG. 3. Knockdown efficiencies for F0X03 and NRF2 in WI-38 cells were analyzed. siRNA oligos for F0X03 or NRF2 were used to transfect WI-38 cells (10 nM final

concentration) and then analyzed by qPCR for they ability to knock down the expression of target genes. Upon -36 hrs of transfection (the time point to start small molecule incubation), the knockdown efficiency is typically -50% to 60% for F0X03 (-70% at 60 hrs or longer), and -80% to 90% for NRF2 (-90% at 60 hrs or longer). Representative data from at least 3 independent transfection experiments are shown (72 hrs of transfection, normalized to B2M, error bar is for standard deviation for all the figures, n = 3. ** P < 0.01, Student's t-test). See Table 6 for additional data. [0019] FIG. 4A-4D. Certain small molecules attenuated poly-Q toxicity in a cellular model of Huntington's. 54 repurchased molecules (initially at 10 μΜ) were introduced to neuron-like PC12 cells that express poly(Q)-tagged GFP (Q103-Htt-EGFP), and candidates showing protective effects were further retested at multiple doses (2.5 μΜ, 5 μΜ, 10 μΜ and 20 μΜ) to address their effects on cell viability upon the induction of toxic poly(Q)103-Htt-EGFP aggregates. The parental PC 12 cells (WT) that do not express poly(Q) were used as the control to demonstrate the specificity of protective effects. Note that induction of poly(Q)103-Htt-EGFP reduced cell viability substantially (right, bottom panel), and several small molecules produced modest yet significant effects to enhance viability, (n = 6. Student's t-test, *** P < 0.001; ** P < 0.01; * < 0.05).

[0020] FIG. 5. Long-term effects of small molecules on cell viability. 38 "core set" small molecules were analyzed and confirmed, in two batches (a) 31 and (b) 2, to promote H ₂ 0 ₂ - resistance of WI-38 cells. Their effects on cell viability were then analyzed upon prolonged incubation (up to 5 days), by measuring ATP levels (n =6 for each molecule). ATP levels were marked on the y axis for day 0 - 24 hrs after seeding, before adding small molecules. Note that rapamycin reduced the ATP level by -50% on day 5 of treatment. At least 11 small molecules also reduced the ATP level by more than 30%, and unlike rapamycin, most of them showed cell toxicity (by cell morphology examination and cell death-imaging). See Table 13 for details. [0021] FIG. 6A-6B. Small molecules extend C. elegans ' lifespan. Small molecules were analyzed for their ability to extend the lifespan of C. elegans. Given the caveat of lifespan assay variations for C. elegans studies, different culture conditions (in liquid and on plate, food concentrations, live or UV- & kanamycin-treated bacteria) were introduced in the assays.

Molecules were analyzed at the highest dose (-60 μΜ, 0.3% DMSO, as higher DMSO concentration has been reported to extend lifespan of C. elegans). Two small molecules that consistently extended lifespan in multiple independent assays are shown. (FIG. 6A) wild-type animals, in liquid, with FuDR to block progeny production, 20°C constant. Control, 21.1 ± 0.5 (mean ± SD), n = 77/81 (observed/total); Gr-4D -treated, 31.9 ± 1.1 (-51.2% increase), n = 41/41, P < 0.001 (log-rank test); 013-treated, 28.1 ± 1.1 (-33.2% increase), n = 36/36, P < 0.001. (FIG. 6 ) (fer-15(b26)II rol-6(su!006)II; fem-l(hcl7)IV) temperature-sensihwe rollers, on plate, without FuDR, 25°C then room temperature (~22°C). Control, 18.4 ± 0.4, n = 65/80; Gr-4D-treated, 22.5 ± 0.4 (~% increase), n = 74/95, P < 0.001 (log-rank test); 013- treated, 23.4 ± 0.4 (~% increase), n = 72/76, P < 0.001. See Table 12 for details.

DETAILED DESCRIPTION

[0022] Applicants have screened a library of 104,121 small molecules in a human primary fibroblast cell line and identified 61 that increased oxidative stress resistance. Thirty hits fall into seven structurally related chemical groups, suggesting that they may promote stress resistance by acting on common targets. Three small molecules increased C. elegans ' stress resistance, and at least twelve extended their lifespan (from -10% to -50%). In human cells, some small molecules affect the activities of FOX03, RF2, and/or mTOR, proteins whose activation or inhibition can extend lifespan in model organisms. This new strategy as suggested by basic aging research may provide small molecules that extend healthy, youthful lifespan and combat age- related diseases.

A. DEFINITIONS

[0023] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0024] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH ₂ 0- is equivalent to -OCH ₂ -.

[0025] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Ci ₀ means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,

(cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.

[0026] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited

by, -CH ₂ CH ₂ CH ₂ CH ₂ -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0027] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched non-cyclic chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH ₂ -CH ₂ -0-CH ₃ , -CH ₂ -CH ₂ - H-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(0)-CH ₃ , -CH ₂ -CH ₂ -S(0) ₂ -CH ₃ , -CH=CH-0-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH- N(CH ₃ )-CH ₃ , -0-CH ₃ , -0-CH ₂ -CH ₃ , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH ₂ - H-OCH ₃ and -CH ₂ -0-Si(CH ₃ ) ₃ . A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.

[0028] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH ₂ -CH ₂ -S-CH ₂ -CH ₂ - and -CH ₂ -S-CH ₂ -CH ₂ - H-CH ₂ -. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0) ₂ R'- represents both -C(0) ₂ R'- and -R'C(0) ₂ -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0) R', -NR'R", -OR, -SR, and/or -S0 ₂ R. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive.

Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0029] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of "alkyl" and

"heteroalkyl," respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non- hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-l,2, dione, lH-l,2,4-triazolyl-5(4H)- one, 4H-l,2,4-triazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3 - yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. A heterocycloalkyl moiety may include one ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include two optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include three optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include four optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include five optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include up to 8 optionally different ring heteroatoms (e.g., O, N, S, Si, or P).

[0030] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C ₄ )alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0031] The term "acyl" means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0032] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1- pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non- limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroaryl ene. A heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S). A heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S). An aryl moiety may have a single ring. An aryl moiety may have two optionally different rings. An aryl moiety may have three optionally different rings. An aryl moiety may have four optionally different rings. A heteroaryl moiety may have one ring. A heteroaryl moiety may have two optionally different rings. A heteroaryl moiety may have three optionally different rings. A heteroaryl moiety may have four optionally different rings. A heteroaryl moiety may have five optionally different rings.

[0033] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring

heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring

heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein. [0034] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0035] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(0 ₂ )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0036] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0037] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR, =0, =NR,

=N-OR, - R'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, -C0 ₂ R, -CO R'R", -OC(0)NR 'R", - R"C(0)R, - R'-C(0) R"R", - R"C(0) ₂ R, -NR-C( R'R"R")= R"", - R-C( R'R")= R "', -S(0)R', -S(0) ₂ R', -S(0) ₂ R'R", - RS0 ₂ R, - R'NR'R", -O R'R",

- R'C=(0) R" R"'R"", -CN, -N0 ₂ , in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R", and R"" each preferably

independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present. When R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, - R'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF ₃ and -CH ₂ CF ₃ ) and acyl (e.g., -C(0)CH ₃ , -C(0)CF ₃ , -C(0)CH ₂ OCH ₃ , and the like).

[0038] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for

example: -OR, -NR'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, -C0 ₂ R, -CONR'R", -OC (0)NR'R", -NR"C(0)R, -NR'-C(0)NR"R", -NR"C(0) ₂ R, -NR-C(NR'R"R")=NR"", -NR-C(NR' R")=NR"', -S(0)R, -S(0) ₂ R, -S(0) ₂ NR'R", -NRS0 ₂ R, -NR'NR"R", -ONR'R",

-NR'C=(0)NR"NR"'R"", -CN, -N0 ₂ , -R, -N ₃ , -CH(Ph) ₂ , fluoro(Ci-C ₄ )alkoxy, and fluoro(Ci- C ₄ )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.

[0039] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure. [0040] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') _q -U-, wherein T and U are

independently -NR-, -0-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.

Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH ₂ ) _r -B-, wherein A and B are independently -CRR'-, -0-, - R-, -S-, -S(O) -, -S(0) ₂ -, -S(0) ₂ R'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the

formula -(CRR') _S -X'- (C"R"R"') _d -, where s and d are independently integers of from 0 to 3, and X' is -0-, - R'-, -S-, -S(O)-, -S(0) ₂ -, or -S(0) ₂ R'-. 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.

[0041] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0042] A "substituent group," as used herein, means a group selected from the following moieties:

(A) oxo, halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, - S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, -NHC= (O)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(i) oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -

S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(a) oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, - S0 ₄ H, -S0 ₂ H ₂ , - H H ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, -NHC= (O)H, - HC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted

heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, - S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, - NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0043] A "size-limited substituent" or " size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0044] A "lower substituent" or " lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C ₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0045] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0046] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted Ci-C ₂ o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Ci ₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-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 heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -Ci ₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0047] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C ₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Ci ₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C ₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -Cio arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0048] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of

Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0049] Thus, the compounds of the present invention may exist as salts, such as with

pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0050] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0051] Provided herein are agents (e.g. compounds, drugs, therapeutic agents) that may be in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents). Additionally, prodrugs can be converted to agents (e.g. compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment. Prodrugs described herein include compounds that readily undergo chemical changes under select physiological conditions to provide agents (e.g. compounds, drugs, therapeutic agents) to a biological system (e.g. in a subject, in a cancer cell, in the extracellular space near a cancer cell).

[0052] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0053] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0054] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0055] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0056] The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0057] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0058] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0059] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention.

[0060] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0061] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0062] The terms "a" or "an," as used in herein means one or more. In addition, the phrase

"substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C ₁ -C ₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C ₁ -C ₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R- substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.

[0063] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0064] The terms "treating" or "treatment" refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, include prevention of an injury, pathology, condition, or disease.

[0065] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g.

achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce protein function, reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug or prodrug is an amount of a drug or prodrug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman,

Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0066] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g. cancer) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a disease associated with cellular stress may be treated with an agent (e.g. compound as described herein) effective for increasing resistance to cellular stress. [0067] "Control" or "control experiment" or "standard control" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. [0068] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme. [0069] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor (e.g. antagonist) interaction means negatively affecting (e.g. decreasing) the level of activity or function of the protein relative to the level of activity or function of the protein in the absence of the inhibitor. In some embodiments inhibition refers to reduction of a disease or symptoms of disease. Thus, inhibition may include, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating,

desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.

[0070] As defined herein, the term "activation", "activate", "activating" and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g.

increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator (e.g. compound described herein). Thus, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein.

[0071] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. [0072] "Anti-cancer agent" or "anti-cancer drug" is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anticancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSKl 120212/ 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., mechloroethamine,

cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum -based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),

adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan), 5-aza-2'-deoxycytidine, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino- 17-Demethoxygeldanamycin (17-AAG), bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen, antiestrogen; antisense oligonucleotides; apoptosis gene modulators; apoptosis regulators; arginine deaminase; BCR/ABL antagonists; beta lactam derivatives; bFGF inhibitor; bicalutamide; camptothecin derivatives; casein kinase inhibitors (ICOS); clomifene analogues; cytarabine dacliximab; dexamethasone; estrogen agonists; estrogen antagonists;

etanidazole; etoposide phosphate; exemestane; fadrozole; finasteride; fludarabine;

fluorodaunorunicin hydrochloride; gadolinium texaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors; MIF inhibitor; mifepristone;

mismatched double stranded RNA; monoclonal antibody; mycobacterial cell wall extract; nitric oxide modulators; oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogen activator inhibitor; platinum complex; platinum compounds; prednisone; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; ribozymes; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; stem cell inhibitor; stem-cell division inhibitors; stromelysin inhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;

telomerase inhibitors; thyroid stimulating hormone; translation inhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists; steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate,

fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette- Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti- CD20 monoclonal antibody conjugated to ^U1 ln, ⁹⁰ Y, or ¹³ \ etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5- nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP- 724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin), carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogen mustards (such as chlorambucil and melphalan), dolastatin and dolastatin analogs (including auristatins: eg. monomethyl auristatin E), anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.), duocarmycins and duocarmycin analogs, enediynes (such as neocarzinostatin and calicheamicins), leptomycin derivaties, maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate, mitomycin C, taxoids, vinca alkaloids (such as vinblastine and vincristine), epothilones (e.g. epothilone B), camptothecin and its clinical analogs topotecan and irinotecan, or the like.

[0073] "Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. [0074] "Patient" or "subject in need thereof or "subject" refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In some embodiments, a subject is human.

[0075] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. [0076] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.

Exemplary cancers that may be treated with a compound or method provided herein include cancer of the prostate, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples may include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0077] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,

hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,

promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0078] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0079] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma. [0080] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair- matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma

mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0081] The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.

[0082] The term "aberrant" as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0083] "Nucleic acid" or "oligonucleotide" or "polynucleotide" or grammatical equivalents used herein means at least two nucleotides covalently linked together. The term "nucleic acid" includes single-, double-, or multiple-stranded DNA, RNA and analogs (derivatives) thereof. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.

[0084] A particular nucleic acid sequence also encompasses "splice variants." Similarly, a particular protein encoded by a nucleic acid encompasses any protein encoded by a splice variant of that nucleic acid. "Splice variants," as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different (alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition.

[0085] "Polypeptide," "peptide," and "protein" are used herein interchangeably and mean any peptide-linked chain of amino acids, regardless of length or post-translational modification. As noted below, the polypeptides described herein can be, e.g., wild-type proteins, biologically- active fragments of the wild-type proteins, or variants of the wild- type proteins or fragments. Variants, in accordance with the disclosure, can contain amino acid substitutions, deletions, or insertions. The substitutions can be conservative or non-conservative.

[0086] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other

pharmaceutical excipients are useful in the present invention.

[0087] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0088] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent). The compound of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation, to increase degradation of a prodrug and release of the drug, detectable agent). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623- 645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857- 863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13 :293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, ^w. J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles. [0089] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) may be contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of cancer). Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein. [0090] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g. symptoms of cancer), kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art. [0091] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0092] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0093] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

[0094] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0095] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent. [0096] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0097] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for cancer such as radiation or surgery.

[0098] The term "EGFR" refers to epidermal growth factor receptor. The term "EGFR" may refer to the nucleotide sequence or protein sequence of human EGRF (e.g., Entrez 1956, UniProt P00533, RefSeq M_005228, GL41327737, RefSeq P_005219, and/or GL29725609). The term "EGFR" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "EGFR" is wild-type EGFR. In some embodiments, "EGFR" is one or more mutant forms. The term "EGFR" XYZ refers to a nucleotide sequence or protein of a mutant EGFR wherein the Y numbered amino acid of EGFR that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, an EGFR is the human EGFR. In embodiments, the EGFR has the nucleotide sequence corresponding to reference number GL41327737. In embodiments, the EGFR has the nucleotide sequence corresponding to RefSeq M 005228.3. In embodiments, the EGFR has the protein sequence corresponding to RefSeq P 005219.2. In embodiments, the EGFR has the protein sequence corresponding to GL29725609.

[0099] The term "PIK3CA" or "pi 10a protein" refers to phosphatidylinositol-4,5-bisphosphate 3 -kinase, catalytic subunit alpha. The term "PIK3CA" refers to the nucleotide sequence or protein sequence of human PIK3CA (e.g., Entrez 5290, UniProt P42336, RefSeq M 006218, GI: 54792081, RefSeq P_006209, and/or GL54792082). The term "PIK3CA" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "PIK3CA" is wild-type PIK3CA. In some embodiments, "PIK3CA" is one or more mutant forms. The term "PIK3CA" XYZ refers to a nucleotide sequence or protein of a mutant PIK3CA wherein the Y numbered amino acid of PIK3CA that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, a PIK3CA is the human PIK3CA. In embodiments, the PIK3CA has the nucleotide sequence corresponding to reference number GI: 54792081. In embodiments, the PIK3CA has the nucleotide sequence corresponding to RefSeq M 006218.2. In embodiments, the PIK3CA has the protein sequence corresponding to RefSeq P 006209.2. In embodiments, the PIK3CA has the protein sequence corresponding to GI: 54792082.

[0100] The term "RB 1" or "pRb" or "RB" refers to the retinoblastoma protein. The term "RBI" refers to the nucleotide sequence or protein sequence of human RBI (e.g., Entrez 5925, UniProt P06400, RefSeq NM 000321, GI: 108773786, RefSeq P_000312, and/or GI:

108773787). The term "RBI" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "RBI" is wild-type RBI . In some embodiments, "RBI" is one or more mutant forms. The term "RBI" XYZ refers to a nucleotide sequence or protein of a mutant RB I wherein the Y numbered amino acid of RBI that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, an RBI is the human RBI . In embodiments, the RB I has the nucleotide sequence corresponding to reference number GI: 108773786. In embodiments, the RBI has the nucleotide sequence corresponding to RefSeq M 000321.2. In embodiments, the RBI has the protein sequence corresponding to RefSeq P 000312.2. In embodiments, the RBI has the protein sequence corresponding to GI: 108773787. [0101] The term "TP53" refers to tumor protein p53. The term "TP53" refers to the nucleotide sequence or protein sequence of human RBI (e.g., Entrez 7157, UniProt P04637, RefSeq

M_000546, GI: 371502114, RefSeq P_000537, and/or GI: 120407068). The term "TP53" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "TP53" is wild-type TP53. In some embodiments, "TP53" is one or more mutant forms. The term "TP53" XYZ refers to a nucleotide sequence or protein of a mutant TP53 wherein the Y numbered amino acid of TP53 that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, a TP53 is the human TP53. In embodiments, the TP53 has the nucleotide sequence corresponding to reference number GL371502114. In embodiments, the TP53 has the nucleotide sequence corresponding to RefSeq M 000546.5. In embodiments, the TP53 has the protein sequence corresponding to RefSeq P 000537.3. In embodiments, the TP53 has the protein sequence corresponding to GI: 120407068. [0102] The term " RF2" or "NFE2L2" refers to the protein nuclear factor erythroid 2-related factor 2. The term " RF2" may refer to the nucleotide sequence or protein sequence of human RF2 (e.g., Entrez 4780, Uniprot Q16236, RefSeq M_00001145412, GI: 926657643, RefSeq P_001138884, and/or GI: 224028257). The term " RF2" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, " RF2" is wild-type RF2. In some embodiments, " RF2" is one or more mutant forms. The term "NRF2" XYZ refers to a nucleotide sequence or protein of a mutant RF2 wherein the Y numbered amino acid of RF2 that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, an RF2 is the human RF2. In embodiments, the RF2 has the nucleotide sequence corresponding to reference number GL926657643. In embodiments, the RF2 has the nucleotide sequence corresponding to RefSeq

M_001145412.3. In embodiments, the RF2 has the protein sequence corresponding to RefSeq P 001138884.1. In embodiments, the RF2 has the protein sequence corresponding to GL224028257. [0103] The term "FOX03" or "FOX03a" refers to the protein Forkhead box 03. The term "FOX03" may refer to the nucleotide sequence or protein sequence of human FOX03 (e.g., Entrez 2309, Uniprot 043524, RefSeq M_001455, GI: 146260266, RefSEQ P_001446, and/or GI: 4503739). The term "FOX03" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "FOX03" is wild- type FOX03. In some embodiments, "FOX03" is one or more mutant forms. The term

"FOX03" XYZ refers to a nucleotide sequence or protein of a mutant FOX03 wherein the Y numbered amino acid of FOX03 that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, an FOX03 is the human FOX03. In

embodiments, the FOX03 has the nucleotide sequence corresponding to reference number GI: 146260266. In embodiments, the FOX03 has the nucleotide sequence corresponding to

RefSeq M 001455.3. In embodiments, the FOX03 has the protein sequence corresponding to RefSeq P 001446.1. In embodiments, the FOX03 has the protein sequence corresponding to GI: 4503739.

[0104] The term "mTOR" refers to the protein "mechanistic target of rapamycin

(serine/threonine kinase)" or "mammalian target of rapamycin". The term "mTOR" may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot

P42345, RefSeq M_004958, or RefSeq P_004949). The term "mTOR" includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, "mTOR" is wild-type mTOR. In some embodiments, "mTOR" is one or more mutant forms. The term "mTOR" XYZ refers to a nucleotide sequence or protein of a mutant mTOR wherein the Y numbered amino acid of mTOR that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant. In embodiments, an mTOR is the human mTOR. In embodiments, the mTOR has the nucleotide sequence corresponding to reference number GL206725550. In embodiments, the mTOR has the nucleotide sequence corresponding to RefSeq M 004958.3. In embodiments, the mTOR has the protein sequence corresponding to reference number GL4826730. In embodiments, the mTOR has the protein sequence

corresponding to RefSeq P 004949.1

[0105] In embodiments, the mTOR is a mutant mTOR. In embodiments, the mutant mTOR is associated with a disease that is not associated with wildtype mTOR. In embodiments, the mTOR includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the sequence above.

[0106] "Analog" and "analogue" are used interchangeably and are used in accordance with their plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound, including isomers thereof. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0107] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value.

[0108] As used herein, the term "cellular stress" refers to the decrease in cellular function caused by a stress stimuli (e.g., from an external or internal source) relative to the absence of the stress stimuli. Non-limiting examples of such stimuli ("stressors") are higher and/or lower temperatures than ideal for the proliferation and/or survival of the cell , exposure to oxidizing species, exposure to toxins, radiation, and mechanical damage. Cellular stress encompasses such non-limiting examples as stress due to DNA damage, stress due to RNA damage, stress due to lipid damage, oxidative stress, stress due to mutagens, toxic stress, metabolic stress, and stress due to protein denaturing (e.g., unfolding) and stress due to protein damage (e.g., covalent modification or heavy metal binding). In embodiments cellular stress is associated with a higher level of unfolded proteins compared to the normal level of unfolded proteins under healthy productive conditions (no cellular stress, average cellular stress, baseline cellular stress, or a reduced level of cellular stress). In embodiments, cellular stress is oxidative stress. In embodiments, cellular stress is DNA damage. In embodiments, cellular stress is denatured and/or damaged proteins. In embodiments, cellular stress is associated with exposure to a heavy metal (e.g. cadmium).

[0109] As used herein, the term "oxidative stress" is cellular stress caused by oxidative species as the stress stimuli. For example oxidative stress refers to an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or cellular damage due to an excess of oxidative species. Non-limiting examples of oxidizing species include superoxide radical, hydroxyl radical, organic hydroperoxide, alkoxy radicals, peroxy radicals, hypochlorous acid, and hydrogen peroxide (Br. J. Exp. Path. (1989) 70, 737- 757).

[0110] The term "longevity" is used in accordance with its plain ordinary meaning and refers to an increased life span caused by the administration of a stress resistance increasing compound relative to the absence of a stress resistance increasing compound. For example, longevity may refer to a long life or the extension of life expectancy beyond an average life expectancy or beyond a predicted life expectancy. A "longevity agent" is an agent (e.g., composition as described herein) capable of extending the life expectancy of a subject in comparison to the life expectancy of the subject in the absence of the agent (Lamming, D. W., et al. (2012). Science (New York, NY), 335(6076), 1638-1643., McCormick, M. A., et al. (2011). Philosophical

Transactions of the Royal Society B: Biological Sciences, 366(1561)). A longevity agent may be capable of inducing one or more anti-aging effects in a subject wherein an aging effect is a condition or symptom of aging normally (e.g., in the absence of the longevity agent) found in a similar subject. Symptoms of aging are well known or may be easily determined by a person having ordinary skill in medicine or the life sciences.

[0111] The term "stress resistance increasing compound" as used herein refers to a compound that is capable of improving cell survival, proliferation, and/or growth relative to the absence of the compound when the cell experiences cellular stress. In embodiments, the stress resistance increasing compound increases the longevity and/or increases the lifespan of a cell. In embodiments, the stress resistance increasing compound increases the longevity and/or increases the lifespan of a subject. In embodiments, the stress resistance increasing compound increases the level of FOX03 activity in a cell. In embodiments, the stress resistance increasing compound increases the level of RF2 activity in a cell. In embodiments, the stress resistance increasing compound inhibits survival of cancer cells. In embodiments, the stress resistance increasing compound reduces the level of mTOR activity in a cell. In embodiments, the stress resistance increasing compound inhibits PARP activity in a cell. In embodiments, the stress resistance increasing compound inhibits SUMO/sentrin specific peptidase (SENP) activity in a cell. In embodiments, the stress resistance increasing compound increases the level of autophagy activity in a cell. In embodiments, the stress resistance increasing compound mitigates (e.g., reduces) cellular stress.

[0112] As used herein, the term "age associated disease" or "aging-associated disease" refers to a disease that occurs more frequently with increasing senescence and/or age. In embodiments, the age associated disease is a cancer, atherosclerosis, neurodegenerative disease, cardiovascular disease, metabolic disease, or inflammatory disease. In embodiments, the neurodegenerative disease is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, or

Huntington's Disease. In embodiments, the metabolic disease is type II diabetes. In

embodiments the cancer is lung cancer. B. COMPOUNDS

0113] In embodiments is provided a compound or a pharmaceutically acceptable salt thereof,

Ring A is aryl or heteroaryl. Ring B is aryl or heteroaryl. R ¹ is independently a halogen, -CX ^X ₃ ,

-CN, -SO _n iR ¹ , -SO _v i R R ⁸ , - HNH ₂ , -ONR R , - HC=(0) HNH ₂ , -NHC=(0) R R ⁸ , -N(0) _m i, - R ⁷ R ⁸ , -C(0)R ⁹ , -C(0)-OR ⁹ , -C(0)NR ⁷ R ⁸ , -OR ¹⁰ , - R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C= (O)R ⁹ , - R ⁷ C(0)-OR ⁹ , - R ⁷ OR ⁹ , -OCXS, -OCHX^, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² is independently a halogen, -CX ² ₃ , -CN, -SOn ₂ R ¹⁴ , -SO _v2 NR ^u R ¹² , -NHNH ₂ , -ONR ^u R ¹² , -NHC=(0)NHNH ₂ , -NHC=(0)NR ^u R ¹² , -N(0) _m2 , -NR ^U R ¹² , -C(0)R ¹³ , -C(0)-OR ¹³ , -C(0)NR ^u R ¹² , -OR ¹⁴ , -NR ^u S0 ₂ R ¹⁴ , -NR ^u C=(0)R ¹³ , -NR ^u C(0)-OR ¹³ , -NR ^u OR ¹³ , -OCX ² ₃ , -OCHX ² 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; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ³ is independently hydrogen, halogen, -CX ³ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(O)- OH, -NHOH, -OCX ³ ₃ , -OCHX ³ 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. R ⁴ is independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ⁴ ₃ , -OCHX ⁴ 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. R ⁵ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ )- to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl. R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX 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; R ⁷ and R ⁸

substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ¹¹ and R ¹² substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. The symbol al is independently an integer from 0 to 7. The symbol bl is independently an integer from 0 to 7. The symbol ml, m2, vl, and v2 are independently 1 or 2. The symbol nl and n2 are independently an integer from 0 to 4. The symbol X, X ¹ , X ² , X ³ , and X ⁴ are independently -CI, -Br, -I, or -F.

[0114] In embodiments, Ring A is aryl, or 5 to 6 membered heteroaryl. In embodiments, Ring A is phenyl. In embodiments, Ring A is 5 to 6 membered heteroaryl. In embodiments, Ring A is 5 membered heteroaryl. In embodiments, Ring A is 6 membered heteroaryl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is phenyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is thienyl. In embodiments, Ring A is napthyl. In embodiments, Ring A is indolyl. In embodiments, Ring A is quinolinyl. In embodiments, Ring A is isoquinolinyl. In embodiments, Ring A is biphenyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is pyrimidyl. In embodiments, Ring A is quinoxalinyl. [0115] In embodiments, Ring A is substituted or unsubstituted pyrazolyl. In embodiments, Ring A is substituted or unsubstituted imidazolyl. In embodiments, Ring A is substituted or unsubstituted oxazolyl. In embodiments, Ring A is substituted or unsubstituted isoxazolyl. In embodiments, Ring A is substituted or unsubstituted thiazolyl. In embodiments, Ring A is substituted or unsubstituted furanyl. In embodiments, Ring A is substituted or unsubstituted pyrrolyl. In embodiments, Ring A is substituted or unsubstituted thienyl. In embodiments, Ring A is substituted pyrazolyl. In embodiments, Ring A is substituted imidazolyl. In embodiments, Ring A is substituted oxazolyl. In embodiments, Ring A is substituted isoxazolyl. In

embodiments, Ring A is substituted thiazolyl. In embodiments, Ring A is substituted furanyl. In embodiments, Ring A is substituted pyrrolyl. In embodiments, Ring A is substituted thienyl. In embodiments, Ring A is unsubstituted pyrazolyl. In embodiments, Ring A is unsubstituted imidazolyl. In embodiments, Ring A is unsubstituted oxazolyl. In embodiments, Ring A is unsubstituted isoxazolyl. In embodiments, Ring A is unsubstituted thiazolyl. In embodiments, Ring A is unsubstituted furanyl. In embodiments, Ring A is unsubstituted pyrrolyl. In embodiments, Ring A is unsubstituted thienyl. In embodiments, Ring A is independently substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, Ring A is independently substituted or unsubstituted 5 or 10 membered heteroaryl. In embodiments, Ring A is unsubstituted benzimidazolyl. In

embodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl. In embodiments,

Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is isothiazolyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is thienyl. In embodiments, Ring A is

independently C ₆ -Cio aryl. In embodiments, Ring A is independently 5 to 10 membered heteroaryl. In embodiments, Ring A is benzimidazolyl. It will be understood that when Ring A is bonded to one or more non-hydrogen R ¹ moieties, then Ring A is substituted. Likewise, it will be understood that when Ring A is not bonded to any R ¹ moieties, or is bonded to R ¹ moieties that are all hydrogen moieties, then Ring A is unsubstituted.

[0116] In embodiments, Ring B is aryl, or 5 to 6 membered heteroaryl. In embodiments, Ring B is phenyl. In embodiments, Ring B is 5 to 6 membered heteroaryl. In embodiments, Ring B is 5 membered heteroaryl. In embodiments, Ring B is 6 membered heteroaryl. In embodiments, Ring B is pyridyl. In embodiments, Ring B is phenyl. In embodiments, Ring B is furanyl. In embodiments, Ring B is thienyl. In embodiments, Ring B is napthyl. In embodiments, Ring B is indolyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is biphenyl. In embodiments, Ring B is thiazolyl. In embodiments, Ring B is pyrimidyl. In embodiments, Ring B is quinoxalinyl.

[0117] In embodiments, Ring B is substituted or unsubstituted pyrazolyl. In embodiments,

Ring B is substituted or unsubstituted imidazolyl. In embodiments, Ring B is substituted or unsubstituted oxazolyl. In embodiments, Ring B is substituted or unsubstituted isoxazolyl. In embodiments, Ring B is substituted or unsubstituted thiazolyl. In embodiments, Ring B is substituted or unsubstituted furanyl. In embodiments, Ring B is substituted or unsubstituted pyrrolyl. In embodiments, Ring B is substituted or unsubstituted thienyl. In embodiments, Ring

B is substituted pyrazolyl. In embodiments, Ring B is substituted imidazolyl. In embodiments,

Ring B is substituted oxazolyl. In embodiments, Ring B is substituted isoxazolyl. In embodiments, Ring B is substituted thiazolyl. In embodiments, Ring B is substituted furanyl. In embodiments, Ring B is substituted pyrrolyl. In embodiments, Ring B is substituted thienyl. In embodiments, Ring B is unsubstituted pyrazolyl. In embodiments, Ring B is unsubstituted imidazolyl. In embodiments, Ring B is unsubstituted oxazolyl. In embodiments, Ring B is unsubstituted isoxazolyl. In embodiments, Ring B is unsubstituted thiazolyl. In embodiments, Ring B is unsubstituted furanyl. In embodiments, Ring B is unsubstituted pyrrolyl. In embodiments, Ring B is unsubstituted thienyl. In embodiments, Ring B is independently hydrogen, substituted or unsubstituted C ₆ -Ci ₀ aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, Ring B is independently substituted or unsubstituted 5 or 10 membered heteroaryl. In embodiments, Ring B is unsubstituted benzimidazolyl. In embodiments, Ring B is pyrazolyl. In embodiments, Ring B is imidazolyl. In embodiments, Ring B is oxazolyl. In embodiments, Ring B is isoxazolyl. In embodiments, Ring B is thiazolyl. In embodiments, Ring B is isothiazolyl. In embodiments, Ring B is furanyl. In embodiments, Ring B is pyrrolyl. In embodiments, Ring B is thienyl. In embodiments, Ring B is

independently C ₆ -Cio aryl. In embodiments, Ring B is independently 5 to 10 membered heteroaryl. In embodiments, Ring B is benzimidazolyl. It will be understood that when Ring B is bonded to one or more non-hydrogen R ² moieties, then Ring B is substituted. Likewise, it will be understood that when Ring B is not bonded to any R ² moieties, or is bonded to R ² moieties that are all hydrogen moieties, then Ring B is unsubstituted. [0118] In embodiments, R ¹ is independently a halogen, -CX , -CN, -SOmR ¹⁰ , -SO _v iNR ⁷ R ⁸ , - HNH ₂ , -O R ⁷ R ⁸ , - HC=(0) HNH ₂ , - HC=(0)NR ⁷ R ⁸ , -N(0) _mb - R ⁷ R ⁸ , -C(0)R ⁹ , -C(0)-OR ⁹ , -C(0) R ⁷ R ⁸ , -OR ¹⁰ , - R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C= (O)R ⁹ , - R ⁷ C(0)-OR ⁹ , - R ⁷ OR ⁹ , -OCX ¹ , -OCHX ^x ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹ is independently unsubstituted C ₁ -C5 alkyl. In embodiments, R ¹ is

independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently unsubstituted Ci- C ₃ alkyl. In embodiments, R ¹ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ¹ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ¹ is independently unsubstituted C ₃ - C ₆ alkyl. In embodiments, R ¹ is independently unsubstituted C ₄ -C6 alkyl. In embodiments, R ¹ is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹ is independently substituted C1-C5 alkyl. In embodiments, R ¹ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently substituted C1-C3 alkyl. In embodiments, R ¹ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ¹ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ¹ is independently substituted C3-C6 alkyl. In embodiments, R ¹ is independently substituted C4-C6 alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 4 to 6 membered

heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹ is independently substituted 6 membered heteroaryl. In embodiments, R ¹ is independently substituted 5 membered heteroaryl. In embodiments, R ¹ is phenyl.

[0119] In embodiments, R ¹ is independently a halogen, -CX , -CN, -SO _n iR ¹⁰ , -SO _v iNR ⁷ R ⁸ , - HNH ₂ , -ONR ⁷ R ⁸ , - HC=(0) HNH ₂ , - HC=(0)NR ⁷ R ⁸ , -N(0) _m i, - R ⁷ R ⁸ , -C(0)R ⁹ , -C(0)-OR ⁹ , -C(0) R ⁷ R ⁸ , -OR ¹⁰ , - R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C= (O)R ⁹ , - R ⁷ C(0)-OR ⁹ , - R ⁷ OR ⁹ ,

1 1 20 20

-OCX 3, -OCHX 2, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl.

[0120] In embodiments, R ¹ is independently a halogen, -CX , -CN, -SO _n iR ¹⁰ , -SO _v iNR ⁷ R ⁸ , -NHNH ₂ , -ONR ⁷ R ⁸ , -NHC=(0)NHNH ₂ , -NHC=(0)NR ⁷ R ⁸ , -N(0) _m i, -NR ⁷ R ⁸ , -C(0)R ⁹ , -C(0)-OR ⁹ , -C(0)NR ⁷ R ⁸ , -OR ¹⁰ , -NR ⁷ S0 ₂ R ¹⁰ , -NR ⁷ C= (O)R ⁹ , -NR ⁷ C(0)-OR ⁹ , -NR ⁷ OR ⁹ ,

1 1 20 20

-OCX 3, -OCHX 2, R -substituted or unsubstituted Ci-C ₆ alkyl, R -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁰ -substituted or unsubstituted C3-C6 cycloalkyl, R ²⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁰ -substituted or unsubstituted phenyl, or R ²⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁰ -substituted or unsubstituted phenyl, or R ²⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is

independently R ²⁰ -substituted Ci-C ₆ alkyl. In embodiments, R ¹ is independently R ²⁰ -substituted C ₁ -C5 alkyl. In embodiments, R ¹ is independently R ²⁰ -substituted C ₁ -C ₄ alkyl. In embodiments,

1 s independently 20 ments, 1 20

R i R -substituted C ₁ -C ₃ alkyl. In embodi R is independently R - substituted C ₁ -C ₂ alkyl. In embodiments, R ¹ is independently R ²⁰ -substituted C ₂ -C ₆ alkyl. In embodiments, R ¹ is independently R ²⁰ -substituted C ₃ -C ₆ alkyl. In embodiments, R ¹ is

independently R ²⁰ -substituted C ₄ -C ₆ alkyl. In embodiments, R ¹ is independently R ²⁰ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹ is independently R ²⁰ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently R ²⁰ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹ is

independently R ²⁰ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹ is independently R ²⁰ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ¹ is independently R ²⁰ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹ is independently R ²⁰ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹ is independently R ²⁰ -substituted 6 membered heteroaryl. In embodiments, R ¹ is independently R ²⁰ - substituted 5 membered heteroaryl. In embodiments, R ¹ is independently R ²⁰ -substituted phenyl.

[0121] In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently -F. In embodiments, R ¹ is independently -CI. In embodiments, R ¹ is independently -Br. In embodiments, R ¹ is independently -I. In embodiments, R ¹ is independently -CF ₃ . In

embodiments, R ¹ is independently -CH ₃ . In embodiments, R ¹ is -SO ₂ H ₂ . In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -OCH ₃ . In embodiments, R ¹ is independently a halogen, -CF ₃ , -S0 ₂ H ₂ , unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C ₂ alkyl. In embodiments, R ¹ is independently -CH ₂ CH ₃ . In embodiments, R ¹ is independently -CH ₃ or - OH.

[0122] In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -SO^R ¹⁴ ,

-SO _v2 R ^u R ¹² , - HNH ₂ , -O R ^u R ¹² , - HC=(0)NHNH ₂ , - HC=(0) R ^u R ¹² , -N(0) _m2 ,

- R ^U R ¹² , -C(0)R ¹³ , -C(0)-OR ¹³ , -C(0) R ^u R ¹² , -OR ¹⁴ , - R ^u S0 ₂ R ¹⁴ , -NR ^u C=(0)R ¹³ , - R ^u C(0)-OR ¹³ , - R ^u OR ¹³ , -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ² is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ² is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ² is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ² is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ² is independently unsubstituted Ci- C ₂ alkyl. In embodiments, R ² is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ² is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ² is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ² is independently substituted Ci-C ₆ alkyl. In embodiments, R ² is independently substituted Ci-C ₅ alkyl. In embodiments, R ² is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ² is independently substituted Ci-C ₃ alkyl. In embodiments, R ² is independently substituted Ci-C ₂ alkyl. In embodiments, R ² is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ² is substituted C ₃ -C ₆ alkyl. In embodiments, R ² is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ² is substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ² is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ² is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ² is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ² is independently substituted or unsubstituted 4 to 6 membered

heterocycloalkyl. In embodiments, R ² is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ² is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ² is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ² is independently unsubstituted 6 membered heteroaryl. In embodiments, R ² is independently unsubstituted 5 membered heteroaryl. In embodiments, R ² is independently substituted 6 membered heteroaryl. In embodiments, R ² is independently substituted 5 membered heteroaryl. In embodiments, R ² is independently substituted phenyl. In embodiments, R ² is independently unsubstituted phenyl.

[0123] In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -SO„2R ¹⁴ ,

-SO _v2 R ^u R ¹² , - HNH ₂ , -O R ^u R ¹² , - HC=(0)NHNH ₂ , - HC=(0) R ^u R ¹² , -N(0) _m2 , - R ^U R ¹² , -C(0)R ¹³ , -C(0)-OR ¹³ , -C(0) R ^u R ¹² , -OR ¹⁴ , - R ^u S0 ₂ R ¹⁴ , -NR ^u C=(0)R ¹³ , - R ^u C(0)-OR ¹³ , - R ^u OR ¹³ , -OCX ² ₃ , -OCHX ² ₂ , R ²³ - substituted or unsubstituted alkyl, R ²³ - substituted or unsubstituted heteroalkyl, R ²³ -substituted or unsubstituted cycloalkyl, R ²³ - substituted or unsubstituted heterocycloalkyl, R ²³ -substituted or unsubstituted aryl, or R ²³ - substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted or unsubstituted cycloalkyl, R ²³ -substituted or unsubstituted

heterocycloalkyl, R ²³ -substituted or unsubstituted aryl, or R ²³ -substituted or unsubstituted heteroaryl.

[0124] In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -SO^R ¹⁴ ,

-SO _v2 R ^u R ¹² , - HNH ₂ , -O R ^u R ¹² , - HC=(0)NHNH ₂ , - HC=(0) R ^u R ¹² , -N(0) _m2 ,

- R ^U R ¹² , -C(0)R ¹³ , -C(0)-OR ¹³ , -C(0) R ^u R ¹² , -OR ¹⁴ , - R ^u S0 ₂ R ¹⁴ , -NR ^u C=(0)R ¹³ , - R ^u C(0)-OR ¹³ , - R ^u OR ¹³ , -OCX ² ₃ , -OCHX ² ₂ , R ²³ - substituted or unsubstituted Ci-C ₆ alkyl, R ²³ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²³ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²³ - substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²³ - substituted or unsubstituted phenyl, or R ²³ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²³ - substituted or unsubstituted 3 to 6 membered

heterocycloalkyl, R ²³ -substituted or unsubstituted phenyl, or R ²³ - substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ² is independently R ²³ -substituted Ci-C ₆ alkyl. In embodiments, R ² is independently R ²³ -substituted C ₁ -C5 alkyl. In embodiments, R ² is independently 23 n embodiments, 2 23

R -substituted C ₁ -C ₄ alkyl. I R is independently R -substituted Ci-C ₃ alkyl. In embodiments, R ² is independently R ²³ -substituted Ci-C ₂ alkyl. In embodiments,

R is independently R -substituted C ₂ -C ₆ alkyl. In embodiments, R is independently R - substituted C ₃ -C ₆ alkyl. In embodiments, R ² is independently R ²³ - substituted C ₄ -C6 alkyl. In embodiments, R ² is independently R ²³ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ² is independently R ²³ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ² is independently R ²³ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ² is independently R ²³ -substituted or unsubstituted C ₄ - C ₆ cycloalkyl. In embodiments, R ² is independently R ²³ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ² is independently R ²³ -substituted or

unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ² is independently R ²³ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ² is independently R ²³ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ² is independently unsubstituted 6 membered heteroaryl. In embodiments, R ² is independently unsubstituted 5 membered heteroaryl. In embodiments, R ² is independently R ²³ -substituted 6 membered heteroaryl. In embodiments, R ² is independently R ²³ -substituted 5 membered heteroaryl. In embodiments, R ² is independently R ²³ -substituted phenyl.

[0125] In embodiments, R ² is independently halogen. In embodiments, R ² is independently -F. In embodiments, R ² is independently -CI. In embodiments, R ² is independently -Br. In embodiments, R ² is independently -I. In embodiments, R ² is independently -CF ₃ . In

embodiments, R ² is independently -CH ₃ . In embodiments, R ² is -SO ₂ H ₂ . In embodiments, R ² is independently -OH. In embodiments, R ² is independently -OCH ₃ . In embodiments, R ² is independently a halogen, -CF ₃ , -SO ₂ H ₂ , unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ² is independently unsubstituted C ₂ alkyl. In embodiments, R ² is independently -CH ₂ CH ₃ . In embodiments, R ² is independently -CH ₃ or - OH.

[0126] In embodiments, R ³ is hydrogen, halogen, -CX ³ ₃ , -CN, -OH, - H ₂ , -COOH,

-CO H2, -NO2, -SH, -S0 ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HSO ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ³ ₃ , -OCHX ³ ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered

heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³ is unsubstituted Ci-C ₆ alkyl. In embodiments, R ³ is unsubstituted C ₁ -C ₅ alkyl. In embodiments, R ³ is unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ³ is unsubstituted Ci-C ₃ alkyl. In embodiments, R ³ is unsubstituted C ₁ -C ₂ alkyl. In

embodiments, R ³ is unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ³ is unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ³ is unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ³ is substituted Ci-C ₆ alkyl. In embodiments, R ³ is substituted C ₁ -C ₅ alkyl. In embodiments, R ³ is substituted C ₁ -C ₄ alkyl. In embodiments, R ³ is substituted Ci-C ₃ alkyl. In embodiments, R ³ is substituted C ₁ -C ₂ alkyl. In embodiments, R ³ is substituted C ₂ -C ₆ alkyl. In embodiments, R ³ is substituted C ₃ -C ₆ alkyl. In embodiments, R ³ is substituted C ₄ -C ₆ alkyl. In embodiments, R ³ is substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³ is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³ is substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³ is substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ³ is substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³ is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³ is unsubstituted 6 membered heteroaryl. In embodiments, R ³ is unsubstituted 5 membered heteroaryl. In embodiments, R ³ is independently substituted 6 membered heteroaryl. In embodiments, R ³ is independently substituted 5 membered heteroaryl. In embodiments, R ³ is independently substituted phenyl. In embodiments, R ³ is independently unsubstituted phenyl. [0127] In embodiments, R ³ is independently hydrogen, halogen, -CX ³ ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -S0 ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ³ ₃ , -OCHX ³ ₂ , R ²⁶ -substituted or unsubstituted alkyl, R ²⁶ -substituted or unsubstituted heteroalkyl, R ²⁶ -substituted or unsubstituted cycloalkyl, R ²⁶ -substituted or unsubstituted heterocycloalkyl, R ²⁶ -substituted or unsubstituted aryl, or R ²⁶ -substituted or unsubstituted heteroaryl.

[0128] In embodiments, R ³ is independently hydrogen, halogen, -CX ³ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

3 3 26 26

-OCX ₃ , -OCHX ₂ , R -substituted or unsubstituted Ci-C ₆ alkyl, R -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁶ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁶ - substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁶ -substituted or unsubstituted phenyl, or R ²⁶ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³ is R ²⁶ - substituted Ci-C ₆ alkyl. In embodiments, R ³ is R ²⁶ -substituted C ₁ -C5 alkyl. In embodiments, R ³ is R ²⁶ -substituted C ₁ -C ₄ alkyl. In embodiments, R ³ is R ²⁶ - substituted Ci-C ₃ alkyl. In

3 26 3 26

embodiments, R is R -substituted Ci-C ₂ alkyl. In embodiments, R is R -substituted C ₂ -C ₆ alkyl. In embodiments, R ³ is substituted C ₃ -C ₆ alkyl. In embodiments, R ³ is R ²⁶ -substituted C ₄ - C ₆ alkyl. In embodiments, R ³ is R ²⁶ - substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³ is R ²⁶ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In

embodiments, R ³ is R ²⁶ - substituted or unsubstituted 2 to 5 membered heteroalkyl. In

embodiments, R ³ is R ²⁶ - substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ³ is R ²⁶ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³ is R ²⁶ - substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³ is R ²⁶ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³ is R ²⁶ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³ is R ²⁶ -substituted 6 membered heteroaryl. In embodiments, R ³ is R ²⁶ -substituted 5 membered heteroaryl. In embodiments, R ³ is independently R ²⁶ -substituted phenyl. [0129] In embodiments, R ³ is hydrogen, -CH ₂ CH ₂ CH ₃ , or -CH ₃ . In embodiments, R ³ is hydrogen. In embodiments, R ³ is -CH ₂ CH ₂ CH ₃ . In embodiments, R ³ is -CH ₃ . In embodiments, R ³ is independently substituted or unsubstituted furanyl. In embodiments, R ³ is independently R ²⁶ -substituted or unsubstituted furanyl. In embodiments, R ³ is independently halogen. In embodiments, R ³ is independently -F. In embodiments, R ³ is independently -CI. In

embodiments, R ³ is independently -Br. In embodiments, R ³ is independently -I. In

embodiments, R ³ is independently -CF ₃ . In embodiments, R ³ is -SO ₂ H ₂ . In embodiments, R ³ is independently -OH. In embodiments, R ³ is independently -OCH ₃ .

[0130] In embodiments, R ⁴ is independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -S0 ₃ H, -SO4H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ⁴ ₃ , -OCHX ⁴ ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is unsubstituted Ci-C ₆ alkyl. In embodiments, R ⁴ is unsubstituted C ₁ -C5 alkyl. In embodiments, R ⁴ is unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ⁴ is unsubstituted Ci-C ₃ alkyl. In embodiments, R ⁴ is unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ⁴ is unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ⁴ is unsubstituted C ₃ - C ₆ alkyl. In embodiments, R ⁴ is unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ⁴ is substituted Ci- C ₆ alkyl. In embodiments, R ⁴ is substituted C ₁ -C5 alkyl. In embodiments, R ⁴ is substituted C ₁ -C4 alkyl. In embodiments, R ⁴ is substituted Ci-C ₃ alkyl. In embodiments, R ⁴ is substituted C ₁ -C ₂ alkyl. In embodiments, R ⁴ is substituted C ₂ -C ₆ alkyl. In embodiments, R ⁴ is substituted C ₃ -C ₆ alkyl. In embodiments, R ⁴ is substituted C4-C ₆ alkyl. In embodiments, R ⁴ is substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁴ is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁴ is substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁴ is substituted or unsubstituted C4-C6 cycloalkyl. In

embodiments, R ⁴ is substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ⁴ is substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁴ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁴ is unsubstituted 6 membered heteroaryl. In embodiments, R ⁴ is unsubstituted 5 membered heteroaryl. In embodiments, R ⁴ is independently substituted 6 membered heteroaryl. In embodiments, R ⁴ is independently substituted 5 membered heteroaryl. In embodiments, R ⁴ is independently substituted phenyl. In embodiments, R ⁴ is independently unsubstituted phenyl. [0131] In embodiments, R ⁴ is independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -NO2, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ⁴ ₃ , -OCHX ⁴ ₂ , R ²⁹ -substituted or unsubstituted alkyl, R ²⁹ -substituted or unsubstituted heteroalkyl, R ²⁹ -substituted or unsubstituted cycloalkyl, R ²⁹ -substituted or unsubstituted heterocycloalkyl, R ²⁹ -substituted or unsubstituted aryl, or R ²⁹ -substituted or unsubstituted heteroaryl.

[0132] In embodiments, R ⁴ is independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ⁴ ₃ , -OCHX ⁴ ₂ , R ²⁹ -substituted or unsubstituted Ci-C ₆ alkyl, R ²⁹ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁹ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁹ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁹ -substituted or unsubstituted phenyl, or

29 4 29

R -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R is R - substituted Ci-C ₆ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C1-C5 alkyl. In embodiments, R ⁴ is R 29 -substituted 4 29

C1-C4 alkyl. In embodiments, R is R -substituted Ci-C ₃ alkyl. In

embodiments, R ⁴ is R ²⁹ -substituted Ci-C ₂ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C ₂ -C ₆ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C ₃ -C ₆ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C4-C6 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In

embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ⁴ is R -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R is R - substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ⁴ is R ²⁹ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁴ is R ²⁹ -substituted 6 membered heteroaryl. In embodiments, R ⁴ is R ²⁹ -substituted 5 membered heteroaryl. In embodiments, R ⁴ is independently R ²⁹ -substituted phenyl.

[0133] In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted C ₆ -Ci ₀ aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is

independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is independently R ²⁹ -substituted or unsubstituted benzimidazolyl. In embodiments, R ⁴ is independently hydrogen or substituted or unsubstituted C7-C10 aryl. In embodiments, R ⁴ is independently hydrogen or substituted or unsubstituted C ₈ -Cio aryl. In embodiments, R ⁴ is independently hydrogen or substituted or unsubstituted C9-C ₁₀ aryl. In embodiments, R ⁴ is substituted or unsubstituted 6 to 10 membered heteroaryl. In embodiments, R ⁴ is substituted or unsubstituted 7 to 10 membered heteroaryl. In embodiments, R ⁴ is substituted or unsubstituted 8 to 10 membered heteroaryl. In embodiments, R ⁴ is substituted or unsubstituted 9 to 10 membered heteroaryl.

[0134] In embodiments, R ⁴ is independently hydrogen or R ²⁹ -substituted or unsubstituted C ₇ - C ₁₀ aryl. In embodiments, R ⁴ is independently hydrogen or R ²⁹ -substituted or unsubstituted C ₈ - C ₁₀ aryl. In embodiments, R ⁴ is independently hydrogen or R ²⁹ -substituted or unsubstituted C9- Cio aryl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 6 to 10 membered heteroaryl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 7 to 10 membered heteroaryl. In

embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 8 to 10 membered heteroaryl. In

embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted 9 to 10 membered heteroaryl.

[0135] In embodiments, R ⁴ is independently R ²⁹ -substituted or unsubstituted furanyl. In embodiments, R ⁴ is hydrogen. In embodiments, R ⁴ is independently R ²⁹ -substituted phenoxy. In embodiments, R ⁴ is independently R ²⁹ -substituted phenyl. In embodiments, R ⁴ is

phenoxybenzyl. In embodiments, R ⁴ is independently halogen. In embodiments, R ⁴ is independently -F. In embodiments, R ⁴ is independently -CI. In embodiments, R ⁴ is

independently -Br. In embodiments, R ⁴ is independently -I. In embodiments, R ⁴ is

independently -CF ₃ . In embodiments, R ⁴ is independently -CH ₃ . In embodiments, R ⁴ is - SO ₂ H ₂ . In embodiments, R ⁴ is independently -OH. In embodiments, R ⁴ is independently - OCH ₃ .

[0136] In embodiments, R ⁴ is substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is hydrogen, substituted or unsubstituted C ₁ -C4 alkyl, substituted or unsubstituted C ₃ -C ₅ cycloalkyl, substituted or unsubstituted 3 to 5 membered heterocycloalkyl, or substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁴ is hydrogen, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted thienyl. In embodiments, R ⁴ is unsubstituted pyrazolyl, unsubstituted imidazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted furanyl, unsubstituted pyrrolyl, or unsubstituted thienyl. In embodiments, R ⁴ is -OCH ₃ . In embodiments, R ⁴ is -Br. In

embodiments, R ⁴ is -CI.

[0137] In embodiments, R ⁴ is substituted or unsubstituted pyrazolyl. In embodiments, R ⁴ is substituted or unsubstituted imidazolyl. In embodiments, R ⁴ is substituted or unsubstituted oxazolyl. In embodiments, R ⁴ is substituted or unsubstituted isoxazolyl. In embodiments, R ⁴ is substituted or unsubstituted thiazolyl. In embodiments, R ⁴ is substituted or unsubstituted furanyl. In embodiments, R ⁴ is substituted or unsubstituted pyrrolyl. In embodiments, R ⁴ is substituted or unsubstituted thienyl. In embodiments, R ⁴ is substituted pyrazolyl. In embodiments, R ⁴ is substituted imidazolyl. In embodiments, R ⁴ is substituted oxazolyl. In embodiments, R ⁴ is substituted isoxazolyl. In embodiments, R ⁴ is substituted thiazolyl. In embodiments, R ⁴ is substituted furanyl. In embodiments, R ⁴ is substituted pyrrolyl. In embodiments, R ⁴ is substituted thienyl. In embodiments, R ⁴ is unsubstituted pyrazolyl. In embodiments, R ⁴ is unsubstituted imidazolyl. In embodiments, R ⁴ is unsubstituted oxazolyl. In embodiments, R ⁴ is unsubstituted isoxazolyl. In embodiments, R ⁴ is unsubstituted thiazolyl. In embodiments, R ⁴ is unsubstituted furanyl. In embodiments, R ⁴ is unsubstituted pyrrolyl. In embodiments, R ⁴ is unsubstituted thienyl. In embodiments, R ⁴ is independently hydrogen, substituted or

unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is independently substituted or unsubstituted 5 or 10 membered heteroaryl. In embodiments, R ⁴ is unsubstituted benzimidazolyl.

[0138] In embodiments, R ⁵ is hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ⁵ is unsubstituted Ci-C ₆ alkyl. In embodiments, R ⁵ is unsubstituted C ₁ -C ₅ alkyl. In embodiments, R ⁵ is unsubstituted C ₁ -C4 alkyl. In embodiments, R ⁵ is unsubstituted Ci-C ₃ alkyl. In embodiments, R ⁵ is unsubstituted Ci- C ₂ alkyl. In embodiments, R ⁵ is unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ⁵ is unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ⁵ is unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ⁵ is substituted Ci-C ₆ alkyl. In embodiments, R ⁵ is substituted C ₁ -C ₅ alkyl. In embodiments, R ⁵ is substituted C ₁ -C4 alkyl. In embodiments, R ⁵ is substituted Ci-C ₃ alkyl. In embodiments, R ⁵ is substituted Ci-C ₂ alkyl. In embodiments, R ⁵ is substituted C ₂ -C ₆ alkyl. In embodiments, R ⁵ is substituted C ₃ -C ₆ alkyl. In embodiments, R ⁵ is substituted C ₄ -C ₆ alkyl. In embodiments, R ⁵ is substituted 3 to 6 membered heteroalkyl. In embodiments, R ⁵ is unsubstituted 3 to 6 membered heteroalkyl. In embodiments, R ⁵ is substituted 4 to 6 membered heteroalkyl. In embodiments, R ⁵ is unsubstituted 4 to 6 membered heteroalkyl. In embodiments, R ⁵ is hydrogen. [0139] In embodiments, R ⁵ is hydrogen, R ³² -substituted or unsubstituted Ci-C ₆ alkyl, or R ³² - substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ⁵ is R ³² -substituted

5 32 5 32

Ci-C ₆ alkyl. In embodiments, R is R -substituted C ₁ -C ₅ alkyl. In embodiments, R is R - substituted C ₁ -C ₄ alkyl. In embodiments, R ⁵ is R ³² -substituted C ₁ -C ₃ alkyl. In embodiments, R ⁵ is R ³² -substituted C ₁ -C ₂ alkyl. In embodiments, R ⁵ is R ³² -substituted C ₂ -C ₆ alkyl. In

5 32 5 32

embodiments, R is R -substituted C ₃ -C ₆ alkyl. In embodiments, R is R -substituted C ₄ -C ₆ alkyl. In embodiments, R ⁵ is R ³² -substituted 3 to 6 membered heteroalkyl. In embodiments, R ⁵ is R ³² -substituted 4 to 6 membered heteroalkyl.

[0140] In embodiments, R ⁵ may optionally be joined to an R ¹ substituent ortho to the - N(R ⁵ )- to form an unsubstituted 5 membered heterocycloalkyl or unsubstituted 5 membered heteroaryl. In embodiments, R ⁵ is hydrogen or R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ )- to form an unsubstituted 6 membered heterocycloalkyl or unsubstituted 6 membered heteroaryl. In embodiments, R ⁵ is hydrogen.

[0141] In embodiments, R ⁷ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁷ is independently unsubstituted

Ci-C ₆ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₁ -C ₅ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ⁷ is independently unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ⁷ is independently substituted Ci-C ₆ alkyl. In embodiments, R ⁷ is independently substituted C ₁ -C ₅ alkyl. In embodiments, R ⁷ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ⁷ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ⁷ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ⁷ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ⁷ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ⁷ is independently substituted C4-C ₆ alkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted C4-C ₆ cycloalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 4 to 6 membered

heterocycloalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ⁷ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁷ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁷ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ⁷ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ⁷ is independently substituted 6 membered heteroaryl. In embodiments, R ⁷ is independently substituted 5 membered heteroaryl. In embodiments, R ⁷ is independently substituted phenyl. In embodiments, R ⁷ is independently unsubstituted phenyl. In embodiments, R ⁷ is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , substituted or unsubstituted Ci- C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R ⁷ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁷ is independently hydrogen. In embodiments, R ⁷ is

independently unsubstituted methyl. [0142] In embodiments, R ⁷ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , R ³⁵ -substituted or unsubstituted alkyl, R ³⁵ -substituted or unsubstituted heteroalkyl, R ³⁵ -substituted or unsubstituted cycloalkyl, R ³⁵ -substituted or unsubstituted heterocycloalkyl, R ³⁵ -substituted or unsubstituted aryl, or R ³⁵ -substituted or unsubstituted heteroaryl.

[0143] In embodiments, R ⁷ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX3, -OCHX ₂ , R ³⁵ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁵ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³⁵ -substituted or unsubstituted C3-C ₆ cycloalkyl, R ³⁵ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁵ -substituted or unsubstituted phenyl, or R ³⁵ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁷ is independently R ³⁵ -substituted Ci-C ₆ alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted C ₁ -C5 alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted C ₁ -C4 alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted C ₁ -C ₃ alkyl. In embodiments, R ⁷ is independently R ³⁵ - substituted Ci-C ₂ alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted C ₂ -C ₆ alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted C ₃ -C6 alkyl. In embodiments, R ⁷ is

independently R ³⁵ -substituted C4-C6 alkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁷ is independently R ³⁵ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁷ is

independently R ³⁵ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁷ is independently R ³⁵ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁷ is independently R ³⁵ -substituted 6 membered heteroaryl. In embodiments, R ⁷ is independently R ³⁵ -substituted 5 membered heteroaryl. In embodiments, R ⁷ is independently R ³⁵ -substituted phenyl.

[0144] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH,

-OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁸ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ⁸ is independently unsubstituted C ₁ -C5 alkyl. In embodiments, R ⁸ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ⁸ is independently unsubstituted C ₁ -C3 alkyl. In embodiments, R ⁸ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ⁸ is independently unsubstituted C ₂ -C6 alkyl. In embodiments, R ⁸ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ⁸ is independently unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ⁸ is independently substituted Ci-C ₆ alkyl. In embodiments, R ⁸ is independently substituted C ₁ -C5 alkyl. In embodiments, R ⁸ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ⁸ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ⁸ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ⁸ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ⁸ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ⁸ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 4 to 6 membered

heterocycloalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ⁸ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁸ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁸ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ⁸ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ⁸ is independently substituted 6 membered heteroaryl. In embodiments, R ⁸ is independently substituted 5 membered heteroaryl. In embodiments, R ⁸ is independently substituted phenyl. In embodiments, R ⁸ is independently unsubstituted phenyl. In embodiments, R ⁸ is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , substituted or unsubstituted Ci- C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R ⁸ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁸ is independently hydrogen. In embodiments, R ⁸ is

independently unsubstituted methyl.

[0145] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , R ³⁶ -substituted or unsubstituted alkyl, R ³⁶ -substituted or unsubstituted heteroalkyl, R ³⁶ -substituted or unsubstituted cycloalkyl, R ³⁶ -substituted or unsubstituted heterocycloalkyl, R ³⁶ -substituted or unsubstituted aryl, or R ³⁶ -substituted or unsubstituted heteroaryl. [0146] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , R ³⁶ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁶ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³⁶ -substituted or unsubstituted C3-C6 cycloalkyl, R ³⁶ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁶ -substituted or unsubstituted phenyl, or R ³⁶ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁸ is

independently R ³⁶ -substituted Ci-C ₆ alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted C ₁ -C5 alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted C ₁ -C4 alkyl. In embodiments,

R 8 is independently R 36 -substituted 8 36

C ₁ -C3 alkyl. In embodiments, R is independently R - substituted C ₁ -C ₂ alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted C ₂ -C ₆ alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted C ₃ -C ₆ alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted C4-C ₆ alkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁸ is independently R ³⁶ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁸ is

independently R ³⁶ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁸ is independently R ³⁶ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁸ is independently R ³⁶ -substituted 6 membered heteroaryl. In embodiments, R ⁸ is independently R ³⁶ -substituted 5 membered heteroaryl. In embodiments, R ⁸ is independently R ³⁶ -substituted phenyl.

[0147] In embodiments, R ⁹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -S0 ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted

3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered. In embodiments, R ⁹ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ⁹ is independently unsubstituted C ₁ -C5 alkyl. In embodiments, R ⁹ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ⁹ is independently unsubstituted Ci- C ₃ alkyl. In embodiments, R ⁹ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ⁹ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ⁹ is independently unsubstituted C ₃ - C ₆ alkyl. In embodiments, R ⁹ is independently unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ⁹ is independently substituted Ci-C ₆ alkyl. In embodiments, R ⁹ is independently substituted C ₁ -C5 alkyl. In embodiments, R ⁹ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ⁹ is independently substituted C1-C3 alkyl. In embodiments, R ⁹ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ⁹ is independently substituted C2-C6 alkyl. In embodiments, R ⁹ is independently substituted C3-C6 alkyl. In embodiments, R ⁹ is independently substituted C4-C6 alkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 4 to 6 membered

heterocycloalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ⁹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁹ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ⁹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ⁹ is independently substituted 6 membered heteroaryl. In embodiments, R ⁹ is independently substituted 5 membered heteroaryl. In embodiments, R ⁹ is independently substituted phenyl. In embodiments, R ⁹ is independently unsubstituted phenyl. In embodiments, R ⁹ is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , substituted or unsubstituted Ci- C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R ⁹ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁹ is independently hydrogen. In embodiments, R ⁹ is

independently unsubstituted methyl.

[0148] In embodiments, R ⁹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO3H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX3, -OCHX ₂ , R ³⁷ -substituted or unsubstituted alkyl, R ³⁷ -substituted or unsubstituted heteroalkyl, R ³⁷ -substituted or unsubstituted cycloalkyl, R ³⁷ -substituted or unsubstituted heterocycloalkyl, R ³⁷ -substituted or unsubstituted aryl, or R ³⁷ -substituted or unsubstituted heteroaryl.

[0149] In embodiments, R ⁹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ ,

-COOH, -CONH ₂ , -NO2, -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX ₂ , R ³⁷ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁷ -substituted or unsubstituted

2 to 6 membered heteroalkyl, R ³⁷ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ³⁷ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁷ -substituted or unsubstituted phenyl, or R ³⁷ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁹ is

independently R ³⁷ -substituted Ci-C ₆ alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted C ₁ -C5 alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted C ₁ -C4 alkyl. In embodiments,

9 31 9 31

R is independently R -substituted Ci-C ₃ alkyl. In embodiments, R is independently R - substituted Ci-C ₂ alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted C ₂ -C ₆ alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted C ₃ -C ₆ alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted C ₄ -C ₆ alkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁹ is independently R ³⁷ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ⁹ is

independently R ³⁷ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ⁹ is independently R ³⁷ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ⁹ is independently R ³⁷ -substituted 6 membered heteroaryl. In embodiments, R ⁹ is independently R ³⁷ -substituted 5 membered heteroaryl. In embodiments, R ⁹ is independently R ³⁷ -substituted phenyl.

[0150] In embodiments, R ¹⁰ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, -NHOH,

-OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted

3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁰ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹⁰ is independently unsubstituted C ₁ -C5 alkyl. In embodiments,

R ¹⁰ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ¹⁰ is independently

unsubstituted Ci-C ₃ alkyl. In embodiments, R ¹⁰ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ¹⁰ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ¹⁰ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ¹⁰ is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ¹⁰ is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹⁰ is independently substituted C ₁ -C5 alkyl. In embodiments, R ¹⁰ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ¹⁰ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ¹⁰ is independently substituted Ci-C ₂ alkyl. In embodiments, R ¹⁰ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ¹⁰ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ¹⁰ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ¹⁰ is independently substituted or

unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁰ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁰ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁰ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁰ is independently substituted 6 membered heteroaryl. In embodiments, R ¹⁰ is independently substituted 5 membered heteroaryl. In embodiments, R ¹⁰ is independently substituted phenyl. In embodiments, R ¹⁰ is independently unsubstituted phenyl. In embodiments, R ¹⁰ is independently hydrogen, -CX ₃ , -CN, -COOH, -CO H ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁰ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁰ is independently hydrogen. In embodiments, R ¹⁰ is independently unsubstituted methyl.

[0151] In embodiments, R ¹⁰ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , R ³⁸ -substituted or unsubstituted alkyl, R ³⁸ -substituted or unsubstituted heteroalkyl, R ³⁸ -substituted or unsubstituted cycloalkyl, R ³⁸ -substituted or unsubstituted heterocycloalkyl, R ³⁸ -substituted or unsubstituted aryl, or R ³⁸ -substituted or unsubstituted heteroaryl. [0152] In embodiments, R ¹⁰ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -NO2, -SH, -SO3H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX3, -OCHX ₂ , R ³⁸ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁸ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³⁸ -substituted or unsubstituted C3-C6 cycloalkyl, R ³⁸ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁸ -substituted or unsubstituted phenyl, or R ³⁸ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁰ is

independently R 38 -substituted Ci-C ₆ alkyl. In embodiments, R 10 is independently R 38 -substituted C1-C5 alkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted C1-C4 alkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted C1-C3 alkyl. In embodiments, R ¹⁰ is independently R ³⁸ - substituted Ci-C ₂ alkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted C ₂ -C ₆ alkyl. In

10 38 10

embodiments, R is independently R -substituted C3-C6 alkyl. In embodiments, R is independently R 38 -substituted 10 38

C4-C6 alkyl. In embodiments, R is independently R -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹⁰ is independently R ³⁸ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted 6 membered heteroaryl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted 5 membered heteroaryl. In embodiments, R ¹⁰ is independently R ³⁸ -substituted phenyl. [0153] In embodiments, R ¹¹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO3H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX3, -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹¹ is independently unsubstituted

Ci-C ₆ alkyl. In embodiments, R ¹¹ is independently unsubstituted C1-C5 alkyl. In embodiments,

R ¹¹ is independently unsubstituted C1-C4 alkyl. In embodiments, R ¹¹ is independently unsubstituted C1-C3 alkyl. In embodiments, R ¹¹ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ¹¹ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ¹¹ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ¹¹ is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ¹¹ is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹¹ is independently substituted C ₁ -C5 alkyl. In embodiments, R ¹¹ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ¹¹ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ¹¹ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ¹¹ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ¹¹ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ¹¹ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹¹ is independently substituted or

unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹¹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹¹ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹¹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹¹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹¹ is independently substituted 6 membered heteroaryl. In embodiments, R ¹¹ is independently substituted 5 membered heteroaryl. In embodiments, R ¹¹ is independently substituted phenyl. In embodiments, R ¹¹ is independently unsubstituted phenyl. In embodiments, R ¹¹ is independently hydrogen, -CX ₃ , -CN, -COOH, -CO H ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹¹ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹¹ is independently hydrogen. In embodiments, R ¹¹ is independently unsubstituted methyl. [0154] In embodiments, R ¹¹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ ,

-COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ₃ , -OCHX ₂ , R ³⁹ -substituted or unsubstituted alkyl, R ³⁹ -substituted or unsubstituted heteroalkyl, R ³⁹ -substituted or unsubstituted cycloalkyl, R ³⁹ -substituted or unsubstituted heterocycloalkyl, R ³⁹ -substituted or unsubstituted aryl, or R ³⁹ -substituted or unsubstituted heteroaryl.

[0155] In embodiments, R ¹¹ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH,

-OCX ₃ , -OCHX ₂ , R ³⁹ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁹ -substituted or unsubstituted

2 to 6 membered heteroalkyl, R ³⁹ -substituted or unsubstituted C3-C6 cycloalkyl, R ³⁹ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁹ -substituted or unsubstituted phenyl, or R ³⁹ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹¹ is

independently R -substituted Ci-C ₆ alkyl. In embodiments, R is independently R -substituted C ₁ -C5 alkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted C ₁ -C4 alkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted C ₁ -C3 alkyl. In embodiments, R ¹¹ is independently R ³⁹ - substituted C ₁ -C ₂ alkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted C ₂ -C6 alkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted C ₃ -C ₆ alkyl. In embodiments, R ¹¹ is independently R 39 -substituted yl. In embodiments, R 11 is independently R 39

C4-C6 alk -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹¹ is independently R ³⁹ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹¹ is independently R ³⁹ -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹¹ is independently R ³⁹ -substituted 6 membered heteroaryl. In embodiments, R ¹¹ is independently R ³⁹ -substituted 5 membered heteroaryl. In embodiments, R ¹¹ is independently R ³⁹ -substituted phenyl.

[0156] In embodiments, R ¹² is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX3, -OCHX2, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted

3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹² is independently unsubstituted C ₁ -C5 alkyl. In embodiments, R ¹² is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ¹² is independently

unsubstituted C ₁ -C3 alkyl. In embodiments, R ¹² is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ¹² is independently unsubstituted C ₂ -C6 alkyl. In embodiments, R ¹² is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ¹² is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ¹² is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹² is independently substituted C ₁ -C5 alkyl. In embodiments, R ¹² is independently substituted C ₁ -C4 alkyl. In embodiments, R ¹² is independently substituted Ci-C ₃ alkyl. In embodiments, R ¹² is independently substituted Ci-C ₂ alkyl. In embodiments, R ¹² is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ¹² is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ¹² is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ¹² is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹² is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹² is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹² is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹² is independently substituted or

unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹² is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹² is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹² is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹² is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹² is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹² is independently substituted 6 membered heteroaryl. In embodiments, R ¹² is independently substituted 5 membered heteroaryl. In embodiments, R ¹² is independently substituted phenyl. In embodiments, R ¹² is independently unsubstituted phenyl. In embodiments, R ¹² is independently hydrogen, -CX ₃ , -CN, -COOH, -CO H ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is independently hydrogen. In embodiments, R ¹² is independently unsubstituted methyl.

[0157] In embodiments, R ¹² is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , R ⁴⁰ -substituted or unsubstituted alkyl, R ⁴⁰ -substituted or unsubstituted heteroalkyl, R ⁴⁰ -substituted or unsubstituted cycloalkyl, R ⁴⁰ -substituted or unsubstituted heterocycloalkyl, R ⁴⁰ -substituted or unsubstituted aryl, or R ⁴⁰ -substituted or unsubstituted heteroaryl.

[0158] In embodiments, R ¹² is independently hydrogen, halogen,

oxo, -CH ₃ , -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ C H ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ⁴⁰ - substituted or unsubstituted Ci-C ₆ alkyl, R ⁴⁰ - substituted or unsubstituted 2 to 6 membered heteroalkyl, R ⁴⁰ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ⁴⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ⁴⁰ -substituted or unsubstituted phenyl, or R ⁴⁰ - substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is independently R ⁴⁰ -substituted Ci-C ₆ alkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted C ₁ -C5 alkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted C ₁ -C4 alkyl. In embodiments, R ¹² is independently R ⁴⁰ - substituted Ci-C ₃ alkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted Ci-C ₂ alkyl. In

12 40 12

embodiments, R is independently R -substituted C ₂ -C ₆ alkyl. In embodiments, R is independently R ⁴⁰ -substituted C ₃ -C ₆ alkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted C4-C6 alkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted or

unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹² is independently R ⁴⁰ - substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ¹² is independently R ⁴⁰ - substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹² is independently R ⁴⁰ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In

embodiments, R ¹² is independently R ⁴⁰ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹² is independently R ⁴⁰ -substituted or unsubstituted 6 membered heteroaryl. In

12 40 12 embodiments, R is independently R -substituted 6 membered heteroaryl. In embodiments, R is independently R ⁴⁰ -substituted 5 membered heteroaryl. In embodiments, R ¹² is independently R ⁴⁰ -substituted phenyl. [0159] In embodiments, R ¹³ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ ,

-COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹³ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₁ -C ₅ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ¹³ is independently

unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ¹³ is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ¹³ is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹³ is independently substituted C ₁ -C ₅ alkyl. In embodiments, R ¹³ is independently substituted Ci-C ₄ alkyl. In embodiments, R ¹³ is independently substituted C ₁ -C3 alkyl. In embodiments, R ¹³ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ¹³ is independently substituted C ₂ -C6 alkyl. In embodiments, R ¹³ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ¹³ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ¹³ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹³ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹³ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹³ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹³ is independently substituted or

unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹³ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹³ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹³ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹³ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹³ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹³ is independently substituted 6 membered heteroaryl. In embodiments, R ¹³ is independently substituted 5 membered heteroaryl. In embodiments, R ¹³ is independently substituted phenyl. In embodiments, R ¹³ is independently unsubstituted phenyl. In embodiments, R ¹³ is independently hydrogen, -CX ₃ , -CN, -COOH, -CO H ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹³ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹³ is independently hydrogen. In embodiments, R ¹³ is independently unsubstituted methyl. [0160] In embodiments, R ¹³ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ -substituted or unsubstituted cycloalkyl, R ⁴¹ -substituted or unsubstituted heterocycloalkyl, R ⁴¹ -substituted or unsubstituted aryl, or R ⁴¹ -substituted or unsubstituted heteroaryl.

[0161] In embodiments, R ¹³ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ₃ , -OCHX ₂ , R ⁴¹ - substituted or unsubstituted Ci-C ₆ alkyl, R ⁴¹ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ⁴¹ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ⁴¹ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ⁴¹ - substituted or unsubstituted phenyl, or R ⁴¹ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹³ is

independently R ⁴¹ -substituted Ci-C ₆ alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted C ₁ -C5 alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted C ₁ -C ₄ alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted C ₁ -C3 alkyl. In embodiments, R ¹³ is independently R ⁴¹ - substituted Ci-C ₂ alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted C ₂ -C ₆ alkyl. In embodiments, R ¹³ is independently R ⁴¹ - substituted C3-C6 alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted C ₄ -C ₆ alkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹³ is independently R ⁴¹ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ¹³ is independently R ⁴¹ - substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ¹³ is independently R ⁴¹ -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹³ is independently R ⁴¹ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹³ is independently R ⁴¹ - substituted 6 membered heteroaryl. In embodiments, R ¹³ is independently R ⁴¹ - substituted 5 membered heteroaryl. In embodiments, R ¹³ is independently R ⁴¹ - substituted phenyl.

[0162] In embodiments, R ¹⁴ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁴ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₁ -C5 alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ¹⁴ is independently

unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ¹⁴ is independently unsubstituted C ₄ - C ₆ alkyl. In embodiments, R ¹⁴ is independently substituted Ci-C ₆ alkyl. In embodiments, R ¹⁴ is independently substituted C ₁ -C5 alkyl. In embodiments, R ¹⁴ is independently substituted C ₁ -C4 alkyl. In embodiments, R ¹⁴ is independently substituted Ci-C ₃ alkyl. In embodiments, R ¹⁴ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ¹⁴ is independently substituted C ₂ -C6 alkyl. In embodiments, R ¹⁴ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ¹⁴ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ¹⁴ is independently substituted or

unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁴ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁴ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁴ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁴ is independently substituted 6 membered heteroaryl. In embodiments, R ¹⁴ is independently substituted 5 membered heteroaryl. In embodiments, R ¹⁴ is independently substituted phenyl. In embodiments, R ¹⁴ is independently unsubstituted phenyl. In embodiments, R ¹⁴ is independently hydrogen, -CX ₃ , -CN, -COOH, -CO H ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁴ is independently hydrogen, -CX ₃ , -COOH, -CO H ₂ , unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁴ is independently hydrogen. In embodiments, R ¹⁴ is independently unsubstituted methyl.

[0163] In embodiments, R ¹⁴ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH,

-OCX3, -OCHX ₂ , R ⁴² -substituted or unsubstituted alkyl, R ⁴² -substituted or unsubstituted heteroalkyl, R ⁴² -substituted or unsubstituted cycloalkyl, R ⁴² -substituted or unsubstituted heterocycloalkyl, R ⁴² -substituted or unsubstituted aryl, or R ⁴² -substituted or unsubstituted heteroaryl.

[0164] In embodiments, R ¹⁴ is independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX3, -OCHX ₂ , R ⁴² -substituted or unsubstituted Ci-C ₆ alkyl, R ⁴² -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ⁴² -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ⁴² -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ⁴² -substituted or unsubstituted phenyl, or R ⁴² -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁴ is

independently R ⁴² -substituted Ci-C ₆ alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C ₁ -C5 alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C ₁ -C ₄ alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C ₁ -C3 alkyl. In embodiments, R ¹⁴ is independently R ⁴² - substituted C ₁ -C ₂ alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C ₂ -C6 alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C3-C6 alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted C ₄ -C6 alkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ¹⁴ is independently R ⁴² - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted C ₄ -C6 cycloalkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In

embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 5 to 6 membered

heterocycloalkyl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ¹⁴ is independently R ⁴² -substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ¹⁴ is independently R ⁴² -substituted 6 membered heteroaryl. In embodiments, R ¹⁴ is independently R ⁴² -substituted 5 membered heteroaryl. In embodiments, R ¹⁴ is independently R ⁴² -substituted phenyl. [0165] In embodiments, R ⁷ and R ⁸ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 or 6 membered heteroaryl.

[0166] In embodiments, R ¹¹ and R ¹² substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 or 6 membered heteroaryl.

[0167] R ²⁰ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -S0 ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁰ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁰ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²⁰ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²⁰ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ²⁰ is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ²⁰ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ²⁰ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²⁰ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ²⁰ is independently

unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ²⁰ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²⁰ is independently substituted C1-C5 alkyl. In embodiments, R ²⁰ is

independently substituted C ₁ -C ₄ alkyl. In embodiments, R ²⁰ is independently substituted Ci-C ₃ alkyl. In embodiments, R ²⁰ is independently substituted Ci-C ₂ alkyl. In embodiments, R ²⁰ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²⁰ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁰ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁰ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁰ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁰ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁰ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²⁰ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²⁰ is independently substituted 6 membered heteroaryl. In embodiments, R ²⁰ is independently substituted 5 membered heteroaryl. In embodiments, R ²⁰ is independently substituted phenyl. In

embodiments, R ²⁰ is independently unsubstituted phenyl.

[0168] In embodiments, R ²⁰ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²¹ -substituted or

unsubstituted alkyl, R ²¹ - substituted or unsubstituted heteroalkyl, R ²¹ -substituted or unsubstituted cycloalkyl, R ²¹ - substituted or unsubstituted heterocycloalkyl, R ²¹ - substituted or unsubstituted aryl, or R ²¹ -substituted or unsubstituted heteroaryl; two adjacent R ²⁰ substituents may optionally be j oined to form a R ²¹ -substituted or unsubstituted cycloalkyl, R ²¹ - substituted or unsubstituted heterocycloalkyl, R ²¹ -substituted or unsubstituted aryl, or R ²¹ -substituted or unsubstituted heteroaryl.

[0169] In embodiments, R ²⁰ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²¹ -substituted or unsubstituted Ci-C ₆ alkyl, R ²¹ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²¹ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²¹ - substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²¹ - substituted or unsubstituted phenyl, or R ²¹ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁰ substituents may optionally be joined to form a R ²¹ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²¹ -substituted or unsubstituted phenyl, or R ²¹ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁰ is independently R ²¹ - substituted Ci-C ₆ alkyl. In embodiments,

R 20 is independently R 21 -substituted 20 21

C ₁ -C5 alkyl. In embodiments, R is independently R - substituted C ₁ -C4 alkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted Ci-C ₃ alkyl. In

20 21 20

embodiments, R is independently R -substituted Ci-C ₂ alkyl. In embodiments, R is independently R 21 -substituted 20 21

C ₂ -C ₆ alkyl. In embodiments, R is independently R -substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted C4-C6 alkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In

embodiments, R ²⁰ is independently R ²¹ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁰ is independently R ²¹ - substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁰ is independently R ²¹ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁰ is independently R ²¹ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁰ is independently R ²¹ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁰ is independently R ²¹ - substituted 6 membered heteroaryl. In embodiments, R ²⁰ is independently R ²¹ -substituted 5 membered heteroaryl. In embodiments, R ²⁰ is independently R ²¹ - substituted phenyl.

[0170] R ²¹ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²¹ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²¹ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²¹ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ²¹ is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ²¹ is independently unsubstituted Ci-C ₂ alkyl. In embodiments, R ²¹ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²¹ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ²¹ is independently

unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ²¹ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²¹ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²¹ is

independently substituted C ₁ -C4 alkyl. In embodiments, R ²¹ is independently substituted Ci-C ₃ alkyl. In embodiments, R ²⁰ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²¹ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²¹ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ²¹ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²¹ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²¹ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²¹ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ²¹ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²¹ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²¹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²¹ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²¹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²¹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²¹ is independently substituted 6 membered heteroaryl. In embodiments, R ²¹ is independently substituted 5 membered heteroaryl. In embodiments, R ²¹ is independently substituted phenyl. In

embodiments, R ²¹ is independently unsubstituted phenyl.

[0171] In embodiments, R ²¹ is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²² -substituted or

unsubstituted alkyl, R ²² -substituted or unsubstituted heteroalkyl, R ²² -substituted or unsubstituted cycloalkyl, R ²² -substituted or unsubstituted heterocycloalkyl, R ²² -substituted or unsubstituted aryl, or R ²² -substituted or unsubstituted heteroaryl; two adjacent R ²¹ substituents may optionally be joined to form a R ²² -substituted or unsubstituted cycloalkyl, R ²² -substituted or unsubstituted heterocycloalkyl, R ²² -substituted or unsubstituted aryl, or R ²² -substituted or unsubstituted heteroaryl.

[0172] In embodiments, R ²¹ is independently halogen, oxo, -CH ₃ , -CF ₃ , -CC1 ₃ , -CN,

-S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²² -substituted or

unsubstituted Ci-C ₆ alkyl, R ²² -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²² - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²² -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²² -substituted or unsubstituted phenyl, or R ²² -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²¹ substituents may optionally be joined to form a R ²² - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²² -substituted or unsubstituted phenyl, or R ²² -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²¹ is independently R ²² -substituted Ci-C ₆ alkyl. In embodiments, R 21 is independently R 22 -substituted 21

C1-C5 alkyl. In embodiments, R is independently R 22 -substituted 21 22

C1-C4 alkyl. In embodiments, R is independently R -substituted C ₁ -C3 alkyl. In embodiments, R ²¹ is independently R ²² -substituted C ₁ -C ₂ alkyl. In embodiments,

R 21 is independently R 22 -substituted 21 ly R 22

C ₂ -C ₆ alkyl. In embodiments, R is independent - substituted C3-C ₆ alkyl. In embodiments, R ²¹ is independently R ²² -substituted C4-C ₆ alkyl. In embodiments, R ²¹ is independently R ²² -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²¹ is independently R ²² -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²¹ is independently R ²² -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²¹ is independently R ²² -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²¹ is independently R ²² -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²¹ is independently R ²² - substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²¹ is independently R ²² - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²¹ is independently R ²² - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²¹ is independently R ²² - substituted 6 membered heteroaryl. In embodiments, R ²¹ is independently R ²² -substituted 5 membered heteroaryl. In embodiments, R ²¹ is independently R ²² -substituted phenyl.

[0173] R ²³ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -SO ₃ H, -SO ₄ H,

-SO2 H2, - HNH2, -O H2, - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²³ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²³ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²³ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²³ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ²³ is independently unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ²³ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ²³ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²³ is independently unsubstituted C ₃ -C6 alkyl. In embodiments, R ²³ is independently

unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ²³ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²³ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²³ is

independently substituted C ₁ -C4 alkyl. In embodiments, R ²³ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ²³ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²³ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²³ is independently substituted C ₃ -C6 alkyl. In embodiments, R ²³ is independently substituted C4-C6 alkyl. In embodiments, R ²³ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²³ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²³ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²³ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ²³ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²³ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²³ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²³ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²³ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²³ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²³ is independently substituted 6 membered heteroaryl. In embodiments, R ²³ is independently substituted 5 membered heteroaryl. In embodiments, R ²³ is independently substituted phenyl. In

embodiments, R ²³ is independently unsubstituted phenyl. [0174] In embodiments, R ²³ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁴ -substituted or

unsubstituted alkyl, R ²⁴ -substituted or unsubstituted heteroalkyl, R ²⁴ -substituted or unsubstituted cycloalkyl, R ²⁴ -substituted or unsubstituted heterocycloalkyl, R ²⁴ -substituted or unsubstituted aryl, or R ²⁴ -substituted or unsubstituted heteroaryl; two adjacent R ²³ substituents may optionally be joined to form a R ²⁴ -substituted or unsubstituted cycloalkyl, R ²⁴ -substituted or unsubstituted heterocycloalkyl, R ²⁴ -substituted or unsubstituted aryl, or R ²⁴ -substituted or unsubstituted heteroaryl. [0175] In embodiments, R ²³ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁴ -substituted or

unsubstituted Ci-C ₆ alkyl, R ²⁴ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁴ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁴ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁴ -substituted or unsubstituted phenyl, or R ²⁴ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²³ substituents may optionally be joined to form a R ²⁴ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁴ -substituted or unsubstituted phenyl, or R ²⁴ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²³ is independently R ²⁴ -substituted Ci-C ₆ alkyl. In embodiments, R 23 is independently R 24 -substituted 23

C ₁ -C5 alkyl. In embodiments, R is independently R -substituted C ₁ -C ₄ alkyl. In embodiments, R is independently R -substituted C ₁ -C3 alkyl. In embodiments, R ²³ is independently R ²⁴ -substituted C ₁ -C ₂ alkyl. In embodiments,

R 23 is independently R 24 -substituted 23 24

C ₂ -C ₆ alkyl. In embodiments, R is independently R - substituted C3-C ₆ alkyl. In embodiments, R ²³ is independently R ²⁴ -substituted C4-C ₆ alkyl. In embodiments, R ²³ is independently R ²⁴ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²³ is independently R ²⁴ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²³ is independently R ²⁴ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²³ is independently R ²⁴ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²³ is independently R ²⁴ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²³ is independently R ²⁴ - substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²³ is independently R ²⁴ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²³ is independently R ²⁴ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²³ is independently R ²⁴ - substituted 6 membered heteroaryl. In embodiments, R ²³ is independently R ²⁴ -substituted 5 membered heteroaryl. In embodiments, R ²³ is independently R ²⁴ -substituted phenyl.

[0176] R ²⁴ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -SO ₃ H, -SO ₄ H,

-SO2 H2, - HNH2, -O H2, - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁴ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁴ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²⁴ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²⁴ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ²⁴ is independently unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ²⁴ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ²⁴ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²⁴ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ²⁴ is independently

unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ²⁴ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²⁴ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²⁴ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ²⁴ is independently substituted C ₁ -C3 alkyl. In embodiments, R ²³ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²⁴ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²⁴ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁴ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁴ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁴ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁴ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁴ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²⁴ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²⁴ is independently substituted 6 membered heteroaryl. In embodiments, R ²⁴ is independently substituted 5 membered heteroaryl. In embodiments, R ²⁴ is independently substituted phenyl. In

embodiments, R ²⁴ is independently unsubstituted phenyl.

[0177] In embodiments, R ²⁴ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁵ -substituted or

unsubstituted alkyl, R ²⁵ - substituted or unsubstituted heteroalkyl, R ²⁵ -substituted or unsubstituted cycloalkyl, R ²⁵ - substituted or unsubstituted heterocycloalkyl, R ²⁵ - substituted or unsubstituted aryl, or R ²⁵ -substituted or unsubstituted heteroaryl; two adjacent R ²⁴ substituents may optionally be joined to form a R ²⁵ -substituted or unsubstituted cycloalkyl, R ²⁵ - substituted or unsubstituted heterocycloalkyl, R ²⁵ -substituted or unsubstituted aryl, or R ²⁵ -substituted or unsubstituted heteroaryl.

[0178] In embodiments, R ²⁴ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -S0 ₄ H,

-S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H,

-NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁵ -substituted or unsubstituted Ci-C ₆ alkyl,

R ²⁵ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁵ -substituted or unsubstituted

C ₃ -C ₆ cycloalkyl, R ²⁵ - substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁵ - substituted or unsubstituted phenyl, or R ²⁵ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁴ substituents may optionally be joined to form a R ²⁵ -substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁵ -substituted or unsubstituted phenyl, or R ²⁵ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁴ is independently R ²⁵ - substituted Ci-C ₆ alkyl. In embodiments,

24 25 24 25

R is independently R -substituted C ₁ -C5 alkyl. In embodiments, R is independently R - substituted C ₁ -C4 alkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted C ₁ -C3 alkyl. In embodiments, R is independently R -substituted Ci-C ₂ alkyl. In embodiments, R is

25 24 25

independently R -substituted C ₂ -C ₆ alkyl. In embodiments, R is independently R -substituted C3-C ₆ alkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In

embodiments, R ²⁴ is independently R ²⁵ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁴ is independently R ²⁵ - substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁴ is independently R ²⁵ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁴ is independently R ²⁵ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁴ is independently R ²⁵ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁴ is independently R ²⁵ - substituted 6 membered heteroaryl. In embodiments, R ²⁴ is independently R ²⁵ -substituted 5 membered heteroaryl. In embodiments, R ²⁴ is independently R ²⁵ - substituted phenyl.

[0179] R ²⁶ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁶ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁶ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²⁶ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²⁶ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ²⁶ is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ²⁶ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ²⁶ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²⁶ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ²⁶ is independently

unsubstituted C4-C ₆ alkyl. In embodiments, R ²⁶ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²⁶ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²⁶ is

independently substituted C ₁ -C4 alkyl. In embodiments, R ²⁶ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ²⁶ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²⁶ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²⁶ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁶ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁶ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁶ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁶ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁶ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²⁶ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²⁶ is independently substituted 6 membered heteroaryl. In embodiments, R ²⁶ is independently substituted 5 membered heteroaryl. In embodiments, R ²⁶ is independently substituted phenyl. In

embodiments, R ²⁶ is independently unsubstituted phenyl.

[0180] In embodiments, R ²⁶ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁷ -substituted or

unsubstituted alkyl, R ²⁷ -substituted or unsubstituted heteroalkyl, R ²⁷ -substituted or unsubstituted cycloalkyl, R ²⁷ -substituted or unsubstituted heterocycloalkyl, R ²⁷ -substituted or unsubstituted aryl, or R ²⁷ -substituted or unsubstituted heteroaryl; two adjacent R ²⁶ substituents may optionally be joined to form a R ²⁷ -substituted or unsubstituted cycloalkyl, R ²⁷ -substituted or unsubstituted heterocycloalkyl, R ²⁷ -substituted or unsubstituted aryl, or R ²⁷ -substituted or unsubstituted heteroaryl.

[0181] In embodiments, R ²⁶ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁷ -substituted or unsubstituted Ci-C ₆ alkyl, R ²⁷ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁷ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁷ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁷ - substituted or unsubstituted phenyl, or R ²⁷ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁶ substituents may optionally be joined to form a R ²⁷ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁷ -substituted or unsubstituted phenyl, or R ²⁷ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁶ is independently R ²⁷ -substituted Ci-C ₆ alkyl. In embodiments, R 26 is independently R 27 -substituted 26 27

C ₁ -C5 alkyl. In embodiments, R is independently R - substituted C ₁ -C ₄ alkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted Ci-C ₃ alkyl. In

26 27 ^" 26

embodiments, R is independently R -substituted Ci-C ₂ alkyl. In embodiments, R is independently R 27 -substituted C ₂ -C ₆ alkyl. In embodiments, R 26 is independently R 27 -substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted C4-C6 alkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In

embodiments, R ²⁶ is independently R ²⁷ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ²⁶ is independently R ²⁷ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁶ is independently R ²⁷ - substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁶ is independently R ²⁷ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁶ is independently R ²⁷ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁶ is independently R ²⁷ - substituted 6 membered heteroaryl. In embodiments, R ²⁶ is independently R ²⁷ -substituted 5 membered heteroaryl. In embodiments, R ²⁶ is independently R ²⁷ -substituted phenyl.

[0182] R ²⁷ is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁷ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁷ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²⁷ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²⁷ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ²⁷ is independently unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ²⁷ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ²⁷ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ²⁷ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ²⁷ is independently

unsubstituted C4-C ₆ alkyl. In embodiments, R ²⁷ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²⁷ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²⁷ is

independently substituted C ₁ -C4 alkyl. In embodiments, R ²⁷ is independently substituted C ₁ -C ₃ alkyl. In embodiments, R ²⁶ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²⁷ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²⁷ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁷ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁷ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁷ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁷ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁷ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²⁷ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²⁷ is independently substituted 6 membered heteroaryl. In embodiments, R ²⁷ is independently substituted 5 membered heteroaryl. In embodiments, R ²⁷ is independently substituted phenyl. In

embodiments, R ²⁷ is independently unsubstituted phenyl.

[0183] In embodiments, R ²⁷ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -SO ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁸ -substituted or

unsubstituted alkyl, R ²⁸ -substituted or unsubstituted heteroalkyl, R ²⁸ -substituted or unsubstituted cycloalkyl, R ²⁸ -substituted or unsubstituted heterocycloalkyl, R ²⁸ -substituted or unsubstituted aryl, or R ²⁸ -substituted or unsubstituted heteroaryl; two adjacent R ²⁷ substituents may optionally be joined to form a R ²⁸ -substituted or unsubstituted cycloalkyl, R ²⁸ -substituted or unsubstituted heterocycloalkyl, R ²⁸ -substituted or unsubstituted aryl, or R ²⁸ -substituted or unsubstituted heteroaryl.

[0184] In embodiments, R ²⁷ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ²⁸ -substituted or unsubstituted Ci-C ₆ alkyl, R ²⁸ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ²⁸ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ²⁸ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁸ - substituted or unsubstituted phenyl, or R ²⁸ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁷ substituents may optionally be joined to form a R ²⁸ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁸ -substituted or unsubstituted phenyl, or R ²⁸ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁷ is independently R ²⁸ -substituted Ci-C ₆ alkyl. In embodiments, R is independently R -substituted C ₁ -C5 alkyl. In embodiments, R is independently R - substituted C ₁ -C4 alkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted Ci-C ₃ alkyl. In

27 28 27

embodiments, R is independently R -substituted Ci-C ₂ alkyl. In embodiments, R is independently R 28 -substituted C ₂ -C ₆ alkyl. In embodiments, R 27 is independently R 28 -substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In

embodiments, R ²⁷ is independently R ²⁸ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁷ is independently R ²⁸ -substituted or

unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁷ is independently R ²⁸ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁷ is independently R ²⁸ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁷ is independently R ²⁸ - substituted 6 membered heteroaryl. In embodiments, R ²⁷ is independently R ²⁸ -substituted 5 membered heteroaryl. In embodiments, R ²⁷ is independently R ²⁸ -substituted phenyl.

[0185] R ²⁹ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁹ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ²⁹ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ²⁹ is independently unsubstituted C ₁ -C4 alkyl. In embodiments, R ²⁹ is independently unsubstituted C ₁ -C3 alkyl. In embodiments, R ²⁹ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ²⁹ is independently unsubstituted C ₂ -C6 alkyl. In embodiments, R ²⁹ is independently unsubstituted C3-C6 alkyl. In embodiments, R ²⁹ is independently

unsubstituted C4-C6 alkyl. In embodiments, R ²⁹ is independently substituted Ci-C ₆ alkyl. In embodiments, R ²⁹ is independently substituted C ₁ -C5 alkyl. In embodiments, R ²⁹ is

independently substituted C ₁ -C4 alkyl. In embodiments, R ²⁹ is independently substituted C ₁ -C3 alkyl. In embodiments, R ²⁹ is independently substituted C ₁ -C ₂ alkyl. In embodiments, R ²⁹ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ²⁹ is independently substituted C3-C ₆ alkyl. In embodiments, R ²⁹ is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁹ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁹ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁹ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ²⁹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ²⁹ is independently substituted 6 membered heteroaryl. In embodiments, R ²⁹ is independently substituted 5 membered heteroaryl. In embodiments, R ²⁹ is independently substituted phenyl. In

embodiments, R ²⁹ is independently unsubstituted phenyl. [0186] In embodiments, R ²⁹ is independently halogen, oxo, -CF ₃ , -CCI ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -SO ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³⁰ -substituted or

unsubstituted alkyl, R ³⁰ -substituted or unsubstituted heteroalkyl, R ³⁰ -substituted or unsubstituted cycloalkyl, R ³⁰ -substituted or unsubstituted heterocycloalkyl, R ³⁰ -substituted or unsubstituted aryl, or R ³⁰ -substituted or unsubstituted heteroaryl; two adjacent R ²⁹ substituents may optionally be joined to form a R ³⁰ -substituted or unsubstituted cycloalkyl, R ³⁰ -substituted or unsubstituted heterocycloalkyl, R ³⁰ -substituted or unsubstituted aryl, or R ³⁰ -substituted or unsubstituted heteroaryl.

[0187] In embodiments, R ²⁹ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³⁰ -substituted or

unsubstituted Ci-C ₆ alkyl, R ³⁰ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³⁰ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ³⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁰ -substituted or unsubstituted phenyl, or R ³⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ²⁹ substituents may optionally be joined to form a R ³⁰ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁰ -substituted or unsubstituted phenyl, or R ³⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁹ is independently R ³⁰ -substituted Ci-C ₆ alkyl. In embodiments, R is independently R -substituted C ₁ -C5 alkyl. In embodiments, R is independently R 30 -substituted 29 30

C ₁ -C ₄ alkyl. In embodiments, R is independently R -substituted Ci-C ₃ alkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted Ci-C ₂ alkyl. In embodiments, R 29 is independently R 30 -substituted C ₂ -C ₆ alkyl. In embodiments, R 29 is independently R 30 - substituted C ₃ -C ₆ alkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted C ₄ -C ₆ alkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ²⁹ is independently R ³⁰ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ²⁹ is independently R ³⁰ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ²⁹ is independently R ³⁰ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ²⁹ is independently R ³⁰ - substituted 6 membered heteroaryl. In embodiments, R ²⁹ is independently R ³⁰ -substituted 5 membered heteroaryl. In embodiments, R ²⁹ is independently R ³⁰ -substituted phenyl. [0188] R ³⁰ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³⁰ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³⁰ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ³⁰ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ³⁰ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ³⁰ is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ³⁰ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ³⁰ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ³⁰ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ³⁰ is independently

unsubstituted C4-C6 alkyl. In embodiments, R ³⁰ is independently substituted Ci-C ₆ alkyl. In embodiments, R ³⁰ is independently substituted C ₁ -C5 alkyl. In embodiments, R ³⁰ is

independently substituted C ₁ -C ₄ alkyl. In embodiments, R ³⁰ is independently substituted Ci-C ₃ alkyl. In embodiments, R ³⁰ is independently substituted Ci-C ₂ alkyl. In embodiments, R ³⁰ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ³⁰ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ³⁰ is independently substituted C4-C6 alkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ³⁰ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³⁰ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³⁰ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³⁰ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ³⁰ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ³⁰ is independently substituted 6 membered heteroaryl. In embodiments, R ³⁰ is independently substituted 5 membered heteroaryl. In embodiments, R ³⁰ is independently substituted phenyl. In

embodiments, R ³⁰ is independently unsubstituted phenyl. [0189] In embodiments, R ³⁰ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³¹ -substituted or

unsubstituted alkyl, R ³¹ - substituted or unsubstituted heteroalkyl, R ³¹ -substituted or unsubstituted cycloalkyl, R ³¹ - substituted or unsubstituted heterocycloalkyl, R ³¹ - substituted or unsubstituted aryl, or R ³¹ -substituted or unsubstituted heteroaryl; two adjacent R ³⁰ substituents may optionally be joined to form a R ³¹ -substituted or unsubstituted cycloalkyl, R ³¹ - substituted or unsubstituted heterocycloalkyl, R ³¹ -substituted or unsubstituted aryl, or R ³¹ -substituted or unsubstituted heteroaryl.

[0190] In embodiments, R ³⁰ is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³¹ -substituted or

unsubstituted Ci-C ₆ alkyl, R ³¹ - substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³¹ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ³¹ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³¹ -substituted or unsubstituted phenyl, or R ³¹ - substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³⁰ substituents may optionally be joined to form a R ³¹ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³¹ -substituted or unsubstituted phenyl, or R ³¹ - substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³⁰ is independently R ³¹ -substituted Ci-C ₆ alkyl. In embodiments, R 30 is independently R 31 -substituted 30

C ₁ -C5 alkyl. In embodiments, R is independently R 31 -substituted 30 31

C ₁ -C4 alkyl. In embodiments, R is independently R -substituted Ci-C ₃ alkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted C ₁ -C ₂ alkyl. In embodiments, R 30 is independently R 31 -substituted C ₂ -C ₆ alkyl. In embodiments, R 30 is independently R 31 - substituted C ₃ -C ₆ alkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted C4-C6 alkyl. In embodiments, R ³⁰ is independently R ³¹ - substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³⁰ is independently R ³¹ - substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³⁰ is independently R ³¹ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³⁰ is independently R ³¹ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³⁰ is independently R ³¹ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³⁰ is independently R ³¹ - substituted 6 membered heteroaryl. In embodiments, R ³⁰ is independently R ³¹ -substituted 5 membered heteroaryl.

[0191] R ³² is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -S0 ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³² is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ³² is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ³² is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ³² is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ³² is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ³² is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ³² is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ³² is independently

unsubstituted C ₄ -C ₆ alkyl. In embodiments, R ³² is independently substituted Ci-C ₆ alkyl. In embodiments, R ³² is independently substituted C1-C5 alkyl. In embodiments, R ³² is

independently substituted C ₁ -C ₄ alkyl. In embodiments, R ³² is independently substituted Ci-C ₃ alkyl. In embodiments, R ³² is independently substituted Ci-C ₂ alkyl. In embodiments, R ³² is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ³² is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ³² is independently substituted C ₄ -C ₆ alkyl. In embodiments, R ³² is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³² is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³² is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³² is independently substituted or unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, R ³² is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³² is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³² is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³² is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³² is independently unsubstituted 6 membered heteroaryl. In embodiments, R ³² is independently unsubstituted 5 membered heteroaryl. In embodiments, R ³² is independently substituted 6 membered heteroaryl. In embodiments, R ³² is independently substituted 5 membered heteroaryl. In embodiments, R ³² is independently substituted phenyl. In

embodiments, R ³² is independently unsubstituted phenyl.

[0192] In embodiments, R ³² is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³³ -substituted or

unsubstituted alkyl, R ³³ -substituted or unsubstituted heteroalkyl, R ³³ -substituted or unsubstituted cycloalkyl, R ³³ -substituted or unsubstituted heterocycloalkyl, R ³³ -substituted or unsubstituted aryl, or R ³³ -substituted or unsubstituted heteroaryl; two adjacent R ³² substituents may optionally be joined to form a R ³³ -substituted or unsubstituted cycloalkyl, R ³³ -substituted or unsubstituted heterocycloalkyl, R ³³ -substituted or unsubstituted aryl, or R ³³ -substituted or unsubstituted heteroaryl.

[0193] In embodiments, R ³² is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³³ -substituted or

unsubstituted Ci-C ₆ alkyl, R ³³ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³³ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ³³ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³³ -substituted or unsubstituted phenyl, or R ³³ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³² substituents may optionally be joined to form a R ³³ - substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³³ -substituted or unsubstituted phenyl, or R ³³ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³² is independently R ³³ -substituted Ci-C ₆ alkyl. In embodiments, R 32 is independently R 33 -substituted 32

C ₁ -C5 alkyl. In embodiments, R is independently R 33 -substituted 32 R 33

C ₁ -C4 alkyl. In embodiments, R is independently -substituted Ci-C ₃ alkyl. In embodiments, R ³² is independently R ³³ -substituted Ci-C ₂ alkyl. In embodiments,

R 32 is independently R 33 -substituted C ₂ -C ₆ alkyl. In embodiments, R 32 is independently R 33 - substituted C ₃ -C ₆ alkyl. In embodiments, R ³² is independently R ³³ -substituted C ₄ -C ₆ alkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³² is independently R ³³ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³² is independently R ³³ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³² is independently R ³³ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³² is independently R ³³ - substituted 6 membered heteroaryl. In embodiments, R ³² is independently R ³³ -substituted 5 membered heteroaryl. In embodiments, R ³² is independently R ³³ -substituted phenyl.

[0194] R ³³ is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO2, -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³³ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³³ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ³³ is independently unsubstituted Ci- C ₅ alkyl. In embodiments, R ³³ is independently unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ³³ is independently unsubstituted Ci-C ₃ alkyl. In embodiments, R ³³ is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ³³ is independently unsubstituted C ₂ -C ₆ alkyl. In embodiments, R ³³ is independently unsubstituted C ₃ -C ₆ alkyl. In embodiments, R ³³ is independently

unsubstituted C4-C6 alkyl. In embodiments, R ³³ is independently substituted Ci-C ₆ alkyl. In embodiments, R ³³ is independently substituted C1-C5 alkyl. In embodiments, R ³³ is

independently substituted C ₁ -C ₄ alkyl. In embodiments, R ³³ is independently substituted Ci-C ₃ alkyl. In embodiments, R ³³ is independently substituted Ci-C ₂ alkyl. In embodiments, R ³³ is independently substituted C ₂ -C ₆ alkyl. In embodiments, R ³³ is independently substituted C ₃ -C ₆ alkyl. In embodiments, R ³³ is independently substituted C4-C6 alkyl. In embodiments, R ³³ is independently substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³³ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³³ is independently substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³³ is independently substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ³³ is

independently substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³³ is independently substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³³ is independently substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³³ is independently substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³³ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ³³ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ³³ is independently substituted 6 membered heteroaryl. In embodiments, R ³³ is independently substituted 5 membered heteroaryl. In embodiments, R ³³ is independently substituted phenyl. In

embodiments, R ³³ is independently unsubstituted phenyl.

[0195] In embodiments, R ³³ is independently halogen, oxo, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³⁴ -substituted or

unsubstituted alkyl, R ³⁴ -substituted or unsubstituted heteroalkyl, R ³⁴ -substituted or unsubstituted cycloalkyl, R ³⁴ -substituted or unsubstituted heterocycloalkyl, R ³⁴ -substituted or unsubstituted aryl, or R ³⁴ -substituted or unsubstituted heteroaryl; two adjacent R ³³ substituents may optionally be j oined to form a R ³⁴ -substituted or unsubstituted cycloalkyl, R ³⁴ -substituted or unsubstituted heterocycloalkyl, R ³⁴ -substituted or unsubstituted aryl, or R ³⁴ -substituted or unsubstituted heteroaryl.

[0196] In embodiments, R ³³ is independently halogen, oxo, -CF ₃ , -CCI3, -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , R ³⁴ -substituted or unsubstituted Ci-C ₆ alkyl, R ³⁴ -substituted or unsubstituted 2 to 6 membered heteroalkyl, R ³⁴ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ³⁴ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁴ - substituted or unsubstituted phenyl, or R ³⁴ -substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ³³ substituents may optionally be joined to form a R ³⁴ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ³⁴ -substituted or unsubstituted phenyl, or R ³⁴ -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³³ is independently R ³⁴ -substituted Ci-C ₆ alkyl. In embodiments,

R 33 is independently R 34 -substituted 33 independently R 34

C ₁ -C5 alkyl. In embodiments, R is - substituted C ₁ -C4 alkyl. In embodiments, R ³³ is independently R ³⁴ -substituted Ci-C ₃ alkyl. In embodiments, R is independently R -substituted C ₁ -C ₂ alkyl. In embodiments, R is independently R 34 -substituted C ₂ -C ₆ alkyl. In embodiments, R 33 is independently R 34 -substituted

C ₃ -C ₆ alkyl. In embodiments, R ³³ is independently R ³⁴ -substituted C4-C6 alkyl. In embodiments,

R ³³ is independently R ³⁴ -substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ³³ is independently R ³⁴ -substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ³³ is independently R ³⁴ -substituted or unsubstituted 2 to 5 membered heteroalkyl. In embodiments, R ³³ is independently R ³⁴ -substituted or unsubstituted C4-C6 cycloalkyl. In embodiments, R ³³ is independently R ³⁴ -substituted or unsubstituted 4 to 6 membered heterocycloalkyl. In embodiments, R ³³ is independently R ³⁴ -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R ³³ is independently R ³⁴ - substituted or unsubstituted 5 membered heteroaryl. In embodiments, R ³³ is independently R ³⁴ - substituted or unsubstituted 6 membered heteroaryl. In embodiments, R ³³ is independently R ³⁴ - substituted 6 membered heteroaryl. In embodiments, R ³³ is independently R ³⁴ -substituted 5 membered heteroaryl. In embodiments, R ³³ is independently R ³⁴ -substituted phenyl.

[0197] Each R ²² , R ²⁵ , R ²⁸ , R ³¹ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , and R ⁴² is independently halogen, oxo, -CH ₃ , -CX ₃ , -CHX ₂ , -CH ₂ X, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0)NH ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)OH, - HOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCX ₃ , -OCHX ₂ , -OCH ₂ X, -SCX ₃ , -SCHX ₂ , -SCH ₂ X, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R ²² is independently hydrogen, unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ²² is independently unsubstituted 3 to 6 membered heteroalkyl. In embodiments, R ²² is independently unsubstituted 4 to 6 membered heteroalkyl. In embodiments, each R ²² , R ²⁵ , R ²⁸ , R ³¹ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , and R ⁴² is independently halogen, oxo, -CH ₃ , -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H,

-NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , unsubstituted C C ₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²² , R ²⁵ , R ²⁸ , R ³¹ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , and R ⁴² are independently halogen, oxo, -CH ₃ , -CX ₃ , -CHX ₂ , -CH ₂ X, -CF ₃ , -CC1 ₃ , -CN, -S(0)CH ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -C(0)CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -SH, -S0 ₃ H, -SO ₄ H,

-S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H,

-NHC(0)OH, -NHOH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCX ₃ , -OCHX ₂ , -OCH ₂ X,

-SCX ₃ , -SCHX ₂ , -SCH ₂ X, unsubstituted Ci-C ₆ alkyl, unsubstituted 2 to 6 membered

heteroalkyl, unsubstituted C ₃ -C ₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²² , R ²⁵ , R ²⁸ , R ³¹ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , and R ⁴² are independently unsubstituted methyl. In embodiments, R ²² , R ²⁵ , R ²⁸ , R ³¹ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , and R ⁴² are independently halogen. [0198] In embodiments, al is independently an integer from 0 to 7. In embodiments, al is independently an integer from 0 to 6. In embodiments, al is independently an integer from 0 to 5. In embodiments, al is independently an integer from 0 to 4. In embodiments, al is

independently an integer from 0 to 3. In embodiments, al is independently an integer from 0 to

2. In embodiments, al is independently an integer from 0 to 1. In embodiments, al is 7. In embodiments, al is 6. In embodiments, al is 5. In embodiments, al is 4. In embodiments, al is

3. In embodiments, al is 2. In embodiments, al is 1. In embodiments, al is 0. In embodiments, bl is independently an integer from 0 to 7. In embodiments, bl is independently an integer from 0 to 6. In embodiments, bl is independently an integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 4. In embodiments, bl is independently an integer from 0 to 3. In embodiments, bl is independently an integer from 0 to 2. In embodiments, bl is independently an integer from 0 to 1. In embodiments, bl is 7. In embodiments, bl is 6. In embodiments, bl is 5. In embodiments, bl is 4. In embodiments, bl is 3. In embodiments, bl is 2. In embodiments, bl is 1. In embodiments, bl is 0. In embodiments, ml is independently an integer from 0 to 2. In embodiments, ml is independently an integer from 0 to 1. In

embodiments, ml is 0. In embodiments, ml is 1. In embodiments, ml is 2. In embodiments, m2 is independently an integer from 0 to 2. In embodiments, m2 is independently an integer from 0 to 1. In embodiments, m2 is 0. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, vl is independently an integer from 0 to 2. In embodiments, vl is independently an integer from 0 to 1. In embodiments, vl is 0. In embodiments, vl is 1. In embodiments, vl is 2. In embodiments, v2 is independently an integer from 0 to 2. In embodiments, v2 is independently an integer from 0 to 1. In embodiments, v2 is 0. In embodiments, v2 is 1. In embodiments, v2 is 2. In embodiments, nl is independently an integer from 0 to 4. In embodiments, nl is independently an integer from 0 to 3. In embodiments, nl is independently an integer from 0 to 2. In embodiments, nl is independently an integer from 0 to 1. In embodiments, nl is 4. In embodiments, nl is 3. In embodiments, nl is 2. In embodiments, nl is 1. In embodiments, nl is 0. In embodiments, n2 is independently an integer from 0 to 4. In embodiments, n2 is independently an integer from 0 to 3. In embodiments, n2 is independently an integer from 0 to 2. In embodiments, n2 is independently an integer from 0 to 1. In embodiments, n2 is 4. In embodiments, n2 is 3. In embodiments, n2 is 2. In embodiments, n2 is 1. In embodiments, n2 is 0.

[0199] In embodiments, X, X ¹ , X ² , X ³ , and X ⁴ are independently -CI, -Br, -I, or -F. In embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X ¹ is -F. In embodiments, X ¹ is -CI. In embodiments, X ¹ is -Br. In embodiments, X ¹ is -I. In embodiments, X ² is -F. In embodiments, X ² is -CI. In embodiments, X ² is -Br. In embodiments, X ² is -I. In embodiments, X ³ is -F. In embodiments, X ³ is -CI. In embodiments, X ³ is -Br. In embodiments, X ³ is -I. In embodiments, X ⁴ is -F. In embodiments, X ⁴ is -CI. In embodiments, X ⁴ is -Br. In embodiments, X ⁴ is -I. [0200] In an embodiment, the compound has the formula (I) and Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , a l. ^ and X ² are as described herein.

[0201] In embodiments, Ring A is phenyl. In embodiments, Ring B is 5 or 6 membered heteroaryl. In embodiments, Ring B is pyridyl. In embodiments, R ¹ is independently a halogen, -CX , -CN, -SO _n iR ¹⁰ , -SCV _I RV, - HNH ₂ , -O R ⁷ R ⁸ , - HC=(0) HNH ₂ ,

- HC=(0) R ⁷ R ⁸ , -N(0) _m i, - R ⁷ R ⁸ , -C(0)R ⁹ , -C(0)-OR ⁹ , -C(0) R ⁷ R ⁸ , -OR ¹⁰ ,

- R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C= (O)R ⁹ , - R ⁷ C(0)-OR ⁹ , - R ⁷ OR ⁹ , -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , - N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , - NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or

unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In

embodiments, R ³ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, al is independently integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 4. In

embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0202] In an embodiment, the compound has the formula:

(Ia) and R ¹ , R ² , R ³ , R ⁴ , al, bl, X ¹ and X ² are as described herein.

[0203] In embodiments, R ³ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³ is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³ is independently substituted or unsubstituted furanyl. In embodiments, R ³ is independently R ²⁶ -substituted or unsubstituted furanyl and R ²⁶ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , - SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁶ is phenyl substituted with halogen. In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently substituted or unsubstituted phenyl. In

4 29 29

embodiments, R is independently R -substituted or unsubstituted furanyl and R is halogen, - CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, - NHOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0204] In an embodiment, the compound has the formula:

(la) and R ¹ , R ² , R ³ , R ⁴ , R ²⁹ , al, bl, X and X ² are as described herein. Ring C is a R ²⁹ -substituted or unsubstituted heterocycloalkyl, R ²⁹ -substituted or unsubstituted aryl, or R ²⁹ -substituted or unsubstituted heteroaryl. In embodiments, Ring C is R ²⁹ -substituted or unsubstituted cycloalkyl, R ²⁹ -substituted or unsubstituted heterocycloalkyl, R ²⁹ -substituted or unsubstituted aryl, or R ²⁹ -substituted or unsubstituted heteroaryl. The symbol z29 is an integer from 0 to 7. In embodiments, z29 is 1.

4 29 29 [0205] In embodiments, R is independently R -substituted or unsubstituted furanyl and R is halogen-substituted or unsubstituted phenyl, or halogen- substituted substituted or unsubstituted 5

to 6 membered heteroaryl. In embodiments, R ⁴ is

[0206] In embodiments, R ⁴ is independently substituted or unsubstituted phenyl. In

4 29 29 embodiments, R is independently R -substituted or unsubstituted phenyl and R is halogen, - CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁹ is

29 29 29 halo en. In embodiments R is -CI. In embodiments R is -Br. In embodiments, R is

[0207] In embodiments, R ³ is independently R ²⁶ -substituted or unsubstituted furanyl and R ²⁶ is halogen-substituted or unsubstituted phenyl, or halogen- substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ³ is It will be understood that when Ring C is bonded to one or more non-hydrogen R moieties, then Ring C is substituted. Likewise, it will be understood that when Ring C is not bonded to any R ²⁹ moieties, or is bonded to R ²⁹ moieties that are all hydrogen moieties, then Ring C is unsubstituted. [0208] In embodiments, R ³ is independently substituted or unsubstituted phenyl. In

embodiments, R ³ is independently R ²⁶ -substituted or unsubstituted phenyl and R ²⁶ is halogen, - CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ²⁶ is halogen. In embodiments, R ²⁶ is -CI. In embodiments, R ²⁶ is -Br. In embodiments, R ²⁶ is

[0209] In embodiments, the compound is Gr-7a, Gr-7b, Gr-7c, or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is Gr-7a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-7b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-7c or an analogue, prodrug, or derivative thereof. [0210] In embodiments, the compound is not Gr-7a, Gr-7b, Gr-7c or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not Gr-7a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-7b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-7c or an analogue, prodrug, or derivative thereof. [0211] In embodiments, the compound is Gr-7a, Gr-7b, or Gr-7c. In embodiments, the compound is Gr-7a. In embodiments, the compound is Gr-7b. In embodiments, the compound is

Gr-7c. [0212] In embodiments, the compound is not Gr-7a, Gr-7b, or Gr-7c. In embodiments, the compound is not Gr-7a. In embodiments, the compound is not Gr-7b. In embodiments, the compound is not Gr-7c.

[0213] In an embodiment, the compound has the formula:

(Ha) and R ¹ , R ² , R ⁴ , al, b l are as described herein.

[0214] In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, - CONH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ¹ 3, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered

heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, - OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, al is independently an integer from 0 to 5. In embodiments, b l is independently an integer from 0 to 5. In embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F. In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is

independently substituted or unsubstituted 5 or 10 membered heteroaryl. In embodiments, R ⁴ is independently R ²⁹ -substituted or unsubstituted benzimidazolyl and R ²⁹ is halogen, -CF ₃ , -CN, - OH, - H ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - H H ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently unsubstituted benzimidazolyl.

[0215] In an embodiment, the compound has the formula:

(lib) and R ¹ , R ² , R ⁴ , al, bl are as described herein. [0216] In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered

heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0) NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, al is independently an integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 5. In embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F. In embodiments, R ⁴ is hydrogen. In embodiments, wherein R ¹ is independently a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0217] In an embodiment, the compound has the formula:

(He) and R ¹ , R ² , R ⁴ , al , b 1 are as described herein.

[0218] In embodiments, Ring B is a pyridyl. In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO4H, -S0 ₂ H ₂ ,

- HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(O)- OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted C C ₃ alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(O)- OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₃ alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R ⁴ is independently hydrogen. In embodiments, al is independently an integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 5. In embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F. In embodiments, R ¹ is independently a halogen. In embodiments, R ² is independently an -OH, unsubstituted Ci-C ₃ alkyl, or unsubstituted 2 to 3 membered heteroalkyl.

[0219] In embodiments, R ⁴ is substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is substituted or unsubstituted Ci-C ₆ alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -S0 ₃ H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HSO ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ² ₃ , -OCHX ² ₂ , or substituted or unsubstituted Ci-C ₆ alkyl. In embodiments, R ² is independently substituted or unsubstituted Ci-C ₆ alkyl. In embodiments, R ² is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ² is independently unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ² is

independently unsubstituted methyl. In embodiments, R ² is independently -OH. In

embodiments, R ¹ is independently a halogen.

[0220] In embodiments, the compound is Gr-4a, Gr-4b, Gr-4c, Gr-4d, Gr-6b, 018 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is Gr-4a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-4b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-4c or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-4d or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-6b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is 018 or an analogue, prodrug, or derivative thereof. [0221] In embodiments, the compound is not Gr-4a, Gr-4b, Gr-4c, Gr-4d, Gr-6b, 018 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not Gr-4a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-4b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-4c or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-4d or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-6b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not 018 or an analogue, prodrug, or derivative thereof.

[0222] In embodiments, the compound is Gr-4a, Gr-4b, Gr-4c, Gr-4d, Gr-6b, or 018. In embodiments, the compound is Gr-4a. In embodiments, the compound is Gr-4b. In

embodiments, the compound is Gr-4c. In embodiments, the compound is Gr-4d. In

embodiments, the compound is Gr-6b. In embodiments, the compound is 018.

[0223] In embodiments, the compound is not Gr-4a, Gr-4b, Gr-4c, Gr-4d, Gr-6b, or 018. In embodiments, the compound is not Gr-4a. In embodiments, the compound is not Gr-4b. In embodiments, the compound is not Gr-4c. In embodiments, the compound is not Gr-4d. In embodiments, the compound is not Gr-6b. In embodiments, the compound is not 018.

[0224] In an embodiment, the compound has the formula:

(Ilia) and R ¹ , R ² , R ⁵ , al, bl are as described herein.

[0225] In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HSO2H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 or 6 membered heteroaryl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁵ is hydrogen or R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ ) - to form an unsubstituted 5 membered heterocycloalkyl or unsubstituted 5 membered heteroaryl. In embodiments, al is independently an integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 2. In embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0226] In embodiments, R ¹ is -SO ₂ NH ₂ . In embodiments, R ¹ is -CF ₃ . In embodiments, R ¹ is - CI. In embodiments, R ¹ is substituted or unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹ is unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹ is unsubstituted C ₁ -C ₂ alkyl. In embodiments, R ¹ is unsubstituted methyl. In embodiments, al is 1. In embodiments, al is 2. In embodiments, R ¹ is halogen. In embodiments, R ¹ is unsubstituted ethyl.

[0227] In embodiments, the compound is Gr-la, Gr-lb, Gr-lc, Gr-ld, Gr-le, Gr-lf, Gr-lg, 013 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is Gla or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-lb or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-lc or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-ld or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-le or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-lf or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-lg or an analogue, prodrug, or derivative thereof. In embodiments, the compound is 013 or an analogue, prodrug, or derivative thereof.

[0228] In embodiments, the compound is not Gr-la, Gr-lb, Gr-lc, Gr-ld, Gr-le, Gr-lf, Gr-lg, 013 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not Gla or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-lb or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-lc or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-ld or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-le or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-lf or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-lg or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not 013 or an analogue, prodrug, or derivative thereof.

[0229] In embodiments, the compound is Gr-la, Gr-lb, Gr-lc, Gr-ld, Gr-le, Gr-lf, Gr-lg, or 013. In embodiments, the compound is Gla. In embodiments, the compound is Gr-lb. In embodiments, the compound is Gr-lc. In embodiments, the compound is Gr-ld. In

embodiments, the compound is Gr-le. In embodiments, the compound is Gr-lf. In

embodiments, the compound is Gr-lg. In embodiments, the compound is 013.

[0230] In embodiments, the compound is not Gr-la, Gr-lb, Gr-lc, Gr-ld, Gr-le, Gr-lf, Gr-lg, or 013. In embodiments, the compound is not Gla. In embodiments, the compound is not Gr- lb. In embodiments, the compound is not Gr-lc. In embodiments, the compound is not Gr-ld. In embodiments, the compound is not Gr-le. In embodiments, the compound is not Gr-lf. In embodiments, the compound is not Gr-lg. In embodiments, the compound is not 013.

[0231] In an embodiment, the compound has the formula:

described herein.

[0232] In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH,

-OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ³ is independently unsubstituted Ci-C ₆ alkyl or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, al is independently an integer from 0 to 5. In embodiments, bl is independently an integer from 0 to 5. In embodiments, X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0233] In embodiments, the compound has the formula:

wherein and R ¹ and R ² are -0(unsubstituted

Ci-C ₆ alkyl) and al, and bl are as described herein. In embodiments, R ¹ and R ² are -OCH ₃ .

[0234] In embodiments, R ³ is independently unsubstituted Ci-C ₆ alkyl. In embodiments, R ³ is independently unsubstituted Ci-C ₄ alkyl. In embodiments, R ³ is independently unsubstituted Ci- C ₃ alkyl. In embodiments, R ³ is independently unsubstituted methyl. In embodiments, R ³ is independently unsubstituted ethyl. In embodiments, R ³ is independently unsubstituted propyl.

[0235] In embodiments, the compound is 015, 023 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is 015 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is 023 or an analogue, prodrug, or derivative thereof.

[0236] In embodiments, the compound is not 015, 023 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not 015 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not 023 or an analogue, prodrug, or derivative thereof.

[0237] In embodiments, the compound is 015 or 023. In embodiments, the compound is 015. In embodiments, the compound is 023.

[0238] In embodiments, the compound is not 015 or 023. In embodiments, the compound is not 015. In embodiments, the compound is not 023.

[0239] In an embodiment, the compound has the formula:

(Va) and R ¹ , R ² , and al are as described herein. In embodiments, R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)-OH, -NHOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ² is independently -S0 ₂ R ¹⁴ , -C(0) R ^u R ¹² , or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ¹¹ , R ¹² , and R ¹⁴ are independently hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, al is independently an integer from 0 to 5.

[0240] In embodiments, R ² is independently -S0 ₂ R ¹⁴ , -C(0)NR ^u R ¹² , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R ¹² is substituted or unsubstituted C ₆ cycloalkyl. In embodiments, R ¹² is unsubstituted C ₆ cycloalkyl. In embodiments, R ¹¹ is hydrogen and R ¹² is substituted or unsubstituted C ₃ -C ₆ cycloalkyl. In embodiments, R ¹¹ is hydrogen and R ¹² is substituted or unsubstituted C ₆ cycloalkyl. In embodiments, R ¹¹ is hydrogen and R ¹² is unsubstituted C ₆ cycloalkyl. In embodiments, R ¹² is unsubstituted Ci-C ₆ alkyl. In embodiments, R ¹² is or unsubstituted methyl. In embodiments, R ¹² is R ⁴⁰ -substituted Ci-C ₆ alkyl and R ⁴⁰ is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is R ⁴⁰ - substituted C ₁ -C ₂ alkyl and R ⁴⁰ is unsubstituted 5 to 6 membered heteroaryl.

[0241] In embodiments, R ¹² is substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is substituted phenyl, or substituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is substituted or unsubstituted phenyl. In embodiments, R ¹² is unsubstituted phenyl. In embodiments, R ¹² is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹² is unsubstituted 5 to 6 membered heteroaryl.

[0242] In embodiments, R ¹¹ is hydrogen and R . ¹² i.s *-o ' .. In embodiments, R ¹¹ is

hydrogen and . In embodiments, R ¹¹ is hydrogen and [0243] In embodiments, R is substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R is substituted phenyl, or substituted 5 to 6 membered heteroaryl. In embodiments, R is unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R is substituted or unsubstituted phenyl. In embodiments, R ¹⁴ is unsubstituted phenyl. In embodiments, R ¹² is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹⁴ is unsubstituted 5 to 6 membered heteroaryl.

[0244] In emb . In embodiments, R [0245] In embodiments, R ¹ and R ² are independently -Br, -CI-OCH ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC(0) HNH ₂ , - HC(0) H ₂ , - HS0 ₂ H, - HC(0)H, - HC(0)-OH, - HOH, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0246] In embodiments, the stress resistance increasing compound has the formula:

[0247] In embodiments, the stress resistance increasing compound has the formula:

[0248] In embodiments, the stress resistance increasing compound

[0249] In embodiments, the compound is Gr-5a, Gr-5b, Gr-5c, Gr-5d or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is Gr-5a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-5b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-5c or an analogue, prodrug, or derivative thereof. In embodiments, the compound is Gr-5d or an analogue, prodrug, or derivative thereof.

[0250] In embodiments, the compound is not Gr-5a, Gr-5b, Gr-5c, Gr-5d or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not Gr-5a or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-5b or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-5c or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not Gr-5d or an analogue, prodrug, or derivative thereof.

[0251] In embodiments, the compound is Gr-5a, Gr-5b, Gr-5c, or Gr-5d. In embodiments, the compound is Gr-5a. In embodiments, the compound is Gr-5b. In embodiments, the compound is Gr-5c. In embodiments, the compound is Gr-5d.

[0252] In embodiments, the compound is not Gr-5a, Gr-5b, Gr-5c, or Gr-5d. In embodiments, the compound is not Gr-5a. In embodiments, the compound is not Gr-5b. In embodiments, the compound is not Gr-5c. In embodiments, the compound is not Gr-5d. [0253] In embodiments, the compound is 011, O20, 06 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is 011 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is O20 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is 06 or an analogue, prodrug, or derivative thereof. [0254] In embodiments, the compound is not Oi l, O20, 06 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound is not 011 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not O20 or an analogue, prodrug, or derivative thereof. In embodiments, the compound is not 06 or an analogue, prodrug, or derivative thereof.

[0255] In embodiments, the compound is 011, O20, or 06. In embodiments, the compound is Oi l . In embodiments, the compound is O20. In embodiments, the compound is 06. [0256] In embodiments, the compound is not Oi l, O20, or 06. In embodiments, the compound is not Oi l . In embodiments, the compound is not 020. In embodiments, the compound is not 06.

[0257] In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3a, Gr-3b, Gr-3c, Gr-6c, 06, Oi l, 012, 014, 017, or 020. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3a. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3b. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3c. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-6c. In embodiments, the compound (e.g., stress resistance increasing compound) is 06. In embodiments, the compound (e.g., stress resistance increasing compound) is 011. In embodiments, the compound (e.g., stress resistance increasing compound) is 012. In embodiments, the compound (e.g., stress resistance increasing compound) is 014. In embodiments, the compound (e.g., stress resistance increasing compound) is 017. In

embodiments, the compound (e.g., stress resistance increasing compound) is 020.

[0258] In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr- le, Gr-3a, Gr-3b, Gr-3c, Gr-6c, Gr-7a, 012, 013, 014, 017 and 023. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-le. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3a. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3b. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3c. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-6c. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-7a. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 012. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 013. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 014. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 017. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 023.

[0259] In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3a,

Gr-3b, Gr-3c, Gr-6c, 06, Oi l, 012, 014, 017, or 020 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3a or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3b or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-3c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is Gr-6c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 06 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 011 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 012 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 014 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 017 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., stress resistance increasing compound) is 020 or an analogue, prodrug, or derivative thereof.

[0260] In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr- le, Gr-3a, Gr-3b, Gr-3c, Gr-6c, Gr-7a, 012, 013, 014, 017 and 023 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-le or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3a or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3b or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-3c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-6c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gr-7a or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 012 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 013 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 014 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 017 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 023 or an analogue, prodrug, or derivative thereof. [0261] In embodiments, the compound is Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-3D, Gr-4A, Gr-4B, Gr-4C, Gr- 4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, OlO, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031; or an analogue, prodrug, or derivative of any of the compounds.

[0262] In embodiments, the compound is Gr-1 A. In embodiments, the compound is Gr-IB. In embodiments, the compound is Gr-lC. In embodiments, the compound is Gr-ID. In

embodiments, the compound is Gr-IE. In embodiments, the compound is Gr-IF. In

embodiments, the compound is Gr-IG. In embodiments, the compound is Gr-2A. In

embodiments, the compound is Gr-2B. In embodiments, the compound is Gr-2C. In

embodiments, the compound is Gr-2D. In embodiments, the compound is Gr-2E. In

embodiments, the compound is Gr-3A. In embodiments, the compound is Gr-3B. In

embodiments, the compound is Gr-3C. In embodiments, the compound is Gr-3D. In

embodiments, the compound is Gr-4A. In embodiments, the compound is Gr-4B. In

embodiments, the compound is Gr-4C. In embodiments, the compound is Gr-4D. In

embodiments, the compound is Gr-5A. In embodiments, the compound is Gr-5B. In

embodiments, the compound is Gr-5C. In embodiments, the compound is Gr-5D. In

embodiments, the compound is Gr-6A. In embodiments, the compound is Gr-6B. In

embodiments, the compound is Gr-6C. In embodiments, the compound is Gr-7A. In

embodiments, the compound is Gr-7B. In embodiments, the compound is Gr-7C. In

embodiments, the compound is 01. In embodiments, the compound is 02. In embodiments, the compound is 03. In embodiments, the compound is 04. In embodiments, the compound is 05. In embodiments, the compound is 06. In embodiments, the compound is 07. In embodiments, the compound is 08. In embodiments, the compound is 09. In embodiments, the compound is OlO. In embodiments, the compound is 011. In embodiments, the compound is 012. In embodiments, the compound is 013. In embodiments, the compound is 014. In embodiments, the compound is 015. In embodiments, the compound is 016. In embodiments, the compound is 017. In embodiments, the compound is 018. In embodiments, the compound is 019. In embodiments, the compound is 020. In embodiments, the compound is 021. In embodiments, the compound is 022. In embodiments, the compound is 023. In embodiments, the compound is 024. In embodiments, the compound is 025. In embodiments, the compound is 026. In embodiments, the compound is 027. In embodiments, the compound is 028. In embodiments, the compound is 029. In embodiments, the compound is O30. In embodiments, the compound is 031.

[0263] In embodiments, the compound is Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-3D, Gr-4A, Gr-4B, Gr-4C, Gr- 4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, OlO, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, or 031.

[0264] In embodiments, the stress resistance increasing compound is Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr- 3D, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, OlO, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, or an analogue, prodrug, or derivative of any of the compounds.

[0265] In embodiments, the stress resistance increasing compound is Gr-IA. In embodiments, the stress resistance increasing compound is Gr-IB. In embodiments, the stress resistance increasing compound is Gr-lC. In embodiments, the stress resistance increasing compound is Gr-ID. In embodiments, the stress resistance increasing compound is Gr-IE. In embodiments, the stress resistance increasing compound is Gr-IF. In embodiments, the stress resistance increasing compound is Gr-IG. In embodiments, the stress resistance increasing compound is Gr-2A. In embodiments, the stress resistance increasing compound is Gr-2B. In embodiments, the stress resistance increasing compound is Gr-2C. In embodiments, the stress resistance increasing compound is Gr-2D. In embodiments, the stress resistance increasing compound is Gr-2E. In embodiments, the stress resistance increasing compound is Gr-3A. In embodiments, the stress resistance increasing compound is Gr-3B. In embodiments, the stress resistance increasing compound is Gr-3C. In embodiments, the stress resistance increasing compound is Gr-3D. In embodiments, the stress resistance increasing compound is Gr-4A. In embodiments, the stress resistance increasing compound is Gr-4B. In embodiments, the stress resistance increasing compound is Gr-4C. In embodiments, the stress resistance increasing compound is Gr-4D. In embodiments, the stress resistance increasing compound is Gr-5A. In embodiments, the stress resistance increasing compound is Gr-5B. In embodiments, the stress resistance increasing compound is Gr-5C. In embodiments, the stress resistance increasing compound is Gr-5D. In embodiments, the stress resistance increasing compound is Gr-6A. In embodiments, the stress resistance increasing compound is Gr-6B. In embodiments, the stress resistance increasing compound is Gr-6C. In embodiments, the stress resistance increasing compound is Gr-7A. In embodiments, the stress resistance increasing compound is Gr-7B. In embodiments, the stress resistance increasing compound is Gr-7C. In embodiments, the stress resistance increasing compound is 01. In embodiments, the stress resistance increasing compound is 02. In embodiments, the stress resistance increasing compound is 03. In embodiments, the stress resistance increasing compound is 04. In embodiments, the stress resistance increasing compound is 05. In embodiments, the stress resistance increasing compound is 06. In embodiments, the stress resistance increasing compound is 07. In embodiments, the stress resistance increasing compound is 08. In embodiments, the stress resistance increasing compound is 09. In embodiments, the stress resistance increasing compound is OlO. In embodiments, the stress resistance increasing compound is 011. In embodiments, the stress resistance increasing compound is 012. In embodiments, the stress resistance increasing compound is 013. In embodiments, the stress resistance increasing compound is 014. In embodiments, the stress resistance increasing compound is 015. In embodiments, the stress resistance increasing compound is 016. In embodiments, the stress resistance increasing compound is 017. In embodiments, the stress resistance increasing compound is 018. In embodiments, the stress resistance increasing compound is 019. In embodiments, the stress resistance increasing compound is 020. In embodiments, the stress resistance increasing compound is 021. In embodiments, the stress resistance increasing compound is 022. In embodiments, the stress resistance increasing compound is 023. In embodiments, the stress resistance increasing compound is 024. In embodiments, the stress resistance increasing compound is 025. In embodiments, the stress resistance increasing compound is 026. In embodiments, the stress resistance increasing compound is 027. In embodiments, the stress resistance increasing compound is 028. In embodiments, the stress resistance increasing compound is 029. In embodiments, the stress resistance increasing compound is 030. In embodiments, the stress resistance increasing compound is 031.

[0266] In embodiments, the compound is not Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr- 1G, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-3D, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, OlO, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031; or an analogue, prodrug, or derivative of any of the compounds.

[0267] In embodiments, the compound is not Gr-IA. In embodiments, the compound is not

Gr-IB. In embodiments, the compound is not Gr-lC. In embodiments, the compound is not Gr- ID. In embodiments, the compound is not Gr-IE. In embodiments, the compound is not Gr-IF. In embodiments, the compound is not Gr-IG. In embodiments, the compound is not Gr-2A. In embodiments the compound s not Gr-2B. In embodiments, the compound is not Gr-2C. In embodiments the compound s not Gr-2D. In embodiments, the compound is not Gr-2E. In embodiments the compound s not Gr-3A. In embodiments, the compound is not Gr-3B. In embodiments the compound s not Gr-3C. In embodiments, the compound is not Gr-3D. In embodiments the compound s not Gr-4A. In embodiments, the compound is not Gr-4B. In embodiments the compound s not Gr-4C. In embodiments, the compound is not Gr-4D. In embodiments the compound s not Gr-5A. In embodiments, the compound is not Gr-5B. In embodiments the compound s not Gr-5C. In embodiments, the compound is not Gr-5D. In embodiments the compound s not Gr-6A. In embodiments, the compound is not Gr-6B. In embodiments the compound s not Gr-6C. In embodiments, the compound is not Gr-7A. In embodiments the compound s not Gr-7B. In embodiments, the compound is not Gr-7C. In embodiments the compound s not 01. In embodiments, the compound is not 02. In

embodiments the compound s not 03. In embodiments, the compound is not 04. In

embodiments the compound s not 05. In embodiments, the compound is not 06. In

embodiments the compound s not 07. In embodiments, the compound is not 08. In

embodiments the compound s not 09. In embodiments, the compound is not OlO. In embodiments the compound s not Oi l . In embodiments, the compound is not 012. In embodiments the compound s not 013. In embodiments, the compound is not 014. In embodiments the compound s not 015. In embodiments, the compound is not 016. In embodiments the compound s not 017. In embodiments, the compound is not 018. In embodiments the compound s not 019. In embodiments, the compound is not 020. In embodiments the compound s not 021. In embodiments, the compound is not 022. In embodiments the compound s not 023. In embodiments, the compound is not 024. In embodiments the compound s not 025. In embodiments, the compound is not 026. In embodiments the compound s not 027. In embodiments, the compound is not 028. In embodiments the compound s not 029. In embodiments, the compound is not 030. In embodiments the compound s not 031.

[0268] In embodiments, the compound is not Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr- IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-3D, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, OlO, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, or 031. [0269] In embodiments, the stress resistance increasing compound is not Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr-2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr- 3D, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5 A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, O10, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031 or an analogue, prodrug, or derivative of any one of the compounds. In embodiments, the stress resistance increasing compound is not Gr-IA, Gr-IB, Gr-lC, Gr-ID, Gr-IE, Gr-IF, Gr-IG, Gr- 2A, Gr-2B, Gr-2C, Gr-2D, Gr-2E, Gr-3A, Gr-3B, Gr-3C, Gr-3D, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5C, Gr-5D, Gr-6A, Gr-6B, Gr-6C, Gr-7A, Gr-7B, Gr-7C, 01, 02, 03, 04, 05, 06, 07, 08, 09, O10, Oi l, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, or 031.

[0270] In embodiments, the stress resistance increasing compound is not Gr-IA. In

embodiments, the stress resistance increasing compound is not Gr-IB. In embodiments, the stress resistance increasing compound is not Gr-lC. In embodiments, the stress resistance increasing compound is not Gr-ID. In embodiments, the stress resistance increasing compound is not Gr-IE. In embodiments, the stress resistance increasing compound is not Gr-IF. In embodiments, the stress resistance increasing compound is not Gr-IG. In embodiments, the stress resistance increasing compound is not Gr-2A. In embodiments, the stress resistance increasing compound is not Gr-2B. In embodiments, the stress resistance increasing compound is not Gr-2C. In embodiments, the stress resistance increasing compound is not Gr-2D. In embodiments, the stress resistance increasing compound is not Gr-2E. In embodiments, the stress resistance increasing compound is not Gr-3 A. In embodiments, the stress resistance increasing compound is not Gr-3B. In embodiments, the stress resistance increasing compound is not Gr-3C. In embodiments, the stress resistance increasing compound is not Gr-3D. In embodiments, the stress resistance increasing compound is not Gr-4A. In embodiments, the stress resistance increasing compound is not Gr-4B. In embodiments, the stress resistance increasing compound is not Gr-4C. In embodiments, the stress resistance increasing compound is not Gr-4D. In embodiments, the stress resistance increasing compound is not Gr-5 A. In embodiments, the stress resistance increasing compound is not Gr-5B. In embodiments, the stress resistance increasing compound is not Gr-5C. In embodiments, the stress resistance increasing compound is not Gr-5D. In embodiments, the stress resistance increasing compound is not Gr-6A. In embodiments, the stress resistance increasing compound is not Gr-6B. In embodiments, the stress resistance increasing compound is not Gr-6C. In embodiments, the stress resistance increasing compound is not Gr-7A. In embodiments, the stress resistance increasing compound is not Gr-7B. In embodiments, the stress resistance increasing compound is not Gr-7C. In embodiments, the stress resistance increasing compound is not 01. In embodiments, the stress resistance increasing compound is not 02. In embodiments, the stress resistance increasing compound is not 03. In embodiments, the stress resistance increasing compound is not 04. In embodiments, the stress resistance increasing compound is not 05. In embodiments, the stress resistance increasing compound is not 06. In embodiments, the stress resistance increasing compound is not 07. In embodiments, the stress resistance increasing compound is not 08. In embodiments, the stress resistance increasing compound is not 09. In embodiments, the stress resistance increasing compound is not O10. In embodiments, the stress resistance increasing compound is not Oi l . In embodiments, the stress resistance increasing compound is not 012. In embodiments, the stress resistance increasing compound is not 013. In embodiments, the stress resistance increasing compound is not 014. In embodiments, the stress resistance increasing compound is not 015. In embodiments, the stress resistance increasing compound is not 016. In embodiments, the stress resistance increasing compound is not 017. In embodiments, the stress resistance increasing compound is not 018. In embodiments, the stress resistance increasing compound is not 019. In embodiments, the stress resistance increasing compound is not 020. In embodiments, the stress resistance increasing compound is not 021. In embodiments, the stress resistance increasing compound is not 022. In embodiments, the stress resistance increasing compound is not 023. In embodiments, the stress resistance increasing compound is not 024. In embodiments, the stress resistance increasing compound is not 025. In embodiments, the stress resistance increasing compound is not 026. In embodiments, the stress resistance increasing compound is not 027. In embodiments, the stress resistance increasing compound is not 028. In embodiments, the stress resistance increasing compound is not 029. In embodiments, the stress resistance increasing compound is not 030. In embodiments, the stress resistance increasing compound is not 031.

[0271] It is understood that the compound may be a stress resistance increasing compound as described herein. It is understood that the compound may not be a stress resistance increasing compound as described herein. In embodiments, the compound is a compound described herein, including in an aspect, embodiment, example, table, figure, or claim. C. PHARMACEUTICAL COMPOSITIONS

[0272] In an aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. in an aspect, embodiment, example, figure, table, or claim).

I l l [0273] In embodiments of the pharmaceutical compositions, the compound, or pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the compound is included in a drug-eluting stent. [0274] In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is an anti-autoimmune disease agent. In embodiments, the second agent is an anti -inflammatory disease agent. In embodiments, the second agent is an anti- neurodegenerative disease agent. In embodiments, the second agent is an anti-metabolic disease agent. In embodiments, the second agent is an anti-cardiovascular disease agent. In

embodiments, the second agent is an anti-aging agent. In embodiments, the second agent is a longevity agent. In embodiments, the second agent is resveratrol, a derivative, an analog, or a prodrug thereof. In embodiments, the second agent is metformin, a derivative, an analog, or a prodrug thereof. In embodiments, the second agent is rapamycin, a derivative, an analog, or a prodrug thereof. In embodiments, the compound is a compound described herein, including in an aspect, embodiment, example, table, figure, or claim.

D. METHODS OF TREATMENT

[0275] In an aspect is provided a method of treating a disease including administering an effective amount of a compound as described herein. In an aspect is provided a compound as described herein for use as a medicament (e.g., for treatment of a disease). In an aspect is provided a compound as describe herein for use in the treatment of a disease (e.g., including administering an effective amount of a compound as described herein). [0276] In an aspect is provided a method of treating a disease including administering an effective amount of a stress resistance increasing compound (e.g. a compound described herein). In an aspect is provided a stress resistance increasing compound (e.g. a compound described herein) for use as a medicament (e.g., for treatment of a disease). In an aspect is provided a stress resistance increasing compound (e.g. a compound described herein) for use in the treatment of a disease (e.g., including administering an effective amount of a stress resistance increasing compound (e.g. a compound described herein)). [0277] In embodiments, the disease is a disease described herein and the compound is a compound described herein. In embodiments, the compound is a compound described herein, including in an aspect, embodiment, example, table, figure, or claim.

[0278] In embodiments, the disease is cancer. In embodiments, the disease is an autoimmune disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is a metabolic disease. In

embodiments, the disease is an inflammatory disease. In embodiments, the disease is a cardiovascular disease. In embodiments, the disease is Cancer (e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma, including B- acute lymphoblastic lymphoma, non-Hodgkin' s lymphomas (e.g., Burkitt' s, Small Cell, and Large Cell lymphomas), Hodgkin' s lymphoma, leukemia (including AML, ALL, and CML), multiple myeloma, or breast cancer (e.g., triple negative breast cancer)), Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison' s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti- GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet' s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial

pemphigoid/benign mucosal pemphigoid, Crohn' s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic' s disease (neuromyelitis optica), Discoid lupus, Dressier' s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia , Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener' s Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto' s encephalitis, Hashimoto's thyroiditis, Hemolytic anemia, Henoch- Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,

Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,

Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease,

Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, atopic dermatitis, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV- associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff s disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia,

Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, diabetes (e.g., type I or type II), obesity, metabolic syndrome, a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function), fungal infection, transplant rejection, or a cardiovascular disease (e.g., congestive heart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia, delayed after depolarizations, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmias, long QT syndromes, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); atherosclerosis; restenosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE

myocardial infarction; coronary artery disease; ischemic heart disease; cardiac ischemia;

ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism;

pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated with atherosclerosis, surgery, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, hormones, or pregnancy); or cardiac arrhythmias

(e.g., supraventricular arrhythmias, atrial arrhythmias, atrial flutter, or atrial fibrillation). In embodiments, the disease is a polycystic disease. In embodiments, the disease is polycystic kidney disease. In embodiments, the disease is stenosis. In embodiments, the disease is restenosis. In embodiments, the disease is neointimal proliferation. In embodiments, the disease is neointimal hyperplasia.

[0279] In another aspect is provided a compound as described herein for use as a medicament. In embodiments, the medicament may be useful for treating aging in a subject in need of such treatment. In embodiments, the use may include administering a compound, or a

pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.

[0280] In another aspect is provided a compound for use in the treatment of aging in a subject in need of such treatment. In embodiments, the use may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.

[0281] In another aspect is provided a method of treating aging in a subject in need of such treatment, the method including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject.

[0282] In another aspect is provided a method of extending lifespan or inducing longevity in a subject in need of such treatment, the method including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject. In embodiments, the lifespan is increased 1 day. In embodiments, the lifespan is increased 2 days. In embodiments, the lifespan is increased 3 days. In embodiments, the lifespan is increased 5 days. In embodiments, the lifespan is increased 7 days. In embodiments, the lifespan is increased 1 month. In embodiments, the lifespan is increased 2 months. In embodiments, the lifespan is increased 6 months. In embodiments, the lifespan is increased 12 months. In embodiments, the lifespan is increased 2 years. In embodiments, the lifespan is increased 5 years. In embodiments, the lifespan is increased from about 1 week to about 10 years. In embodiments, the lifespan is increased an average of 1 day. In embodiments, the lifespan is increased an average of 2 days. In embodiments, the lifespan is increased an average of 3 days. In embodiments, the lifespan is increased an average of 5 days. In embodiments, the lifespan is increased an average of 7 days. In embodiments, the lifespan is increased an average of 1 month. In embodiments, the lifespan is increased an average of 2 months. In embodiments, the lifespan is increased an average of 6 months. In embodiments, the lifespan is increased an average of 12 months. In embodiments, the lifespan is increased an average of 2 years. In embodiments, the lifespan is increased an average of 5 years. In embodiments, the lifespan is increased an average of from about 1 week to about 10 years. In embodiments, the lifespan is increased an average of at least 1 day. In embodiments, the lifespan is increased an average of at least 2 days. In embodiments, the lifespan is increased an average of at least 3 days. In embodiments, the lifespan is increased an average of at least 5 days. In embodiments, the lifespan is increased an average of at least 7 days. In embodiments, the lifespan is increased an average of at least 1 month. In embodiments, the lifespan is increased an average of at least 2 months. In embodiments, the lifespan is increased an average of at least 6 months. In embodiments, the lifespan is increased an average of at least 12 months. In embodiments, the lifespan is increased an average of at least 2 years. In embodiments, the lifespan is increased an average of at least 5 years. In embodiments, the lifespan is increased an average of at least from about 1 week to about 10 years. In

embodiments, the lifespan extension is measured as a comparison to control (e.g., in the absence of the compound). [0283] In another aspect is provided a compound as described herein for use as a medicament. In embodiments, the medicament may be useful for extending life span or inducing longevity in a subject in need of such treatment. In embodiments, the use may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject. [0284] In an aspect is provided a method of increasing resistance to cellular stress in a subject, the method including administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein (including embodiments) to the subject.

[0285] In embodiments, the cellular stress is oxidative stress. In embodiments, the cellular stress is associated with DNA damage. In embodiments, the cellular stress is associated with exposure to a heavy metal.

[0286] In an aspect is provided a method of increasing lifespan in a subject in need, the method including administering a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein) to the subject.

[0287] In an aspect is provided a method of treating an age associated disease in a subject in need, the method comprising administering a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein) to the subject. [0288] In embodiments, the age associated disease is a cancer, neurodegenerative disease, cardiovascular disease, metabolic disease, or inflammatory disease. In embodiments, the neurodegenerative disease is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, or Huntington's Disease. In embodiments, the metabolic disease is type II diabetes. In embodiments the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is adenosquamous carcinoma.

[0289] In an aspect is provided a method of inhibiting proliferation of cancer cells, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). [0290] In an aspect is provided a method of inhibiting survival of cancer cells, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0291] In embodiments, the cancer cells are EGFR positive, PIK3CA positive, RB I negative, and TP53 negative. In embodiments, the cancer cells are EGFR positive. In embodiments, the cancer cells are PIK3CA positive. In embodiments, the cancer cells are RB I negative. In embodiments, the cancer cells are TP53 negative.

[0292] In an aspect is provided a method of increasing the level of FOX03 activity in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method increases the level of FOX03 activity in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0293] In an aspect is provided a method of increasing the level of RF2 activity in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method increases the level of NRF-2 activity in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0294] In an aspect is provided a method of decreasing the level of NF-κΒ activity in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method increases the level of NF-κΒ activity in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0295] In an aspect is provided a method of increasing the level of autophagy in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method increases the level of autophagy in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0296] In an aspect is provided a method of increasing the level of mTOR activity in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In an aspect is provided a method of decreasing the level of mTOR activity in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method increases the level of mTOR activity in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein). In embodiments, the method decreases the level of mTOR activity in a cell, relative to the absence of the compound, or a pharmaceutically acceptable salt thereof (e.g., a stress resistance increasing compound or a compound described herein).

[0297] In embodiments, the method of increasing the level of FOX03 activity in a cell includes contacting the cell with the compound Gr-7a, Gr-7c, 023 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method of increasing the level of FOX03 activity in a cell includes contacting the cell with the compound Gr-7a or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of FOX03 activity in a cell includes contacting the cell with the compound Gr-7c or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of FOX03 activity in a cell includes contacting the cell with the compound 023 or an analogue, prodrug, or derivative thereof. [0298] In embodiments, the method increases the level of FOX03 activity in a cell relative to the absence of the compound Gr-7a or an analogue, prodrug, or derivative thereof. In

embodiments, the method increases the level of FOX03 activity in a cell relative to the absence of the compound Gr-7c or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of FOX03 activity in a cell relative to the absence of the compound 023 or an analogue, prodrug, or derivative thereof.

[0299] In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-5a, Gr-5b, Gr-5d, Gr-6b, Gr-7c, 06, 013, 015, 018, 020 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-5a or an analogue, prodrug, or derivative thereof. In

embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-5b or an analogue, prodrug, or derivative thereof. In

embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-5d or an analogue, prodrug, or derivative thereof. In

embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-6b. In embodiments, the method of increasing the level of NRF2 activity in a cell includes contacting the cell with the compound Gr-7c or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound 06 or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound 013 or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound 015 or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound 018 or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of NRF2 activity in a cell includes contacting the cell with the compound 020 or an analogue, prodrug, or derivative thereof. [0300] In embodiments, the method increases the level of NRF2 activity in a cell relative to the absence of the compound Gr-5a, Gr-5b, Gr-5d, Gr-6b, Gr-7c, 06, 013, 015, 018, 020 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr- 5a or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-5b or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-5d or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of NRF2 activity in a cell relative to the absence of the compound Gr-6b. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-7c or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound 06 or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound 013 or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound 015 or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of

RF2 activity in a cell relative to the absence of the compound 018 or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound 020 or an analogue, prodrug, or derivative thereof.

[0301] In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-4a, Gr-5b, Gr-5c, Gr-4d or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-4a or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-4b or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound Gr-4c or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of RF2 activity in a cell includes contacting the cell with the compound G4d or an analogue, prodrug, or derivative thereof.

[0302] In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Gr-la, Gr-lc, Gr-ld, Gr-lg, Oi l, 023 or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Gr-la or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Gr-lc or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Gr-ld or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Gr-lg or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound Oi l or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the level of autophagy in a cell includes contacting the cell with the compound 023 or an analogue, prodrug, or derivative thereof.

[0303] In embodiments, the method of increasing the lifespan in a subject in need includes administering a compound Gr-4a, Gr-4b, Gr-4c, Gr-4d or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method of increasing the lifespan in a subject in need includes administering a compound Gr-4a or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the lifespan in a subject in need includes administering a compound Gr-4b or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the lifespan in a subject in need includes administering a compound Gr-4c or an analogue, prodrug, or derivative thereof. In embodiments, the method of increasing the lifespan in a subject in need includes administering a compound Gr-4d or an analogue, prodrug, or derivative thereof.

[0304] In embodiments, the method increases the level of NRF2 activity in a cell relative to the absence of the compound Gr-4a, Gr-5b, Gr-5c, Gr-4d or an analogue, prodrug, or derivative thereof (of any one of the compounds). In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-4a or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-4b or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound Gr-4c or an analogue, prodrug, or derivative thereof. In embodiments, the method increases the level of RF2 activity in a cell relative to the absence of the compound G4d or an analogue, prodrug, or derivative thereof.

[0305] In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gle, G3a, G3b, G3c, G6c, G7a, 012, 013, 014, 017 and 023 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gle or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is G3a or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is G3b or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is G3c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is G6c or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is G7a or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 012 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 013 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 014 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 017 or an analogue, prodrug, or derivative thereof. In embodiments, the compound (e.g., compound capable of increasing lifespan) is 023 or an analogue, prodrug, or derivative thereof.

[0306] In embodiments, the compound (e.g., compound capable of increasing lifespan) is Gle, G3a, G3b, G3c, G6c, G7a, 012, 013, 014, 017 and 023. In embodiments, the compound (e.g., compound capable of increasing lifespan is Gle. In embodiments, the compound (e.g.

compound capable of increasing lifespan is G3a. In embodiments, the compound (e.g.

compound capable of increasing lifespan is G3b. In embodiments, the compound (e.g compound capable of increasing lifespan is G3c. In embodiments, the compound (e.g.

compound capable of increasing lifespan is G6c. In embodiments, the compound (e.g.

compound capable of increasing lifespan is G7a. In embodiments, the compound (e.g.

compound capable of increasing lifespan is 012. In embodiments, the compound (e.g compound capable of increasing lifespan is 013. In embodiments, the compound (e.g compound capable of increasing lifespan is 014. In embodiments, the compound (e.g compound capable of increasing lifespan is 017. In embodiments, the compound (e.g compound capable of increasing lifespan is 023.

EMBODIMENTS

[0307] Embodiment PI . A method of increasing resistance to cellular stress in a subject, said method comprising administering an effective amount of a stress resistance increasing compound to said subject.

[0308] Embodiment P2. The method of Embodiment PI, wherein said cellular stress is oxidative stress.

[0309] Embodiment P3. The method of Embodiment PI, wherein said cellular stress is associated with DNA damage.

[0310] Embodiment P4. A method of increasing lifespan in a subject in need, said method comprising administering a stress resistance increasing compound to said subject. [0311] Embodiment P5. A method of treating an age associated disease in a subject in need, said method comprising administering a stress resistance increasing compound to said subject.

[0312] Embodiment P6. The method of Embodiment P5, wherein age associated disease is a cancer, neurodegenerative disease, cardiovascular disease, metabolic disease, or inflammatory disease.

[0313] Embodiment P7. The method of Embodiment P6, wherein the neurodegenerative disease is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, or

Huntington's Disease.

[0314] Embodiment P8. The method of Embodiment P6, wherein the metabolic disease is type II diabetes.

[0315] Embodiment P9. The method of Embodiment P6, wherein the cancer is lung cancer.

[0316] Embodiment PI 0. The method of Embodiment P6, wherein the cancer is non-small cell lung cancer.

[0317] Embodiment PI 1. The method of Embodiment P6, wherein the cancer is

adenosquamous carcinoma.

[0318] Embodiment P12. A method of inhibiting proliferation of cancer cells, said method comprising contacting said cell with a stress resistance increasing compound.

[0319] Embodiment P13. A method of inhibiting survival of cancer cells, said method comprising contacting said cell with a stress resistance increasing compound. [0320] Embodiment P14. The method of one of Embodiments P12 to PI 3, wherein said cancer cells are EGFR positive, PIK3CA positive, RBI negative, and TP53 negative.

[0321] Embodiment PI 5. A method of increasing the level of FOX03 activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0322] Embodiment PI 6. A method of increasing the level of RF2 activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0323] Embodiment PI 7. A method of increasing the level of autophagy in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0324] Embodiment PI 8. A method of reducing the level of mTOR activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound. [0325] Embodiment PI 9. The method of one of Embodiments PI to P18, wherein the stress resistance increasing compound has the formula:

wherein

Ring A is aryl or heteroaryl;

Ring B is aryl or heteroaryl;

R ¹ is independently a halogen, -CX , -CN, -SO _n iR ¹⁰ , -SO _v i R ⁷ R ⁸ , - HNH ₂ , -O R ⁷ R ⁸ , - HC=(0) HNH ₂ , - HC=(0) R ⁷ R ⁸ , -N(0) _m i, - R ⁷ R ⁸ , -C(0)R ⁹ ,

-C(0)-OR ⁹ , -C(0) R ⁷ R ⁸ , -OR ¹⁰ , - R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C=(0)R ⁹ , - R ⁷ C(0)-OR ⁹ ,

- R ⁷ OR ⁹ ,

-OCX ¹ , -OCHX^, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ² is independently a halogen, -CX ² ₃ , -CN, -SO^R ¹⁴ , -SO _v2 R ^u R ¹² , - HNH ₂ , -O R ^u R ¹² , - HC=(0) HNH ₂ , - HC=(0) R ^u R ¹² , -N(0) _m2 , - R ^U R ¹² , -C(0)R ¹³ ,

-C(0)-OR ¹³ , -C(0) R ^u R ¹² , -OR ¹⁴ , - R ^u S0 ₂ R ¹⁴ , - R ^u C=(0)R ¹³ , - R ^u C(0)-OR ¹³ , - R ^u OR ¹³ , -OCX ² ₃ , -OCHX ² 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; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ³ are independently hydrogen, halogen, -CX ³ ₃ , -CN, -OH, -NH ₂ , -COOH,

-CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ³ ₃ , -OCHX ³ 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;

R ⁴ are independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ⁴ ₃ , -OCHX ⁴ 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;

R ⁵ is hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ )- to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently hydrogen, halogen, -CX ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ₃ , -OCHX 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; R ⁷ and R ⁸

substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ¹¹ and R ¹² substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

al is independently an integer from 0 to 7;

bl is independently an integer from 0 to 7;

ml, m2, vl, and v2 are independently 1 or 2;

nl and n2 are independently an integer from 0 to 4;

X, X ¹ , X ² , X ³ , and X ⁴ are independently -CI, -Br, -I, or -F.

[0326] Embodiment P20. The method of Embodiment PI 9, wherein the stress resistance increasing compound has the formula:

wherein

Ring A is phenyl;

Ring B is 5 or 6 membered heteroaryl;

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ ,

-NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ³ is independently hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ⁴ is independently hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

al is independently an integer from 0 to 5;

bl is independently an integer from 0 to 4;

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

[0327] Embodiment P21. The method of Embodiment P20, wherein Ring B is pyridyl.

[0328] Embodiment P22. The method of Embodiment P20, wherein the stress resistance increasing compound has the formula:

[0329] Embodiment P23. The method of one of Embodiments P20 to P22, wherein R ³ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0330] Embodiment P24. The method of one of Embodiments P20 to P22, wherein R ³ is independently substituted or unsubstituted 5 to 6 membered heteroaryl.

[0331] Embodiment P25. The method of one of Embodiments P20 to P22, wherein R ³ is independently substituted or unsubstituted furanyl.

[0332] Embodiment P26. The method of one of Embodiments P20 to P22, wherein R ³ is independently R ²⁶ -substituted or unsubstituted furanyl; and

R ²⁶ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC= (O)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0333] Embodiment P27. The method of one of Embodiments P20 to P26, wherein R ⁴ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0334] Embodiment P28. The method of one of Embodiments P20 to P26, wherein R ⁴ is independently substituted or unsubstituted phenyl.

[0335] Embodiment P29. The method of one of Embodiments P20 to P26, wherein R ⁴ is independently R ²⁹ -substituted or unsubstituted phenyl; and

R ²⁹ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC= (O)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted C C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0336] Embodiment P30. The method of Embodiment PI 9, wherein the stress resistance increasing compound is:

[0337] Embodiment P31. The method of Embodiment P 19, wherein the stress resistance increasing compound has the formula:

wherein

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX^, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered

heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ - C ₁ 0 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl;

al is independently an integer from 0 to 5;

bl is independently an integer from 0 to 5;

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

[0338] Embodiment P32. The method of Embodiment P31, wherein R ⁴ is independently hydrogen, substituted or unsubstituted C ₆ -Ci ₀ aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. [0339] Embodiment P33. The method of Embodiment P31, wherein R ⁴ is independently substituted or unsubstituted 5 or 10 membered heteroaryl.

[0340] Embodiment P34. The method of Embodiment P31, wherein R ⁴ is independently R ²⁹ -substituted or unsubstituted benzimidazolyl; and

R ²⁹ is halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted C C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0341] Embodiment P35. The method of Embodiment PI 9, wherein the stress resistance increasing compound has the formula:

wherein

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -NO2, -SH, -SO3H, -SO4H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered

heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(ONH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ - C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl;

al is independently an integer from 0 to 5;

bl is independently an integer from 0 to 5;

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

[0342] Embodiment P36. The method of Embodiment P35, wherein R ⁴ is independently hydrogen.

[0343] Embodiment P37. The method of Embodiment P35, wherein R ¹ is independently a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0344] Embodiment P38. The method of Embodiment PI 9, wherein the stress resistance increasing compound has the formula:

wherein

Ring B is a pyridyl;

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -SO3H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl;

R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO2, -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ ,

-NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl;

R ⁴ is independently hydrogen;

al is independently an integer from 0 to 5;

bl is independently an integer from 0 to 5;

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

[0345] Embodiment P39. The method of Embodiment P38, wherein R ¹ is independently a halogen.

[0346] Embodiment P40. The method of one of Embodiment P38 to P39, wherein R ² is independently an -OH, unsubstituted C1-C3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl.

[0347] Embodiment P41. The method of Embodiment PI 9, wherein the compound is:

wherein

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 or 6 membered heteroaryl;

R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ ,

-NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R ⁵ is hydrogen or R ⁵ may optionally be joined to an R ¹ substituent ortho to the - N(R ⁵ )- to form an unsubstituted 5 membered heterocycloalkyl or unsubstituted 5 membered heteroaryl;

al is independently an integer from 0 to 5;

b l is independently an integer from 0 to 2;

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

[0349] Embodiment P43. The method of Embodiment PI 9, wherein the compound is:

[0350] Embodiment P44. The method of one of Embodiment P19 to P43, wherein R ¹ is independently a halogen, -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₂ H ₂ , -OCX ^x ₃ , -OCHX ^x ₂ , substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0351] Embodiment P45. The method of one of Embodiment P19 to P43, wherein R ¹ is independently a halogen, -CF ₃ , -SO ₂ H ₂ , unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0352] Embodiment P46. The method of one of Embodiment P19 to P45, wherein R ² is independently a halogen, -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₂ H ₂ , -OCX ^x ₃ , -OCHX^, substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl. [0353] Embodiment P47. The method of one of Embodiment P19 to P45, wherein R ² is independently a halogen, unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0354] Embodiment P48. The method of Embodiment PI 9, wherein the stress resistance increasing compound has the formula:

wherein

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ ,

-NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;

R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ ,

-NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;

R ³ is independently unsubstituted Ci-C ₆ alkyl or unsubstituted 2 to 6 membered heteroalkyl;

al is independently an integer from 0 to 5; bl is independently an integer from 0 to 5;

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

[0355] Embodiment P49. The method of Embodiment P48, wherein R ¹ is independently a halogen, -CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(O)- OH, - HOH, -OCXS, -OCHX^, unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0356] Embodiment P50. The method of one of Embodiment P48 to P49, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H,

-S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0357] Embodiment P51. The method of one of Embodiment P48 to P50, wherein R ³ is unsubstituted Ci-C ₄ alkyl. [0358] Embodiment P52. The method of Embodiment PI 9, wherein the compound is:

[0359] Embodiment P53. The method of Embodiment PI 9, wherein the stress resistance increasing compound has the formula:

wherein

R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ ,

- HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX^, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;

R ² is independently -S0 ₂ R ¹⁴ , -C(0)NR ^u R ¹² , or substituted or unsubstituted 2 to 6 membered heteroalkyl;

R ¹¹ , R ¹² , and R ¹⁴ are independently hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

al is independently an integer from 0 to 5; and

X ¹ is independently -CI, -Br, -I, or -F.

[0360] Embodiment P54. The method of Embodiment P53, wherein R ¹ is independently a halogen, unsubstituted C ₁ -C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0361] Embodiment P55. The method of Embodiment PI 9, wherein the stress resistance

(Gr-5b),

[0362] Embodiment P56. The method

[0363] Embodiment P57. The method

[0364] Embodiment P58. The method

[0365] Embodiment P59. The method

[0366] Embodiment P60. The method

[0367] Embodiment P61. The method

[0368] Embodiment P62. The method

resistance increasing compound has the formula:

[0370] Embodiment P64. The method of Embodiment PI 6, wherein the stress resistance increasing compound has the formul

[0371] Embodiment P65. The method of Embodiment PI 6, wherein the stress resistance increasing compound has the formula:

Embodiment P66. The method of Embodiment PI 7 wherein the stress resistance increasing compound has the formula: O ^w 2p N (Gr-la), (Gr-lc),

O -ld), ° (Gr-lg), (Oi l), or

[0373] Embodiment P67. The method of Embodiment P4, wherein the stress resistance increasing compound is Gr-le, Gr-3a, Gr-3b, Gr-3c, Gr-6c, Gr-7a, 012, 013, 014, 017, or 023.

[0374] Embodiment P68. The method of Embodiment P4, wherein the stress resistance increasing compound is:

Additional Embodiments

[0375] Embodiment 1. A method of increasing resistance to cellular stress in a subject, said method comprising administering an effective amount of a stress resistance increasing compound to said subject. [0376] Embodiment 2. The method of embodiment 1, wherein said cellular stress is oxidative stress.

[0377] Embodiment 3. The method of embodiment 1, wherein said cellular stress is associated with DNA damage.

[0378] Embodiment 4. A method of increasing lifespan in a subject in need, said method comprising administering a stress resistance increasing compound to said subject.

[0379] Embodiment 5. A method of treating an age associated disease in a subject in need, said method comprising administering a stress resistance increasing compound to said subject.

[0380] Embodiment 6. The method of embodiment 5, wherein age associated disease is a cancer, neurodegenerative disease, cardiovascular disease, metabolic disease, or inflammatory disease.

[0381] Embodiment 7. The method of embodiment 6, wherein the neurodegenerative disease is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, or

Huntington's Disease.

[0382] Embodiment 8. The method of embodiment 6, wherein the metabolic disease is type II diabetes.

[0383] Embodiment 9. The method of embodiment 6, wherein the cancer is lung cancer. [0384] Embodiment 10. The method of embodiment 6, wherein the cancer is non-small cell lung cancer.

[0385] Embodiment 11. The method of embodiment 6, wherein the cancer is

adenosquamous carcinoma.

[0386] Embodiment 12. A method of inhibiting proliferation of cancer cells, said method comprising contacting said cell with a stress resistance increasing compound.

[0387] Embodiment 13. A method of inhibiting survival of cancer cells, said method comprising contacting said cell with a stress resistance increasing compound.

[0388] Embodiment 14. The method of one of embodiments 12 to 13, wherein said cancer cells are EGFR positive, PIK3CA positive, RBI negative, and TP53 negative.

[0389] Embodiment 15. A method of increasing the level of FOX03 activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0390] Embodiment 16. A method of increasing the level of RF2 activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0391] Embodiment 17. A method of increasing the level of autophagy in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0392] Embodiment 18. A method of reducing the level of mTOR activity in a cell, said method comprising contacting the cell with a stress resistance increasing compound.

[0393] Embodiment 19. The method of one of embodiments 1 to 18, wherein the stress resistance increasing compound has the formula:

wherein Ring A is a aryl or heteroaryl; Ring B is a aryl or heteroaryl; R ¹ is independently a halogen, -CX , -CN, -SO _n iR ¹⁰ , -SO _v iNR ⁷ R ⁸ , - HNH ₂ , -O R ⁷ R ⁸ , - HC=(0) HNH ₂ , - HC=(0) R ⁷ R ⁸ , -N(0) _m i, - R ⁷ R ⁸ , -C(0)R ⁹ ,-C(0)-OR ⁹ , -C(0) R ⁷ R ⁸ , -OR ¹⁰ , - R ⁷ S0 ₂ R ¹⁰ , - R ⁷ C=(0)R ⁹ , - R ⁷ C(0)-OR ⁹ , - R ⁷ OR ⁹ , -OCX^, -OCHX^, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or

unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ² is independently a halogen, -CX ² 3, -CN, -SO„2R ¹⁴ , -SO _v2 NR ^u R ¹² , -NHNH ₂ , -ONR ^u R ¹² , -NHC=(0)NHNH ₂ ,

-NHC=(0)NR ^u R ¹² , -N(0) _m2 , -NR ^U R ¹² , -C(0)R ¹³ , -C(0)-OR ¹³ , -C(0)NR ^u R ¹² , -OR ¹⁴ , -NR ^u S0 ₂ R ¹⁴ , -NR ^u C=(0)R ¹³ , -NR ^u C(0)-OR ¹³ , -NR ^u OR ¹³ , -OCX ² ₃ , -OCHX ² 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; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ³ are independently hydrogen, halogen, -CX ³ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ³ ₃ , -OCHX ³ 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;R ⁴ are independently hydrogen, halogen, -CX ⁴ ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ⁴ ₃ , -OCHX ⁴ 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; R ⁵ is hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ )- to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently hydrogen, halogen, -CX ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ₃ , -OCHX 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; R ⁷ and R ⁸ substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ¹¹ and R ¹² substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted

heterocycloalkyl or substituted or unsubstituted heteroaryl; al is independently an integer from 0 to 7; bl is independently an integer from 0 to 7; ml, m2, vl, and v2 are independently 1 or 2; nl and n2 are independently an integer from 0 to 4; X, X ¹ , X ² , X ³ , and X ⁴ are independently -CI, -Br, -I, or -F.

[0394] Embodiment 20. The method of embodiment 19, wherein the stress resistance increasing compound has the formula:

(I); wherein Ring A is a phenyl; Ring B is a 5 or 6 membered heteroaryl; R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ ,

-COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCXS, -OCHX ^x ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CO H ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0)NHNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ³ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; al is independently an integer from 0 to 5; bl is independently an integer from 0 to 4; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0395] Embodiment 21. The method of embodiment 20, wherein Ring B is a pyridyl.

[0396] Embodiment 22. The method of embodiment 20, wherein the stress resistance increasing compound has the formula:

[0397] Embodiment 23. The method of one of embodiments 20 to 22, wherein R ³ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0398] Embodiment 24. The method of one of embodiments 20 to 22, wherein R ³ is independently substituted or unsubstituted 5 to 6 membered heteroaryl.

[0399] Embodiment 25. The method of one of embodiments 20 to 22, wherein R ³ is independently substituted or unsubstituted furanyl.

[0400] Embodiment 26. The method of one of embodiments 20 to 22, wherein R ³ is independently R ²⁶ -substituted or unsubstituted furanyl; and R ²⁶ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC= (O)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0401] Embodiment 27. The method of one of embodiments 20 to 26, wherein R ⁴ is independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0402] Embodiment 28. The method of one of embodiments 20 to 26, wherein R ⁴ is independently substituted or unsubstituted phenyl.

[0403] Embodiment 29. The method of one of embodiments 20 to 26, wherein R ⁴ is independently R ²⁹ -substituted or unsubstituted phenyl; and R ²⁹ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC= (O)H, - HC(0)-OH, -NHOH,

-OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

0404] Embodiment 30. The method of embodiment 19, wherein the stress resistance

[0405] Embodiment 31. The method of embodiment 19, wherein the stress resistance increasing compound has the formula:

(Ha); wherein R ¹ is independently a halogen,

-CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(O)- OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ² 3, -OCHX ² 2, substituted or unsubstituted C C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl; al is independently an integer from 0 to 5; bl is independently an integer from 0 to 5; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0406] Embodiment 32. The method of embodiment 31, wherein R ⁴ is independently hydrogen, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

[0407] Embodiment 33. The method of embodiment 31, wherein R ⁴ is independently substituted or unsubstituted 5 or 10 membered heteroaryl.

[0408] Embodiment 34. The method of embodiment 31, wherein R ⁴ is independently R ²⁹ -substituted or unsubstituted benzimidazolyl; and R ²⁹ is halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC= (O)H, - HC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , phenoxy, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0409] Embodiment 35. The method of embodiment 19, wherein the stress resistance increasing compound has the formula:

-CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH,

- HOH, -OCX 3, -OCHX ₂ , substituted or unsubstituted C C ₆ alkyl, substituted or

unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl; R ² is independently a halogen,

-CX ² ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ ,

- HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(O H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(O)- OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ⁴ is independently hydrogen, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl; al is independently an integer from 0 to 5; b l is independently an integer from 0 to 5; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0410] Embodiment 36. The method of embodiment 35, wherein R ⁴ is independently hydrogen.

[0411] Embodiment 37. The method of embodiment 35, wherein R ¹ is independently a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0412] Embodiment 38. The method of embodiment 19, wherein the stress resistance increasing compound has the formula:

(lie); wherein Ring B is a pyridyl; R is independently a halogen, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H,

- HC=(0)H, - HC(0)-OH, -NHOH, -OCXS, -OCHX^, substituted or unsubstituted C C ₃ alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; R ² is independently a halogen, -CX ² ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ ,

- HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(O)- OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₃ alkyl, or substituted or unsubstituted 2 to 3 membered heteroalkyl; R ⁴ is independently hydrogen; al is independently an integer from 0 to 5; bl is independently an integer from 0 to 5; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0413] Embodiment 39. The method of embodiment 38, wherein R ¹ is independently a halogen.

[0414] Embodiment 40. The method of one of embodiments 38 to 39, wherein R ² is independently an -OH, unsubstituted Ci-C ₃ alkyl, or unsubstituted 2 to 3 membered heteroalkyl.

[0415] Embodiment 41. The method of embodiment 19, wherein the compound is:

[0416] Embodiment 42. The method of embodiment 19, wherein the stress resistance increasing compound has the formula: (Ilia); wherein R is independently a halogen, -CX 3,

-CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO4H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 or 6 membered heteroaryl; R ² is independently a halogen, -CX ² 3, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² 3, -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R ⁵ is hydrogen or R ⁵ may optionally be joined to an R ¹ substituent ortho to the -N(R ⁵ )- to form an unsubstituted 5 membered heterocycloalkyl or unsubstituted 5 membered heteroaryl; al is independently an integer from 0 to 5; bl is independently an integer from 0 to 2; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0417] Embodiment 43. The method of embodiment 19, wherein the compound is:

(Gr-le), (Gr-lf), (Gr-lg), or (013).

[0418] Embodiment 44. The method of one of embodiments 19 to 43, wherein R ¹ is independently a halogen, -CX ^l ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₂ H ₂ , -OCXS, -OCHX^, substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0419] Embodiment 45. The method of one of embodiments 19 to 43, wherein R ¹ is independently a halogen, -CF ₃ , -S0 ₂ H ₂ , unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl. [0420] Embodiment 46. The method of one of embodiments 19 to 45, wherein R ² is independently a halogen, -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ NH ₂ , -OCXS, -OCHX ^x ₂ , substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0421] Embodiment 47. The method of one of embodiments 19 to 45, wherein R ² is independently a halogen, unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0422] Embodiment 48. The method of embodiment 19, wherein the stress resistance increasing compound has the formula: (IVa); wherein R is independently a halogen,

-CX , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ ,

- HNH ₂ , -O H ₂ , - HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, -NHC(O)- OH, - HOH, -OCXS, -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(0)-OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ , substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ³ is independently unsubstituted Ci-C ₆ alkyl or unsubstituted 2 to 6 membered heteroalkyl; al is independently an integer from 0 to 5; bl is independently an integer from 0 to 5; X ¹ and X ² are independently -CI, -Br, -I, or -F.

[0423] Embodiment 49. The method of embodiment 48, wherein R ¹ is independently a halogen, -CX , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(O)- OH, -NHOH, -OCX ¹ 3, -OCHX^, unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0424] Embodiment 50. The method of one of embodiments 48 to 49, R ² is independently a halogen, -CX ² ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC=(0)NHNH ₂ , -NHC=(0)NH ₂ , -NHS0 ₂ H, -NHC=(0)H, -NHC(O)- OH, -NHOH, -OCX ² ₃ , -OCHX ² ₂ unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0425] Embodiment 51. The method of one of embodiments 48 to 50, wherein R ³ is unsubstituted Ci-C ₄ alkyl.

[0426] Embodiment 52. The method of embodiment 19, wherein the compound is:

[0427] Embodiment 53. The method of embodiment 19, wherein the stress resistance increasin compound has the formula:

(Va); wherein R ¹ is independently a halogen, -CX ^X ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC=(0) HNH ₂ , - HC=(0) H ₂ , - HS0 ₂ H, - HC=(0)H, - HC(0)-OH, - HOH, -OCX ^x ₃ , -OCHX^, substituted or unsubstituted Ci-C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ² is independently -S0 ₂ R ¹⁴ , -C(0) R ^u R ¹² , or substituted or unsubstituted 2 to 6 membered heteroalkyl; R ¹¹ , R ¹² , and R ¹⁴ are independently hydrogen, substituted or unsubstituted Ci-C ₆ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; al is independently an integer from 0 to 5; and X ¹ is independently - CI, -Br, -I, or -F.

[0428] Embodiment 54. The method of embodiment 53, wherein R ¹ is independently a halogen, unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0429] Embodiment 55. The method of embodiment 19, wherein the stress resistance increasing compound is:

[0430] Embodiment 56. The method of one of embodiments 19-29, 31-40, 42, 44-51, 53, or 54, wherein al is 2.

[0431] Embodiment 57. The method of one of embodiments 19-29, 31-40, 42, 44-51, 53, or 54, wherein al is 1.

[0432] Embodiment 58. The method of one of embodiments 19-29, 31-40, 42, 44-51, 53, or 54, wherein al is 0.

[0433] Embodiment 59. The method of one of embodiments 19-29, 31-40, 42, or 44-51, wherein bl is 2.

[0434] Embodiment 60. The method of one of embodiments 19-29, 31-40, 42, or 44-51, wherein bl is 1.

[0435] Embodiment 61. The method of one of embodiments 19-29, 31 -40, 42, or 44-51 , wherein bl is 0. [0436] Embodiment 62. The method of one of embodiments 1 to 18, wherein the stress resistance increasing compound has the formula:

[0437] Embodiment 63. The method of embodiment 15, wherein the stress resistance increasing compound has the formula:

[0438] Embodiment 64. The method of embodiment 16, wherein the stress resistance increasing compound has the formula:

[0439] Embodiment 65. The method of embodiment 16, wherein the stress resistance increasing compound has the formula:

[0440] Embodiment 66. The method of embodiment 17, wherein the stress resistance increasin compound has the formula:

[0441] Embodiment 67. The method of embodiment 4, wherein the stress resistance increasing compound is Gr-le, Gr-3a, Gr-3b, Gr-3c, Gr-6c, Gr-7a, 012, 013, 014, 017, or 023.

[0442] Embodiment 68. The method of embodiment 4, wherein the stress resistance increasing compound is:

EXAMPLES

Example 1. High-throughput Screen Identifies Small Molecules That Promote Stress Resistance and Link to Aging

[0443] Increased resistance to environmental stress at the cellular level is often correlated with organismal longevity, as seen for cells from long-lived mutants and wild animal species.

Likewise, in many experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find small molecules that could potentially promote healthy aging in humans, applicants have screened 104,121 small molecules in a human primary fibroblast cell line and identified 61 that increased oxidative stress resistance. Thirty hits fall into seven structurally related chemical groups, suggesting that they may promote stress resistance by acting on common targets. Three small molecules increased C. elegans ' stress resistance, and at least twelve extended their lifespan (from -10% to -50%). In human cells, some small molecules affect the activities of FOX03, RF2, and/or mTOR, proteins whose activation or inhibition can extend lifespan in model organisms.

[0444] In animals, single-gene mutations in many nutrient, energy and stress-sensing genes, such as genes affecting IGF-1 and mTOR signalling, extend youthfulness and lifespan and counter age-related diseases (Bartke, 2011; Fontana et al., 2010; Kenyon, 2010b). Intriguingly, these genes lie in the center of intertwined networks that consist of multiple components, many of which could serve as targets for pharmacological interventions to slow aging and extend healthy lifespan. In fact, in lieu of genetic approaches to inhibit mTOR, or to activate AMPK or sirtuins, small molecules (rapamycin, metformin, resveratrol) that modulate these proteins have been observed to prolong lifespan in several different species (Bjedov et al., 2010; Cabreiro et al., 2013; De Haes et al., 2014; Harrison et al., 2009; Martin-Montalvo et al., 2013; Onken and Driscoll, 2010; Robida-Stubbs et al., 2012; Wilkinson et al., 2012). Remarkably, the same small molecules have been used in humans to treat cancer and diabetes, two prominent diseases that afflict a large size of aging population. Together, these findings highlight the possibility that certain therapeutical small molecules, by acting on longevity-influencing proteins, could extend the healthy life of humans. [0445] Besides these genetic and pharmacological regulators, studies in experimental animals also have revealed phenotypes that correlate with an increased lifespan, such as enhanced resistance to different types of stresses. First, long-lived mutants (such as GH-receptor mutant mice) and their cells tend to be stress resistant (Miller, 2009). Second, cells from long-lived wild animals, such as brown bats and naked mole rats, are resistant to oxidizing radicals (e.g., hydrogen peroxide), heavy metals, and DNA-damaging agents (Harper et al., 2007; Lewis et al., 2012; Salmon et al., 2008). Third, forkhead box O (FOXO) proteins (such as FOX03) and nuclear factor erythroid 2-related factor 2 ( FE2L2/ RF2), key regulators of stress responses, are also crucial to promote longevity in several species, including worms (Bishop and Guarente, 2007; Kenyon et al., 1993; Libina et al., 2003; Ogg et al., 1997; Tullet et al., 2008), flies

(Giannakou et al., 2004; Hwangbo et al., 2004; Sykiotis and Bohmann, 2008), and mice (Leiser and Miller, 2010; Shimokawa et al., 2015; Steinbaugh et al., 2012). In humans, exceptional longevity-associated FOX03 A polymorphisms have been identified in multiple cohorts of centenarians (Kenyon, 2010b), and RF2 activation has been shown to delay senescence in human fibroblasts (Kapeta et al., 2010). From another perspective, approximately 10-15% of mutants selected for stress-resistance in genetic screens in yeast, worms, and plants, turn out to be long-lived (Cao et al., 2003; de Castro et al., 2004; Kennedy et al., 1995; Kim and Sun, 2007). Recently, by screening a library of compounds with known mammalian pharmacology, Ye and coworkers identified 60 that promoted longevity of C. elegans, and of these, 33 increased C. elegans ' resistance to oxidative stress (Ye et al., 2014). These findings, again, appeared to corroborate the idea of enriching for longevity regulators by carrying out primary screens for stress resistance. In particular, this approach could be taken to identify small molecules that promote stress resistance in human cells, and some of these molecules, and particularly, those that have direct or indirect effects on known aging regulators, could be starting points for developing interventions that slow aging and counteract age-related disease in humans.

[0446] Applicants have isolated small molecules that enhanced the resistance of a human primary cell line to hydrogen peroxide. A substantial fraction of molecules were shown to affect FOX03, RF2, and/or mTOR activity, and also extended the lifespan of C. elegans.

[0447] PARP Inhibitor Assay. The assay was performed with the HT Fluorescent

Homogeneous PARP Inhibition Assay Kit (Trevigen), following manufacturer's instructions.

Briefly, nicotinamide adenine dinucleotide, human PARPl and activated-DNA solution was added onto a 96-well plate. 54 repurchased small molecules, at 10 μΜ final concentration, were introduced onto the 96-well assay plate and incubated in a humid chamber at room temperature for 30 min in dark. Cycling mixture, with resazurin and cycling enzyme diaphorase, was then added and incubated further for 1 hr in dark. Reaction was terminated by adding the stopping buffer. Fluorescence was then measured on a FlexStation 3 multi-mode microplate reader (544 nm excitation/ 590 nm emission).

[0448] qPCR Analysis & FOX03 & NRF2 Interference to Address Dependency. For qPCR analysis, WI-38 cells were treated with small molecules (at 10 μΜ) (biological quadruplicates) for 24 hrs and processed for RNA isolation and reverse transcription (RT) with the Cells-to-Ct Kit (Life Technologies), following manufacturer's instructions. RT products were diluted with H ₂ 0 and used for qPCR analysis on an ABI 7300 system (Life Technologies) (technical triplicates). Relative expression levels of target genes were normalized to the genes B2M, PPIA and GAPDH. To knock down the expression of FOX03 or NRF2, WI-38 cells were transfected, using the RNAiMAX reagents (Life Technologies), with siRNA oligos (at 10 nM final concentration, 10 ml culture medium) for FOX03 (Life Technologies) or NRF2 (Integrated DNA Technologies) on 10-cm petri dishes for 36 hrs, and then detached and aliquoted onto 96-well (for qPCR analysis) or 384-well plates (for H ₂ 0 ₂ -stress treatment). -24 hrs later, small molecules were introduced and incubated with cells for 24 hrs. Cells were then either processed with the Cells-to-Ct Kit to prepare RT products for qPCR analysis or subjected to H ₂ 0 ₂ (700 μΜ) for 3 hrs and assayed for viability. The knockdown efficiency of FOX03 or NRF2 was checked at 36 hrs post-transfection and at the end as well.

[0449] mTOR Inhibition (RPS6 Phosphorylation Status) Analysis. In-Cell Western assays were performed, following a standard immuno-staining protocol. Briefly, WI-38 cells were treated with small molecules for 24 hrs, and then processed and incubated with primary antibody cocktail (Cell Signaling, mouse anti-RPS, 1 :25; rabbit-anti-pRPS6-(Ser-235/236), 1 : 100) overnight at 4°C. Next day, samples were processed and incubated with fluorophore-conjugated secondary antibodies (Cell Signaling, DyLight 680-goat anti-mouse, 1 :500; DyLight 800-goat anti-rabbit, 1 : 1,000). Images were collected on an Odyssey Imager (LI-COR) and analyzed with the Image Studio Lite software (version 5.0.21).

[0450] Autophagy Induction Analysis. Immuno-staining of LC3A/B was performed, following a standard protocol. Briefly, WI-38 cells were treated with small molecules for 24 hrs, and then processed and incubated with primary antibody (Cell Signaling, rabbit anti-LC3A/B, 1 : 100) overnight at 4°C. Next day, samples were processed and incubated with fluorophore-conjugated secondary antibody and further incubated with DAPI dye. Images were collected on the INCell Analyzer 2000 (Experiment 1 : 10X objective; Experiment 2: 20X objective) and analyzed with the Developer Toolbox. For Experiment 2, lysosomal-associated membrane protein 2 (LAMP2) was also counter-stained to identify the LC3A/B puncta that colocalize with lysosome and the data were analyzed by the MetaXpress software (Molecular Devices, version 5.1). The intensity of total (Exp. 1) or LAMP2-colocalized LC3A/B puncta (Exp. 2) was normalized the total numbers nuclei in the fields. [0451] Poly(Q) Toxicity & Viability Analysis. Viability assays were performed as described before (Aiken et al., 2004). PC12 cells that stably express the inducible poly(Q)103-Htt-EGFP were grown in culture. Ponasterone A (Life Technologies), an ecdysone analog, was added to 10 μΜ final concentration to induce transgene expression, and formation of puncta was examined and confirmed using the Eclipse 200 fluorescent microscope (Nikon). Cell viability was analyzed 48 hrs later by measuring ATP content with CellTiter-Glo. The parental WT-PC12A cells that do not express the poly(Q)103-Htt-EGFP were used as the negative control to exclude the small molecules that may enhance viability in general.

[0452] Lifespan Assays. Liquid culture-based lifespan assays were performed, following the protocol as described before (Solis and Petrascheck, 2011). Briefly, newly hatched wild-type worms were fed ampicillin-resistant OP50 bacteria (gift from Michael Petrascheck at Scripps) and treated with small molecules (67 μΜ final concentration, 0.2% DMSO) at the young adult stage. FUdR was used to block progeny production. The molecules were analyzed in 96-well plates, with 4 wells for each small molecule. Multiple control wells with DMSO (0.2% final concentration) were included. Likewise, small molecules were also analyzed for their ability to extend lifespan on solid agar, following procedures as described before (Cabreiro et al., 2013). Hypochlorite-synchronized temperature-sensitive sterile mutants, CF4059, (fer-15(b26)II rol- 6(sul 006)11; fem-l(hcl7)IV), were raised on large agar plates seeded with OP50 bacteria at 25°C. Day 1 adults were transferred onto mini-plates, seeded with OP50 bacteria (UV-irradiated, kanamycin-treated) and supplemented with small molecules (-60 μΜ final concentration, 0.2% DMSO). Worms were scored every other day. Cumulative survival was analyzed using the STATA software (log-rank test).

[0453] We also tested the small molecules (at 67 μΜ) for their ability to confer H ₂ 0 ₂ - resistance. The worms were treated with the small molecules in liquid, with H ₂ 0 ₂ (500 μΜ final concentration) added on day 4 of adulthood, and scored for viability everyday [0454] In vitro PARP inhibitor assays revealed 10 additional inhibitors of PARP1 : Gr-2 A, Gr- 2B, Gr-2C, Gr-2D (note that these molecules belong to the same structural group, Gr-2), as well as Gr-6A (but not the other members of this group), 01, 03, 04, 012 and 022, among 54 repurchased small molecules. [0455] A total of 11 molecules (Gr-IF, Gr-3A, Gr-3B, Gr-3C, Gr-4D, Gr-7C, 06, 013, 014, 018 and 022) have confirmed human protein targets, including NF-kappaB signaling

components.

[0456] Characterization and validation. Applicants were able to obtain 54 small molecules for the follow-up characterizations. Applicants confirmed 52 fresh molecules by the ATP assay, and further validated 38 by the PI cell-death imaging assay. These 38 molecules then became the "core set" of compounds for further analyses in cells and in nematode Caenorhabditis elegans. A total of 37 of 38 validated molecules also protected primary human dermal fibroblasts (HDFp, isolated from the skin of pooled donors, from Zen-Bio) from H ₂ 0 ₂ , suggesting that their protective effects are not limited to a specific cell line.

[0457] Safety Concerns. To inquire whether these molecules could adversely affect normal cells, applicants analyzed their effects on two DNA damage-associated cellular markers, phosphorylated histone variant γΗ2Α.Χ and tumor protein p53 binding protein 1 (TP53BP1). Nine small molecules (Gr-1 A, Gr-lC, Gr-ID, Gr-IF - these 4 belong to one structural class, Gr- 1, - Gr-3A, Gr-3C, Gr-6C, 021 and 027) increased the percentage of both γΗ2Α.Χ- and

TP53BPl-positive cells in multiple independent assays (in the absence of H ₂ 0 ₂ ). Consistent with these results, of these, 4 molecules (Gr-lC, Gr-ID, Gr-IF and 021) also increased the percentage of propidium iodide-positive (dead) cells under normal conditions.

[0458] High-throughput Oxidative Stress Resistance Small-Molecule Screen. Applicants used the WI-38 human primary fibroblast cell line for the screen because previous studies demonstrating the peroxide-, cadmium- and methyl methane sulfonate (MMS)-resi stance of cells from long-lived mouse mutants and long-lived species employed primary skin fibroblasts (Harper et al., 2007; Harper et al., 2011; Salmon et al., 2005). Not all types of cells derived from long-lived and stress-resistant animals are stress-resistant in culture. Some, such as hepatocytes, are more likely to undergo apoptosis (Kennedy et al., 2003). Likewise, human mammary epithelial cells (HMECs) incubated in IGF- 1 -deficient serum are sensitized to die when exposed to hydrogen peroxide (Guevara-Aguirre et al., 2011). In addition, primary cells are expected to offer advantages over tumor cells, which, due to the profound heterogeneity of genetic alterations, could behave remarkably differently in a screen. [0459] The initial screen was focused on identifying small molecules that can increase the resistance to hydrogen peroxide using ATP levels initially as a proxy for viability (CellTiterGlo assay). Applicants screened 104, 121 small molecules selected to maximize the coverage of chemical space. WI-38 cells of an early population doubling level (PDL) were screened with small molecules at the 10 μΜ final concentration, a dose that has been shown to produce high structural diversity in many small-molecule screens (Walters and Namchuk, 2003). Applicants selected a three-hour treatment with 700 μΜ H ₂ 0 ₂ , and this condition consistently produced high Z' values. Importantly, small interfering RNAs (siRNAs) against the insulin/IGF-1 signal- transduction gene AKT1 and the RF2 inhibitor gene KEAP1 both increased stress resistance under these conditions (to hydrogen peroxide, as well as cadmium and MMS) indicating that recovery of these types of perturbations that increase lifespan in animals.

[0460] A total of 104,121 compounds were analyzed on 327 microplates, each using DMSO as the negative control (n=16 wells), and the phosphatase inhibitor calyculin (50 nM) as the "positive control" (n=16 wells). The Z' numbers, which are determined by the difference between positive and negative controls and by the extent of variation, were used to evaluate assay robustness. Z' score, defined as 1 - [(3X standard deviation of positive controls + 3X standard deviation of negative controls)/ (mean of positive controls - mean of negative controls)], is used to access the quality of a high-throughput screen assay. A Z' value greater than 0.5 indicates a robust assay, and the average Z' value was determined to be 0.61. A normalization value was calculated for each run (generally -30 plates) to control for inter-day variation. Molecules were discarded, whereby stimulating proliferation could significantly increase ATP signals in the absence of H ₂ 0 ₂ . Altogether, a total of 209 small molecules were isolated (0.2% of molecules tested) that produced signals at least 2.5-fold higher than the DMSO control. We also analyzed these molecules in the absence of H ₂ 0 ₂ and ruled out the possibility that, by stimulating proliferation, they can significantly increase ATP signals. Further testing of the candidates at six different final concentrations (0.6 μΜ to 20 μΜ) confirmed 127 small molecules that consistently produced protective effects against H ₂ 0 ₂ at one or more of these doses. (Table 10)

[0461] To eliminate false positives that increased ATP levels but not cell viability (Thorne et al., 2010), we carried out a secondary cell-imaging assay. Propidium iodide (PI), a cell non- permeable dye, stains DNA in late apoptotic/necrotic cells when membrane integrity is lost. 107 hits, at 1.25 μΜ and/or 10 μΜ, were found to reduce the percentage of Pi-positive dead cells, and were retained for analysis (Table 10).

[0462] Of 209 candidate hits, at least 40 are derivatives of 8-hydroxyquinoline, a well-known reactive-oxygen species (ROS) scavenger that can protect cells from H ₂ 0 ₂ stress (Wang et al., 2010). Therefore, applicants carried out an ROS scavenger assay, using 2,2-diphenyl-l- picrylhydrazyl (DPPH) (Sharma and Bhat, 2009), a radical-containing purple dye that can be reduced by ROS scavengers. After the ROS-scavenger and PI retests, 61 top hits were identified that passed the retests and did not show obvious ROS scavenger activities. Intriguingly, besides 31 orphan compounds, 30 of these molecules fall into one of seven structural classes (with at least 3 members in one group), suggesting that they may act on common targets in the cells to promote H ₂ 0 ₂ -resistance. In addition, the orphan compounds, 07 and 022 are similar to each other, as are 015 and 023.

[0463] In multiple independent experiments, applicants confirmed that 52 fresh small molecules could increase the viability of WI-38 cells upon H ₂ 0 ₂ stress. By performing Amplex Red assays, it was verified that the molecules did not quench H ₂ 0 ₂ and excluded this possible explanation for their protective effects (FIG. 1). Pi-imaging assays confirmed that 38 molecules could protect WI-38 cells at multiple time points (3, 4, 5 hours) during H ₂ 0 ₂ treatment (Table

11). These 38 compounds also protected primary human dermal fibroblasts (HDFs; isolated from the skin of multiple donors) from H ₂ 0 ₂ , suggesting that the protective capacity of these molecules is not limited to the WI-38 cell line. Thus, these 38 small molecules became the core of the following characterizations. [0464] For many stress conditions tested previously, one significant correlation to longevity is the cellular resistance to H ₂ 0 ₂ or CdCl ₂ . Applicants then tested these small molecules, at five different final concentrations (0.25 μΜ to 20 μΜ), for cadmium and MMS resistance in WI-38 cells. Two (Gr-6A and 022) of 38 molecules reproducibly conferred multiplex resistance to cadmium, MMS and H ₂ 0 ₂ , and 13 did not confer resistance to either cadmium or MMS in the assays used (Tables 5, 8, and 12). 21 molecules increased the resistance to both cadmium and H ₂ 0 ₂ only, likely due to ROS-producing ability of both H ₂ 0 ₂ and heavy metals as seen in Tables described herein.

[0465] Potential toxicity of the Small Molecules. To predict the long-term effects of our molecules on human cells, we introduced small molecules (at 10 μΜ final concentration) to WI- 38 fibroblasts and assayed for viability by measuring ATP levels during a course of 5 days of continuous treatment (in the absence of H ₂ 0 ₂ ; the ability of these molecules to promoted H ₂ 0 ₂ - resistance was confirmed by testing a portion of the cells on day 2 of treatment). In addition, cell death was scored by Pi-imaging on day 2 and day 5 of treatment.

[0466] Of 38 "core set" molecules, at least 10, including Gr-IF, Gr-3B, Gr-3C, Gr-6C, Gr-7A, Gr-7C, 011, 021, 023 & 027, reduced the ATP content by more than 30% after 5 days of continuous incubation (Table 13), suggesting potential anti-proliferative activity and/or cell toxicity of these molecules under the conditions tested. Consistent with this interpretation, as indicated by the examination of cell population and morphology, as well as cell death-imaging, 7 molecules (Gr-3B, Gr-6C, Gr-7C, Oi l, 021 & 027) reduced cell number substantially and increased the fraction of Pi-positive dead cells under the conditions tested. Likewise, most cells treated with another two (Gr-7A & 023) were not viable under the tested conditions. In contrast, rapamycin (5uM), a potent inhibitor of mTOR, reduced the ATP content by -50%, yet did not significantly increase cell death under the conditions tested.

[0467] To ask whether our molecules could adversely affect cells by causing DNA damage, we analyzed their effects on two DNA damage-associated cell markers, phosphorylated histone variant γΗ2Α.Χ and tumor protein p53 binding protein 1 (TP53BP1). γΗ2Α.Χ is required for checkpoint-mediated cell cycle arrest and DNA repair following double-stranded DNA breaks. Phosphorylation of γΗ2Α.Χ by a group of PI3K-like kinases (ATM, ATR, and DNA-PK) occurs rapidly in response to DNA damage (Perez-Cadahia et al., 2010). Likewise, in response to DNA damages, TP53BP1 is phosphorylated and translocated into the nucleus; retention of TP53BP1 at DNA breaks requires phosphorylated γΗ2Α.Χ (Panier and Boulton, 2014). We found that 9 small molecules [Gr-1 A, Gr-lC, Gr-ID, Gr-IF (these 4 belong to one structural class), Gr-3A, Gr-3C, Gr-6C, 021 and 027] increased the percentage of both γΗ2Α.Χ- and TP53BPl-positive cells under the assayed conditions in at least two independent experiments (Table 14).

[0468] We found that 4 of these molecules (Gr-lC, Gr-ID, Gr-IF and 021) increased the percentage Pi-positive dead cells under normal conditions (Gr-lC, 3.5±1.3%, P = 0.002; Gr-ID, 4.2±1.4%, = 0.001; Gr-IF, 3.3±0.8%, P = 3.26E-14; and 021, 1.1±0.4%, P = 0.008; vs.

control, 0.4±0.2%) (Table 11).

[0469] In addition, the Pi-positive fraction was also increased for WI-38 cells treated with another 7 small molecules (Gr-IB, 1.0%±0.3%, P = 0.006; Gr-IG, 7.1%±1.1%, P = 2.09E-05; Gr-7B, 3.6%±0.7%, P = 8.77E-05; Oi l, 1.9%±0.7%, P = 0.004; 015, 3.8%±0.7%, P = 5.30E- 05; O20 0.7%±0.3%, P = 0.030; and 023, 2.6%±1.4%, P = 0.011), though these did not appear to increase both γΗ2Α.Χ and TP53BP1 foci in treated cells (Table 14).

[0470] In summary, 15 of the 38 molecules (4 of Group 1 but not the other 3 of this group, all 3 of Group 3, all 3 of Group 7, plus other 5 molecules) we chose to study in greater depth kill cells and damage DNA upon longer exposure under the conditions tested. The finding that small molecules that increase stress resistance also damage DNA suggests that they may protect cells from H ₂ 0 ₂ by inducing cell-protective responses, a "hormesis" mechanism. Increased DNA damage could elevate the risk of malignant transformation when affected cells do not undergo senescence and apoptosis. However, even if this is the case, these DNA-damaging small molecules could be valuable, as they may act like certain cytotoxic agents (e.g., doxorubicin) and produce toxicity on highly proliferative tumor cells in vivo. Consistent with this hypothesis, our preliminary data indicated that two small molecules, Gr-7A and Gr-7B, when examined in both WI-38 and other tumor cell lines at a given dose (10 μΜ), exerted more pronounced toxicity on the HTB-178 lung tumor cells (EGFR+, PIK3CA+, RB1-, TP53-). [0471] Properties of Newly Identified Small Molecules That Increase Oxidative Stress Resistance. We used both MetaDrug data-mining pathway tool (Ekins et al., 2007) and

Similarity Ensemble Approach (SEA) statistical method (Keiser et al., 2007) to ask whether any of our compounds resemble known therapeutic drugs. Although the screen library was not designed to contain known drugs, we recovered several PARP (poly-(ADP ribose) polymerase) inhibitors and chalcones.

[0472] Screen Hits and Longevity Regulators. Remarkably, FOX03A DNA variants have been associated with exceptional human longevity in at least eight different populations around the world, though how these variants exactly affect FOX03 activity is not known.

[0473] We have taken the strategy to identify the first compounds that activate any one of many life-extending pathways. This is a great strength: In animals, FOXO can extend life not only in response to reduced insulin or IGF-1 signaling, but in response to increased activity of AMP kinase (Apfeld et al., 2004; Greer et al., 2007), the heat-shock transcription factor (Hsu et al., 2003; Morley and Morimoto, 2004), certain microRNAs (Smith- Vikos and Slack, 2012), a longevity pathway regulated by the reproductive system (Kenyon, 2010a), and, in some studies, sirtuins (Berdichevsky et al., 2006; Rizki et al., 2011).

[0474] Other conditions extend life independently of daf-16/foxo, like increased activity of the SKN-1/NRF2 oxidative-stress and xenobiotic phase II detoxification-regulator. SKN-1/NRF2 promotes longevity in insulin/IGF- 1 -pathway mutant (Tullet et al., 2008) and calorically restricted worms (Bishop and Guarente, 2007) and in fly keapl mutants (Sykiotis and Bohmann, 2008). It is activated in long-lived IGF-l-pathway mouse mutants (Steinbaugh et al., 2012), and in long-lived mice lacking the glutathione S-transferase gene mGsta4 (Singh et al., 2010). More recently, constitutive Nrf2-signaling activity has been found to be associated with maximum lifespan potential of several rodent species, including the naked mole rats (Lewis et al., 2015), and enhanced cell signaling via Nrf2 and p53 has been suggested to be protective against spontaneous neoplasia and tumorigenesis in the naked mole rats (Lewis et al., 2012).

[0475] The enrichment of NRF2-activating small molecules is consistent with the anti- oxidative role of NRF2, and it may have implications for human aging as well. In human fibroblasts, declined RF2 function has been shown to occur in replicative senescence and NRF2 silencing led to premature senescence (Kapeta et al., 2010). Conversely, RF2 activation enhanced the survival of cells following oxidative stress and extended replicative lifespan of human fibroblasts. (Hybertson et al., 2011). Thus, small molecule modulators of the KEAPl- RF2-ARE pathway could be potential preventive and therapeutic agents (Magesh et al., 2012).

[0476] Small Molecule Screen Library. Applicants screened a "diversity library" that contains 104, 121 small molecules (~24K from ChemBridge; ~50K from ChemDiv; and ~30K from SPECS) selected to maximize the coverage of chemical space. These compounds were provided as lOmM stock by the Small Molecule Discovery Center (SMDC) at UCSF, with information in the database for query purpose. Applicants screened WI-38 cells (human fibroblasts, lung-derived, ATCC, CCL-75) at an early population doubling level (PDL) with 104, 121 small molecules selected to maximize the coverage of chemical space. Compounds were provided as lOmM stocks by the Small Molecule Discovery Center (SMDC), and chemical information, including the structures, simplified molecular-input line-entry system (SMILES) IDs, PubChem links and possible in silico docking, is available for query. Cells were incubated with small molecules, at 10 μΜ final concentration, for 24 hours and then subject to 700 μΜ H ₂ O ₂ for 3 hours. Applicants identified 209 (0.20%) small molecules that significantly enhanced the viability of H ₂ 0 ₂ -stressed cells, by measuring the ATP content (2.5-fold cutoff, normalized to the DMSO negative controls). Applicants retested and confirmed 127 (0.12%) hits, and then, validated 107 (0.10%) by a secondary propidium iodide (PI) cell-death imaging assay for cell viability. Applicants further eliminated potential scavengers of reactive oxygen species (ROS), using the 2,2-diphenyl-l-picrylhydrazyl (DPPH) assay, and confirmed 61 (0.06%) top hits that passed the series of retests. To eliminate false positives that increased ATP levels (Thorne et al., 2010), applicants also carried out a secondary imaging assay for cell viability. Propidium iodide (PI), a cell non-permeable dye, stains DNA in late apoptotic/necrotic cells when membrane integrity is lost. A total of 107 hits, at 1.25 μΜ and/or 10 μΜ, were found to reduce the percentage of Pi-positive dead cells, with statistically significant effects.

[0477] Chemical Data Analysis: Applicants used the SARvision (CHEMapps) software and found that, of 61 top hits, 30 molecules fall into 7 structurally related chemical groups (with at least 3 members in one group), suggesting that they may promote stress resistance by acting on common targets. In addition, 07 and 022, as well 015 and 023, are similar to each other.

These molecules were named according to their respective groups, for example, Gr-1 A, Gr-IB, etc; and the other orphan molecules as 01, 02, etc. Applicants used both the MetaDrug data- mining pathway tool and the Similarity Ensemble Approach (SEA) statistical method to ask whether any of our compounds resembles a known therapeutic drug. Although the screen library was not designed to contain known drugs, several PARP [poly-(ADP ribose) polymerase] inhibitors and chalcones were recovered.

[0478] Cell Culture & H ₂ 0 ₂ -resistance Screen. Human fetus lung-derived WI-38 cells (ATCC) at an early population doubling level (PDL -30; these cells reach complete senescence at PDL -50) were used for the screen. To reduce the influence of culture variations, sufficient amount of cells of the same PDL (initial PDL -23) were propagated, frozen as stocks in liquid nitrogen, and then used later for the whole screen as well as for subsequent characterizations of isolated small molecules. [0479] Cells were cultured in OptiMEM (Life Technologies) supplemented with 10% fetal bovine serum (FBS). In a 384 multi-well format, -2,000 cells were added per well by WellMate (Thermo Fisher) liquid dispenser and cultured in a C0 ₂ incubator at 37°C for 24 hours. Then small molecules were introduced from stock plate with pin-tool on a Biomek FXP (Beckman) automation workstation at 10 μΜ final concentration, 0.1% DMSO. Twenty four hours later, the cells were subject to a three-hour treatment with 700 μΜ H ₂ 0 ₂ , and CellTiter-Glo reagent

(Promega) was added at the end and the luminescence signals were analyzed using an Analyst HT plate reader (Molecule Devices). Control seeding plates were always prepared and anlayzed for ATP content in the end. In the absence of H ₂ 0 ₂ , the variation is typically less than 10%.

[0480] CdCl ₂ and MMS resistance Assays. The setups on 384-well plates and incubation times were the same as for H ₂ 0 ₂ until the time of incubation with the stressors, which was 12 hours for both cadmium and MMS assays. Applicants tested several conditions, including conditions used to assay fibroblasts from long-lived animals (Salmon et al., 2005). These conditions produced better results with the positive controls (KEAP1 and AKT1 siRNAs) in the MMS assay. Thus, for MMS, the cells were shifted from growth media - OptiMEM + 10% FBS, to DMEM (Gibco) + 2% BSA (no serum) just before adding small molecules, which occurred 24 hours before MMS addition.

[0481] Isolated small molecules were tested for MMS and cadmium resistance twice in two independent assays. Each small molecule was analyzed at five different concentrations (0.25 μΜ to 20 μΜ final concentration), with technical triplicates for each dose. Data were analyzed using a global variance t-test.

[0482] DPPH Assay. The assay was performed, following procedures as described in a review (Sharma and Bhat, 2009). DPPH (Sigma) stock solution (25mM) was prepared in methanol and diluted to 50 μΜ in acetic acid-buffered methanol (0.1 M, pH 5.5). 50μ1 solution was dispensed by WellMate liquid dispenser onto three 384-well plates (technical triplicates). 209 primary hits were introduced onto the 384-well assay plates by pin-tool on a Biomek FXP automation workstation at 10 μΜ final concentration. Plates were sealed and incubated in a humid chamber at 30°C in dark. Absorbance at 519 nm was measured on a FlexStation 3 multi-mode microplate reader (Molecular Devices) 3 hrs and 24 hrs later. Several knonw ROS scavenager, including N- acetyl cysteine (NAC), amodiaquin dihydrochloride (AmD) and 8-hydroxyquinoline quinoline (Sigma), were used as the controls and assayed at several doses (1 μΜ, 10 μΜ, 100 μΜ). These controls, at 10 μΜ final concentration, could reduce the readings (normalized to DMSO negative control) by ~ 20% to 50% in 3 hrs. Small molecules that consistently reduced the absorbance by 10%) or more were considered as potential ROS scavengers.

[0483] Imaging Analysis. WI-38 cells were seeded on 384-well plates for 24 hrs and then incubated with small molecules for 24 hrs. H ₂ 0 ₂ (700 μΜ final concentration) prepared in OptiMEM or OptiMEM only was added and incubated further for 3 hours, and Hoechst 33342 (Life Technologies) (10 μg/ml final concentration) and propidium iodide (Life Technologies) (2.5 μΜ final concentration) were added for the last 30 minutes. Images were collected on an INCell Analyzer 2000 (GE) and analyzed with the Developer software. In a typical H ₂ 0 ₂ -stress assay, ~23.7±6.9%> DMSO-treated control cells scored positive for propidium-iodide staining (~1.0±0.8%> for non-stressed cells). [0484] DNA Damage Marker Analysis. WI-38 cells were seeded on 96-well plates and cultured for 24hrs and then incubated with small molecules for another 24 hrs. As the positive control to damage DNA, H ₂ 0 ₂ was supplemented at 700 μΜ final concentration for the last 3 hrs. Cells were washed with phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde and then blocked with 5% normal goat serum (Cell Signaling), plus 0.3%> Triton X-100, for 1 hr. Primary antibody cocktail (rabbit anti-phospho-histone γΗ2Α.Χ (Ser-139), 1 : 100; anti-phospho- TP53BP1 (Ser-1778), 1 : 100), prepared in 1% BSA and 0.3% Triton X-100/ PBS, was then introduced and incubated overnight at 4C. Next day, samples were washed with PBS and further incubated with fluorophore-conjugated secondary antibody (1 : 1,000) for 1 hr in the dark.

Samples were then washed and incubated with DAPI dye (Life Technologies) (4 μg/ml final concentration) for the last 10 minutes. Images were collected on an INCell Analyzer 2000 (GE) and analyzed with the Developer software. In a representative experiment, the percentages of cells that scored positive for these DNA damage markers were: γΗ2Α.Χ: DMSO, ~1.7±0.4%; H ₂ 0 ₂ , ~50.9±4.2%. TP53BP1 : DMSO, ~1.0±0.2%; H ₂ 0 ₂ , ~45.8±5.1%. [0485] WI-38 cells were seeded (-8,000 cells per well) on 96-well plates and cultured for 24 hrs and then incubated with small molecules for another 24 hrs. Doxorubicin (300 nM, 24 hrs) and Η ₂ 0 ₂ (700 μΜ, 3 hrs) were also introduced as the positive controls to damage DNA. Cells were washed with phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde for 30 min and then blocked with 5% normal goat serum (Cell Signaling) and 0.3% Triton X-100 for 1 hr. Primary antibody cocktail (Cell Signaling, rabbit anti-phospho-histone γΗ2Α.Χ (Ser-139), 1 : 100; anti-phospho-TP53BPl (Ser-1778), 1 : 100) was prepared in PBS with 1% BSA and 0.3% Triton X-100 and incubated overnight at 4°C. Next day, samples were washed with PBS and further incubated with fluorophore-conjugated secondary antibody (1 : 1,000) for 1 hr in dark. Samples were then washed and incubated with DAPI dye (Life Technologies) (4 μg/ml final

concentration) for 30 minutes. Images were collected on the INCell Analyzer 2000 (10X objective) and analyzed with the Developer Toolbox. Cells that showed immuno-staining intensity above a software-defined threshold were scored.

[0486] AmplexRed Assay. The assay was performed using the Amplex Red Hydrogen

Peroxide/Peroxidase Assay Kit (Life Technologies), following manufacturer's instructions.

Briefly, small molecules (at 10 μΜ final concentration) were pre-incubated with 700 μΜ H ₂ 0 ₂ in water for 3 hrs in a 37°C C0 ₂ incubator. Amplex Red reagent was mixed with horseradish peroxidase (HRP) in buffer and then incubated with 1 : 10 diluted small molecule/ H ₂ 0 ₂ mixture for 30 min in dark. Fluorescence at 590 nm was measured on a FlexStation 3 multi-mode microplate reader (Molecular Devices).

[0487] The objective of this example is to screen for a cellular phenotype that is common to cells from many long-lived animal mutants, and from long-lived species of mammals and birds to identify resistance to multiple forms of environmental stress. A total of 104,121 small molecules were screened for their ability to protect primary human fibroblasts from a lethal dose of hydrogen peroxide, and then approximately 60 hits were reexamined for their ability to protect cells from the DNA-damaging agent MMS and the heavy metal cadmium. Many of these compounds conferred resistance to multiple stressors, and a number inhibited TOR activity and appeared to affect FOX03 and/or NRF2 activities, and/or extended C. elegans ' lifespan.

[0488] Recently, it has been realized that pan assay interference compounds (PAINS), due to their reactive chemical features, could introduce promiscuous results and misleading readouts in chemical screens (Baell and Walters, 2014; Baell and Holloway, 2010). After examination of the small molecules, 7 of 61 screen hits as well as 5 of 38 validated hits (Gr-6C, 06, 015, 021 and 023), contained at least part of the PAINS moieties (Tables la-lf, and Table 5). Of these, Gr-6C contains a rhodanine moiety and 023 shows both enone and catechol structures, and they extended C. elegans' lifespan in 3 of 3 and 3 of 4 trials, respectively. 06 (phenolic Mannich base) and 015 (enone) induce bot HMOXl and NQOl by more than 1.5-fold. In fact, 015 induced HM0X1 by almost 50-fold and it also protected worms from hydrogen peroxide. 021, with rhodanine structure, scored positive for DNA-damage markers and promoted H ₂ 0 ₂ - resistance in a NR 2-dependent fashion.

[0489] The screen did not enrich for PAINS (P = 0.068, hypergeometric distribution probability, for all 61 hits). Certain molecules identified as PAINS-like, in that they enhance stress resistance, induce expression of FOX03- and NRF2-regulated genes, and extend the lifespan of C. elegcms. In this regard, these PAINS-like molecules may produce global benefits, a specific biological context, in the whole animal.

[0490] Screen Hits and Longevity Regulators. This screen was designed to isolated small molecules that promote resistance to multiplex stress, and of the top 38 hits, a number of molecules had effects on several key regulators of aging, including FOX03 (3), NRF2 (14) and mTOR (4).

[0491] The rate of aging can be influenced by many factors, including a network of signaling proteins and transcription factors that also sense nutrients, energy levels and stress. Perturbing many genes in this network can extend healthy youthfulness and increase disease-resistance and lifespan (Bartke, 2011; Fontana et al., 2010). The insulin/IGF-1 pathway, which regulates growth and metabolism, was the first lifespan pathway to be identified (Kenyon et al., 1993). Mutations in the Insulin/IGF- 1 -receptor daf-2 gene doubled the lifespan of C. elegans, in a manner that requires daf-16 (Kenyon et al., 1993), which encodes a FOXO transcription factor that extends lifespan by regulating a diverse collection of cell-protective, proteostasis, metabolic, innate-immunity and other genes (Murphy et al., 2003). This endocrine regulation of has been shown to be conserved among many different experimental animals (Kenyon, 2010b).

[0492] In humans, in a population of Ashkenazi Jews, partial loss-of-function IGF- 1 -receptor mutations (Tazearslan et al., 2011) and other IGF- 1 -pathway mutations (Yousin Suh, pers.

comm.) are more frequently found in centenarians. Similarly, a pathway-level analysis of GWAS longevity data highlighted core insulin and IGF-l-pathway genes (Deelen et al., 2013). Remarkably, FOX03A DNA variants have been associated with exceptional human longevity in at least eight different populations around the world, though how these variants exactly affect FOX03 activity is not known. [0493] We have taken a strategy to identify the first compounds that activate any one of many life-extending pathways. This is a great strength: In animals, FOXO can extend life not only in response to reduced insulin or IGF-1 signaling, but in response to increased activity of AMP kinase (Apfeld et al., 2004; Greer et al., 2007), the heat-shock transcription factor (Hsu et al., 2003; Morley and Morimoto, 2004), certain microRNAs (Smith- Vikos and Slack, 2012), a longevity pathway regulated by the reproductive system (Kenyon, 2010a), and, in some studies, sirtuins (Berdichevsky et al., 2006; Rizki et al., 2011).

[0494] Other conditions extend life independently of daf-16/foxo, like increased activity of the SKN-1/NRF2 oxidative-stress and xenobiotic phase II detoxification-regulator. SKN-1/NRF2 promotes longevity in insulin/IGF- 1 -pathway mutant (Tullet et al., 2008) and calorically restricted worms (Bishop and Guarente, 2007) and in fly keapl mutants (Sykiotis and Bohmann, 2008). It is activated in long-lived IGF-l-pathway mouse mutants (Steinbaugh et al., 2012), and in long-lived mice lacking the glutathione S-transferase gene mGsta4 (Singh et al., 2010). More recently, constitutive Nrf2-signaling activity has been found to be associated with maximum lifespan potential of several rodent species, including the naked mole rats (Lewis et al., 2015), and enhanced cell signaling via Nrf2 and p53 has been suggested to be protective against spontaneous neoplasia and tumorigenesis in the naked mole rats (Lewis et al., 2012).

[0495] The enrichment of RF2-activating small molecules is consistent with the anti- oxidative role of RF2, and it may have implications for human aging as well. In human fibroblasts, declined RF2 function has been shown to occur in replicative senescence and RF2 silencing could lead to premature senescence (Kapeta et al., 2010). Conversely, RF2 activation could enhance the survival of cells following oxidative stress and extended replicative lifespan of human fibroblasts. Thus, small molecule modulators of the KEAP1- RF2-ARE pathway could be potential preventive and therapeutic agents (Magesh et al., 2012). [0496] Potential Mechanism(s) Of Action. At least 11 small molecules (Gr-IF, Gr-3A, Gr- 3B, Gr-3C, Gr-4D, Gr-7C, 06, 013, 014, 018 and 022) have been identified with confirmed human protein targets (Tables la- If). Besides, the behavior of these molecules appeared to be rather different form other outstanding PAINS that present overwhelmingly in different bioassays. A summary of compounds and targets are located in Table 2 and Table 9. [0497] NF-kappaB Signaling. Of 11 molecules with potential targets, Gr-3C had been identified as a molecule that induced the NF-kappaB inhibitor NFKBIA in two screens (EC ₅₀ , 8.5 μΜ and 11.0 μΜ), coherent with its role as an RELA inhibitor (IC ₅₀ , 2.0 μΜ) in HUVEC cells in another study. These studies also isolated and confirmed Gr-3A (EC50, 11.0 μΜ and 12.0 μΜ) as an FKBIA-inducing compound. These results are consistent with in silico docking analysis, using the ZINC software (Irwin et al., 2012), which predicted that Gr-3C could bind to both NFKBIA and RELA. Interestingly, applicants have found that siRNA knockdown of NFKB2, a related member of the NF-kappaB/REL family (Chen and Greene, 2004), promoted H ₂ 0 ₂ - resistance in our siRNA screen.

[0498] NF-kappaB signaling pathway controls cell survival, differentiation, and proliferation. Key components of the pathway have been shown be crucially involved in inflammation

(Lawrence, 2009) and have been implicated in many diseases, including cancer, autoimmune diseases, neurodegenerative diseases, cardiovascular diseases, and diabetes, etc (Hayden and Ghosh, 2012). Recently, prevention of aging-related hypothalamic or brain IKK-beta and NF- kappaB activation has been shown to retard aging and extend lifespan in mice (Zhang et al., 2013), providing more evidence to highlight the significance of chronic inflammation in aging (Jenny, 2012; Salminen et al., 2008). Given these notes, our small molecules that could inhibt NF-kappaB signaling may provide the reagents for future analysis in animals. In fact, it is noted that all three molecules could extend C. elegan's lifespan (3 of 3 trials, -8% to 33%).

[0499] Cancer. Many long-lived animal mutants are resistant to age-related diseases (Le Couteur et al., 2012), including cancer (Ikeno et al., 2009), protein-aggregation diseases (Cohen et al., 2009; Morley et al., 2002) and heart disease (Birse et al., 2010; Harrington et al., 2007; Wessells et al., 2004). Thus, the small molecules sought after may counter multiple age-related diseases. Different species in nature have very different lifespans, but within each, the elderly are most susceptible to cancer. This correlation in nature between slow aging and delayed cancer suggests that the same pathways that slow aging may antagonize cancer, and, in fact, many longevity pathways have anti-cancer activity. Importantly, these pathways inhibit a wide variety of cancers, which is predicted for our small molecules. Preliminary data indicated that two small molecules (Gr-7A and Gr-7B, both of which demonstrating mTOR-inhibiting activities, at 10 μΜ) could significantly reduce the viability of the HTB-178 lung tumor cells. Furthermore, another small molecule (017, at 5 μΜ) could significantly reduce cell viability in two breast cancer-derived tumor cell lines that harbor different sets of mutations.

Example 2. PARP modulating compounds

[0500] PARP inhibitors. PARP mediates the cellular responses and executes the actions to different stress signals upon many types of stresses (oxidative, genotoxic, inflammatory, metabolic, etc) (Luo and Kraus, 2012). PARP inhibitors, by preventing PARP from diverting NAD+ to the synthesis of poly(ADP-ribose), could significantly modulate the stress-related consequences, from cell death, tissue damage, to age-associated dysfunction and oxidative damage-related pathologies. PARP inhibitors can also kill certain tumor types because of their effects on DNA repair pathways (Chan et al., 2010; Mason et al., 2014; Rouleau et al., 2010), and specifically, they have been shown to be effective in clinical trials among cancer patients carrying BRCAl/2 mutations (Fong et al., 2009).

[0501] PARP inhibition is known to increase resistance to DNA-damaging agents such as hydrogen peroxide (Zhang et al., 2007). (Banasik et al., 1992), (Costantino et al., 2001). By in vitro assays for PARP inhibition, we identified, from the 38 "core set" hits, Gr-6A (but not the other members of this group), 01, 014 and 022 (structurally similar to 07) as inhibitors of PARPl (FIG. 2) When we extended the analysis to the other members of the original group of 54 molecules, we found, besides 07, additional PARP inhibitors as well (Gr-2A, Gr-2B, Gr-2C, Gr- 2E - note that these molecules belong to the same structural group, 03 and 04). All 11 PARP inhibitors preserved ATP upon Η ₂ 0 ₂ stress.

[0502] Recently, several studies have revealed very interesting features of PARP inhibition in the perspective of promoting health. First, deletion of Parpl has been shown to increase mitochondrial metabolism through NAD+ preservation and SIRTl activation and protect animals from metabolic disease (Bai et al., 2011). Second, long-term treatment with PARP inhibitors has been found to enhance mitochondrial functions and improve fitness of skeletal muscles in mice, and also, reverse mitochondrial defects in primary myotubes of obese humans and attenuate metabolism defects in NDUFS1 mutant fibroblasts (Pirinen et al., 2014). Third, disruption of the worm orthologue pme-1, as well as PARP inhibitors, could induce the mitochondria unfolded protein response (mtUPR) and extend lifespan in a manner that requires both sir-2.1 and daf- 16/foxo in C. elegans (Mouchiroud et al., 2013). Consistent with the previous reports, applicants also found that several of the identified PARP inhibitors extended C. elegans' lifespan (for example, 07, -10% - 34%, 4 of 4 trials; 014, -10% or more, 3 of 3 trials).

[0503] PARP inhibitors & Protein SUMOylation. The isolation of multiple PARP- inhibiting small molecules, including several with structures distinct from known classes of PARP inhibitors, is consistent with the role of PARP in DNA damage response. Inhibition of PARP-1 has been shown to preserve ATP levels and improve antioxidant status, and maintain anti-apoptotic Bcl-x levels in the kidney following chemotherapy-induced injury (Weaver and Yang, 2013). Consistent with the recent findings of PARP inhibition-associated benefits, preservation of NAD+, which declines with age, has also been shown to restores mitochondrial function in muscles of aged mice (Gomes et al., 2013). Interestingly, the neuroprotective P7C3 aminopropyl carbazole chemicals have been shown to, by activating NAMPT and improving NAD+ salvage, promote survival of neurons in rodent models of neurodegeneration or nerve cell injury (Wang et al., 2014a). Here, the DNA-damaging doxorubicin has been shown to reduce intracellular NAD+ levels, most likely by activating PARP. In addition, PARP-1, via activation of NF-kappaB, has been shown to enhance amyloid beta peptide-induced neuronal damages (Martire et al., 2013). PAPR inhibition could attenuate ischemia/reperfusion-induced

neurodegeneration in the retina (Li et al., 2012) and reduce alpha-synuclein- and MPP+-induced cytotoxicity in a cellular model of Parkinson's disease (Outeiro et al., 2007). These findings have suggested potential neuroprotective effects of PAPR inhibitors in neurodegenerative diseases.

[0504] Two molecules (Gr-IF and 013) have been identified in other screens and confirmed to inhibit SUMO/sentrin specific peptidases (SENPs) (Gr-IF: SENP6, 2 screens, -80% inhibition at 10.0 μΜ or 12.5 μΜ; SENP7, 2 screens, -90% inhibition at 5.0 μΜ or 12.5 μΜ; SENP8, 3 screens, -60% - 80% inhibition at 10.0 μΜ to 12.5 μΜ. 013 : SENP6, 2 screens, -50% inhibition at 10.0 μΜ or 12.5 μΜ; SENP8, 1 screen, -50% inhibition at 20.0 μΜ). Small ubiquitin-related modifiers (SUMOs) are ubiquitin-like proteins that can be covalently attached to a variety of target proteins (Geiss-Friedlander and Melchior, 2007). SENPs, a class of SUMO- specific proteases, are required to remove SUMOylation modification of target proteins, which affect many cellular processes, including apoptosis, DNA damage repair, ribosome maturation, and transcription, etc (Hickey et al., 2012; Yeh, 2009). SUMOylation of many proteins increases greatly following certain cellular stresses, such as heat shock and hydrogen peroxide (Zhou et al., 2004), yet the underlying mechanisms and cellular consequences are not fully understood.

Perturbed SUMOylation balance has been implicated in various diseases including cancer, atherosclerosis and heart diseases, and the designing and developing of novel SENP inhibitors have gained increased interests recently (Kumar and Zhang, 2015).

[0505] The concurrent isolation of PARP inhibitors and potential SUMO-modulators in this screen could be interesting. It is known that SUMOylation of PARP could block its acetylation and restrain the consequent activation of NF-kappaB (Messner et al., 2009). Thereby, SENP inhibitors are expected to, by maintaining SUMOylation levels, block PARP-mediate NF-kappaB activation. In addition, it has been shown that senescent cells develop a PARP-1 and NF- kappaB-associated secretome (PNAS), and inhibition of PARP-1 or NF-kappaB prevents the pro- invasive properties of the secretome (Ohanna et al., 2011). [0506] PARP inhibitors. PARP mediates the formation of poly(ADP-ribose) in response to various cellular stresses (oxidative, genotoxic, inflammatory, metabolic, etc) (Luo and Kraus, 2012), thereby initiating protective DNA-repair and other processes. PARP inhibitors, by preventing PARP from diverting NAD ⁺ to the synthesis of poly(ADP-ribose), can significantly modulate consequences of stress, affecting cell death, tissue damage, and age-associated dysfunction and oxidative damage-related pathologies. PARP inhibitors can also kill certain tumor types because of their effects on DNA repair pathways (Chan et al., 2010; Mason et al., 2014; Rouleau et al., 2010); specifically, they have been shown to be effective in clinical trials among cancer patients carrying BRCAl/2 mutations (Fong et al., 2009). [0507] PARP inhibition is known to increase resistance to DNA-damaging agents such as hydrogen peroxide (Zhang et al., 2007). (Banasik et al., 1992), (Costantino et al., 2001). By in vitro assays for PARP inhibition, we identified, from the 38 "core set" hits, Gr-6A (but not the other members of this group), 01, 014 and 022 (structurally similar to 07) as inhibitors of PARPl (FIG. 2). When we extended the analysis to the other members of the original group of 54 molecules, we found, besides 07, additional PARP inhibitors as well (Gr-2A, Gr-2B, Gr-2C, Gr-2E - note that these molecules belong to the same structural group, 03 and 04). All 11 PARP inhibitors preserved ATP upon H ₂ 0 ₂ stress.

[0508] Recently, several studies have revealed very interesting features of PARP inhibition with potential health benefits. First, deletion of Parpl has been shown to increase mitochondrial metabolism through NAD ⁺ preservation and SIRTl activation and to protect animals from metabolic disease (Bai et al., 2011). Second, long-term treatment with PARP inhibitors has been found to enhance mitochondrial function and improve fitness of skeletal muscles in mice.

Moreover, PARP inhibition can reverse mitochondrial defects in primary myotubes of obese humans and attenuate metabolic defects in NDUFS1 -mutant fibroblasts (Pirinen et al., 2014). Third, disruption of the C. elegans PARP orthologue pme-1, as well as PARP inhibitors, could induce the mitochondria unfolded protein response (mtUPR) and extend lifespan in a manner that requires both sir-2.1 and daf-16/foxo (Mouchiroud et al., 2013). Consistent with these previous reports, we found that several of our PARP inhibitors extended C. elegans ' lifespan (specifically, 07, -10% - 34%, 4 of 4 trials; and 014, -10% or more, 3 of 3 trials). [0509] PARP Inhibitor Assay. The assay was performed with the HT Fluorescent

Homogeneous PARP Inhibition Assay Kit (Trevegen), following manufacturer's instructions. Briefly, nicotinamide adenine dinucleotide, human PARPl and activated-DNA solution was added onto a 96-well plate. 54 repurchased small molecules, at 10 μΜ final concentration, were introduced onto the 96-well assay plate and incubated in a humid chamber at room temperature for 30 min in dark. Cycling mixture, with resazurin and cycling enzyme diaphorase, was then added and incubated further for 1 hr in dark. Reaction was stopped by adding the stopping buffer. Fluorescence was measured on a FlexStation 3 multi-mode microplate reader (544 nm excitation/ 590 nm emission). Two known PARP inhibitors, including PJ-34 (Tocris) (IC ₅₀ : -20 nM) (200 nM) and MK-4827 (IC ₅₀ : ~3.8 nM), were used as the controls at 200 nM and 40 nM, respectively. These PARP inhibitors could increase the readings to 2.4- to 3.0-fold (normalized to DMSO negative control).

[0510] 14 identified PARP inhibitors, including the 4-amino-l,8-naphthalimide analog, represented a significant fraction of our total 61 hits. A few validated PARP inhibitors, consistent with previous reports, extended C. elegans' lifespan (for example, 07, -10% - 34%, 4 of 4 trials; 014, -10% or more, 3 of 3 trials). Furthermore, some of these are structurally different from known PARP inhibitors and do not appear to have been identified by others.

PARP inhibitors have been tested in clinical trials, particularly for cancer patients carrying mutation in the BRCA1 and BRCA2 DNA repair genes. Recently, several studies have revealed very interesting features of PARP inhibition in the perspective of promoting health, and our findings of novel PARP inhibitors could provide us with the necessary reagents to pursue this possibility.

[0511] Recently, several studies have revealed very interesting features of PARP inhibition with potential health benefits. First, deletion of Parpl has been shown to increase mitochondrial metabolism through NAD ⁺ preservation and SIRTl activation and to protect animals from metabolic disease (Bai et al., 2011). Second, long-term treatment with PARP inhibitors has been found to enhance mitochondrial function and improve fitness of skeletal muscles in mice.

Moreover, PARP inhibition can reverse mitochondrial defects in primary myotubes of obese humans and attenuate metabolic defects in NDUFS1 -mutant fibroblasts (Pirinen et al., 2014). Third, disruption of the C. elegans PARP orthologue pme-1, as well as PARP inhibitors, could induce the mitochondria unfolded protein response (mtUPR) and extend lifespan in a manner that requires both sir-2.1 and daf-16/foxo (Mouchiroud et al., 2013). Consistent with these previous reports, we found that several of our PARP inhibitors extended C. elegans ' lifespan (specifically, 07, -10% - 34%, 4 of 4 trials; and 014, -10% or more, 3 of 3 trials).

Example 3. Chalcones

[0512] Chalcones. Chalcones are aromatic ketones (l,3-diaryl-2-propen-l-ones). They have many beneficial health effects, including anti-cancer, anti-HIV, anti-malarial, anti-inflammatory, and anti-allergic activities (Batovska and Todorova, 2010; Sahu et al., 2012). Chalcones have a wide variety of molecular targets, many of which have relevance for cancer, which could explain their anti-proliferative activities against cell lines derived from many types of tumors (Solomon and Lee, 2012; Yadav et al., 2011). Several proteins, including HSF-1, FOX03 and RF2, as well as the chaperone machinery, have been shown to mediate the beneficial effects of chalcones.

[0513] The 104, 121 -compound library contained 71 chalcones, with exact core structure match. Of these, 4 were in our top 61 H ₂ 0 ₂ -resistant hits (Gr-4A, Gr-4B, Gr-4C and Gr-4D - the chalcone group), and one of these, Gr-4D (see Table al-lf) appeared particularly interesting, as it could induce both FOX03- and RF2-regulated genes. This molecule also increased lifespan (up to -50%, 4 of 4 trials) consistently in worms. (Table 7). (Calamini et al., 2012). Several proteins, including HSF-1, FOX03 and RF2, as well as the chaperone machinery, have been shown to mediate the beneficial effects of chalcones. Likewise, the effects of our chalcone compounds on these key regulators of stress response may explain, at least in part, the benefits that we have observed in cells and in worms. Example 4. FOXO modulating compounds

[0514] Effects on Longevity-modulating Proteins. Applicants examined our molecules in many cellular assays to score them in the context of aging. Specifically, it is important to understand whether these molecules could activate proteins, including FOX03 and RF2, known to extend lifespan, inhibit mTOR (another potential cause of life extension), induce autophagy (strong association with longevity in experimental species), and/or attenuate toxic protein aggregation, etc.

[0515] qPCR Analysis & FOX03 & NRF2 Interference. For qPCR analysis, WI-38 cells were treated with small molecules (at 10 μΜ) (biological quadruplicate) for 24 hrs and processed for RNA isolation and reverse transcription (RT) with the Cells-to-Ct Kit (Life Technologies), following manufacturer's instructions. RT products were diluted with H ₂ 0 and used for qPCR analysis on a LightCycler 480 system (Roche) (technical triplicates). Relative expression levels of target genes were normalized to the genes B2M, PPIA and GAPDH. To knock down the expression of FOXO 3 or NRF2, WI-38 cells were transfected with siRNA oligos (at 10 nM final concentration) for FOXO 3 (Life Technologies) or NRF2 on 10-cm petri dish for 36 hrs, and then detached and aliquoted onto 96-well plates. -24 hrs later, small molecules were introduced and incubated with cells for 24 hrs. Cells were then processed with the Cells-to-Ct Kit to prepare RT products for qPCR analysis. The knockdown efficiency of FOX03 or NRF2 was checked at 36 hrs post-transfection and at the end as well. [0516] qPCR analyses indicated that 13 molecules (Gr-IA, Gr-IB, Gr-lC, Gr-IE, Gr-4A, Gr- 4C, Gr-4D, Oi l, 012, 013, 014, 015, 020) could produce significant induction of at least two (of five selected) representative F0X03 -regulated genes. Another 3 (Gr-7A, Gr-7C and 023) could induce robust expression (greater than 1.5-fold) of at least 2 F0X03 target genes. By analyzing stress resistance upon FOXO 3 -knockdown, applicants also found that at least 4 molecules (Gr-7A, Gr-7C, 015 and 020) required F0X03 to promote H ₂ 0 ₂ -resistance of WI-38 cells (in at least 2 of 3 independent experiments).

[0517] Many perturbations that increase lifespan and stress resistance in animals do so in a FOXO-dependent fashion (Kenyon, 2010c). Humans have several FOXO genes, but FOX03, which promotes stress resistance in mammalian cell culture (Kops et al., 2002; Nemoto and Finkel, 2002; Tran et al., 2003), is the one that has been linked to exceptional longevity in humans (Anselmi et al., 2009; Flachsbart et al., 2009; Li et al., 2009; Pawlikowska et al., 2009; Soerensen et al., 2010; Willcox et al., 2008). FOXOl, in contrast, appears to be responsible for some symptoms of diabetes in mouse models (Cheng and White, 2011). For this reason, applicants have focused on analyzing potential ability of our small molecules to activate FOX03. Of 38 small molecules, we found 10 (Gr-IA, Gr-IB, Gr-IE, Gr-4A, Gr-4C, Gr-4D, Oi l, 013, 015, O20) that produced significant, induction of at least two of five FOX03 -regulated genes analyzed, including SOD2 (superoxide dismutase), GADD45A (cell cycle regulator), CAT (catalase), DDB1 (damage-specific DNA binding protein), and TXNIP (thioredoxin interacting protein) (Table la-lf). Another 4 molecules (Gr-7A, Gr-7C, 012 and 023) could induce robust expression (greater than 1.5-fold) of at least 2 FOX03 target genes.

[0518] Applicants used siRNA to knock down FOX03 expression by -70% in an attempt to identify whether the activation of these genes depends on activity of FOX03 and/or RF2.

Here, a negative result does not mean that FOXO proteins are not activated: in flies, dfoxo inhibition prevents insulin/IGF- 1 -pathway mutations from increasing lifespan but not from increasing oxidative stress resistance (Slack et al., 2011). We used siRNA to knock down FOXO 3 expression by -60% to 70% (FIG. 3; see data in Table 6). At least 4 small molecules (Gr-7A, Gr-7C, 015 and O20) required FOX03 to promote H ₂ 0 ₂ -resi stance of WI-38 cells (in at least 2 of 3 independent experiments) (Table la-lf) under conditions tested. (Given the caveat that FOXO 3 was not fully knocked down, partial dependency was scored when the H ₂ 0 ₂ - resistance capacity was reduced by at least 25% but less than 50% upon siRNA knockdown). At least for Gr-7A and Gr-7C, which are structurally related, the observed i O O3-dependency for H ₂ 0 ₂ -resistance is consistent with their strong effects to induce FOX03 target genes (Tables la- lf , Table 6, & Table 15), including SOD2 and GADD45A. Example 5. NRF2 modulating compounds

[0519] F2/SKN-1, the oxidative stress and xenobiotic phase 2 detoxification protein, can extend animal lifespan (Sykiotis and Bohmann, 2008; Tullet et al., 2008). Applicants analyzed these small molecules for their ability to increase the expression of RF2-regulated genes, including HMOX1 (heme oxygenase (decy cling) 1; anti-oxidant), NQOl (NAD(P)H

dehydrogenase, quinone 1; phase 2 detoxification enzyme), GCLC (glutamate-cysteine ligase, catalytic; ) and GSTM1 (glutathionine S transferase) (Hur and Gray, 2011; Suzuki et al., 2013).

[0520] 3 small molecules (Gr-lC, 011, 017) could induce expression of at least two genes above. To our surprise, 15 additional molecules (Gr-IA, Gr-4A, Gr-4B, Gr-4C, Gr-4D, Gr-5A, Gr-5B, Gr-5D, Gr-6B, Gr-7C, 06, 013, 015, 018 and O20) could induce, by more than 1.5-fold, the expression of at least two RF2 target genes. These data indicate an enrichment for RF2- activating small molecules in our screen. Of these, all the chalcones (group 4) induced several RF2-regulated genes (Tables la-lf), including HMOX1 (>= 4.0-fold) and NQOl (>=2.0-fold). These findings are consistent with the notion that chalcones, as known electrophilic Michael acceptors, could block KEAP1 through Michael addition reactions with its cysteine sulfhydryl groups, and thereby, activate RF2 and downstream xenobiotic stress responses. Conversely, none the PARP inhibitors caused obvious increased expression of either FOX03 or NRF2 target genes under the conditions tested, suggesting that they act through other pathways to promote stress resistance. [0521] Consistent with the observation of multiple NRF2-activating molecules, applicants then found that NRF2 siRNA knockdown (by -90% or more, FIG. 3) could significantly attenuate the ability of at least 12 small molecules (Gr-IA, Gr-6B, Gr-7A, Gr-7B, Gr-7C, 01, 015, 018, O20, 021, 022 and 023) to promote H ₂ 0 ₂ -resistance of WI-38 cells (in at least 2 of 3 independent experiments) (Tables la-lf). Of these, 015 and O20 consistently (in 3 of 3 experiments) required RF2 to promote H ₂ 0 ₂ -resi stance, and their resistance capacities were reduced by

-90%) on average upon RF2 knockdown under conditions tested. 015 is a small molecule that could induce HMOX1 by almost 50-fold in WI-38 cells, and it also protected C. elegans from hydrogen peroxide (in 2 of 2 trials). In addition, the ability of chalcone Gr-4D to promote H ₂ 0 ₂ - resistance appeared to be partially dependent on NRF2, but not FOX03 under conditions tested. Applicants also noted that several small molecules, including Gr-IA, Gr-7A, Gr-7C and 023, but not the others, could reduce the survival of NRF2 siRNA-transfected cells in the absence of H ₂ 0 ₂ under conditions tested. Example 6. MTOR modulating compounds

[0522] mTOR inhibition. Mammalian target of rapamycin (mTOR) is a crucial regulator of cell growth and metabolism and has been implicated in aging and many diseases, including cancer, diabetes and neurological diseases (Dazert and Hall, 2011; Zoncu et al., 2011). The strong connections between mTOR and diseases and aging have stimulated the interests to develop novel mTORCl/2 inhibitors, besides rapamycin, ATP-competitive, phosphatidic acid- competitive, and farnesyltransferase-inhibiting, etc (Benjamin et al., 2011). In addition, the anti- diabetes drug metformin (Kalender et al., 2010), as well as other AMPK activators such as 2- deoxy-D-glucose (Inoki et al., 2003) and AICAR (Shaw et al., 2004), could inhibit mTORCl . Applicants examined the effects of our molecules (at three doses, 5 μΜ, 10 μΜ and 20 μΜ) on the phosphorylation status of ribosomal protein S6 (RPS6), a readout of mTOR activity, to ask whether they could inhibit mTOR. Rapamycin, as a control, could substantially reduce the phosphorylated form of RPS6 (normalized, by 95%). Quantitative analysis indicated that, 4 of 38 small molecules (Gr-7A, Gr-7B, Gr-7C and 027) consistently reduced the ratios of phosphorylated RPS6 (p-RPS6) to total RPS6 (30% - 60%, at 10 μΜ, (Tables la-lf)). This group of small molecules, like rapamycin, appeared to have anti-proliferative activities and may have significant long-term toxicity on cells under the conditions tested. Conversely, the PARP inhibitors nor the chalcones reduced the p-RPS6/RPS6 ratio, suggesting that our different hits affect the cells in different ways. [0523] Sestrin. Through direct effects on anti-oxidant peroxiredoxins and through the AMPK and mTOR pathways, sestrins could suppress ROS production and protect cells from oxidative stress, transformation, and genomic instability (Budanov and Karin, 2008). Studies have indicated that sestrin could be a pro-longevity factor. RNAi inhibition of the sestrin gene sesn-1 has been shown to shorten lifespan, while its overexpression promotes longevity of C. elegans (Yang et al., 2013). Loss of Drosophila dSesn has been shown to lead to age-associated pathologies, including fat accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which could be blocked by pharmacological activation of AMPK or inhibition of TOR (Lee et al., 2010). Likewise, sestrin deficiencies in mice led to exacerbated obesity-induced diabetic conditions (Lee et al., 2013; Lee et al., 2012). Furthermore, sestrins have been shown to activate Nrf2, by promoting p62-dependent autophagic degradation of Keapl, and prevent oxidative damage in the liver of mice (Bae et al., 2013)). In this study, at least 9 small molecules (Gr-IA, Gr-lC, Gr-ID, Gr-IF, Gr-4D, Oi l, O20, 021 and 027) were found to induce the expression (more than 1.5-fold) of SESN1, which could count for, at least in part, their anti -oxidative capacity. Of the 9 small molecules, 6 (Gr-IA, Gr-lC, Gr-ID, Gr-IF, 021 and 027) scored positive for the DNA damage-markers γΗ2Α.Χ and TP53BP1, which appeared to be consistent with previous findings that genotoxic stress, through the induction of p53, could up-regulate sestrins (Budanov and Karin, 2008). Nonetheless, both p53 and Nrf2 are highly expressed in the long-lived, stress-resistant naked mole rats, which could explain the prevention of cancer in these animals (Lewis et al., 2012). In this regard, it is possible that even the small molecules that may induce sestrin through p53 activation could still be beneficial.

[0524] Sestrin genes are regulated by FOX03 (Nogueira et al., 2008), NRF2 (Shin et al., 2012) and p53 (Budanov et al., 2004). In a parallel siRNA screen, 83 siRNA clones that increased the H202-resistance of WI-38 cells. Of these, approximately 65 clones could induce SESN1 by at least 1.5-fold - this raises the alert that some of these clones may cause DNA damages in cells. Interestingly, no observations were made regarding substantial attenuation of SESN1 induction by these siRNA clones upon FOX03 or NRF2 knockdown, indicating that neither FOX03 nor NRF2 under conditions tested.

[0525] We examined the effects of our molecules (at three doses, 5 μΜ, 10 μΜ and 20 μΜ) on the phosphorylation status of ribosomal protein S6 (RPS6), a downstream readout of mTOR activity, to ask whether they could inhibit mTOR. Rapamycin, as a control, substantially reduced the phosphorylated form of RPS6 (normalized, by 95%). Quantitative analysis indicated that 4 of 38 small molecules (Gr-7A, Gr-7B, Gr-7C and 027) consistently reduced the ratios of phosphorylated RPS6 (p-RPS6) to total RPS6 (30% - 60%, at 10 μΜ, Table 16). Conversely, neither the PARP inhibitors nor the chalcones reduced the p-RPS6/RPS6 ratio under the conditions tested, again suggesting that our different hits affect the cells in different ways.

However, we noted that this group of mTOR-inhibiting small molecules appeared to have long- term toxicity on cells (Table 13).

[0526] mTOR Inhibition (RPS6 Phosphorylation Status) Methods and Analysis In-Cell Western assays were performed, following the same procedures to analyze DNA-damage markers. WI-38 cells were incubated with small molecules for 24 hrs, and then processed and incubated with primary antibody cocktail (mouse anti-RPS, 1 :25; rabbit-anti-pRPS6, 1 : 100) overnight at 4°C. Next day, samples were processed and incubated with fluorophore-conjugated secondary antibodies (goat anti-mouse, 1 :500; goat anti-rabbit, 1 : 1,000) in antibody dilution buffer. Images were collected on an Odyssey Imager (LI-COR) and analyzed with the Image Studio Lite software. Rapamycin was used as the control, at 2.5 μΜ, 5 μΜ and 10 μΜ, and reduced the ratio of pRPS6/RPS6 by 90% or more (normalized to DMSO negative control). [0527] Quantitative In-Cell Western imaging analysis indicated that 4 of 38 molecules (Gr-7A, Gr-7B, Gr-7C and 027) consistently reduced the ratios of phosphorylated ribosomal protein S6 (p-RPS6) to total RPS6, a readout of mTOR activity.

Example 7. Autophagy modulating compounds

[0528] Autophagy induction. The induction of autophagy, a cytoprotective self-eating process, has been observed consistently in long-lived animals, including calorically restricted, in which nutrient and growth-related signaling pathway activities are reduced (de Cabo et al., 2014; Madeo et al., 2015). Key regulators of the autophagy process have been shown to influence longevity in many experimental organisms, including yeast, worms, and flies (de Cabo et al., 2014). Recently, it has been shown that naked mole rats, compared with lab mice, have high levels of autophagy in their livers (Zhao et al., 2014). In addition, like rapamycin, polyamine spermidine has been shown to, by inducing autophagy, extend lifespan in several species (Eisenberg et al., 2009). Applicants examined the small molecules for their ability to increase the formation of autophagy-associated LC3 A/B puncta in cells. Applicants found at least 6 small molecules (Gr-IA, Gr-lC, Gr-ID, Gr-IG, Oi l and 023) that could induce LC3A/B puncta by 2- fold or more (Tables la- If, Table 17). As noted above, the Group 1 molecules enhanced the levels of DNA-damage markers and reduced the total numbers of cells (Tables la-lf, Tables 13 & 14). Additionally, 4 of these molecules (Gr-IA, Gr-lC, Oi l and 023) also induce FOX03- regulated genes, while FOX03 activation is known to promote autophagy (Feng et al., 2015). [0529] Autophagy Induction Analysis. These assays were performed, following the same procedures to analyze DNA-damage markers. WI-38 cells were incubated with small molecules for 24 hrs, and then processed and incubated with primary antibody (rabbit anti-LC3 A/B, 1 : 100) overnight at 4C. The next day, samples were processed and incubated with fluorophore- conjugated secondary antibody and further incubated with DAPI dye. Images were collected on an INCell Analyzer 2000 and analyzed with the Developer software. Total LC3 A/B puncta intensity was normalized the total numbers of D API-positive nuclei.

Example 8. Neurodegernative disease modulating compounds

[0530] Poly-Q toxicity attenuation. Toxic protein aggregation is a key feature of many age- related neurodegenerative diseases, including Alzheimer's and Huntington's disease (Caughey and Lansbury, 2003; Ross and Poirier, 2004). A number of animal models (Phillips et al., 2009) and cell models (Schlachetzki et al., 2013) have been established to study these diseases. For this purpose, PC12 rat pheochromocytoma cells display neuronal features and produce

neurotransmitters and have been used extensively to study neuronal phenotypes, including synaptic transmission and neurological diseases. PC12 cells, stably expressing GFP fused to the poly(Q) tract (exon 1) of mutant human huntingtin gene HTT (Q103-Htt-EGFP), has been engineered to establish a cellular model of Huntington's disease (HD) (Aiken et al., 2004). In this model, induced expression of poly(Q)103-Htt-EGFP could lead to the formation of aggregates and exert substantial toxicity in cells. Applicants screened our 54 molecules (initially at 10 μΜ) in this FID model, and then by testing several candidates at multiple doses (2.5 μΜ, 5 μΜ, 10 μΜ and 20 μΜ), found 4 (Gr-1 A, Gr-lC, Gr-6B and Gr-7C) that consistently increased the viability of PC12 cells upon the induction of toxic poly(Q)103-Htt-EGFP aggregates. Except for Gr-6B, the others appeared to cause toxicity to PC 12 cells under non-induced conditions, (Table 13 & 14).

In these cells, induced expression of poly(Q)103-Htt-EGFP leads to the formation of aggregates and exert substantial toxicity. (Aiken et al., 2004), (Aso and Ferrer, 2014; Booz, 2011). We analyzed our molecules (initially at 10 μΜ) in this HD model, and then by retesting several candidates at multiple doses (2.5 μΜ, 5 μΜ, 10 μΜ and 20 μΜ), found 4 (Gr-1 A, Gr-lC, Gr-6B and Gr-7C) that consistently increased the viability of PC12 cells upon the induction of toxic poly(Q)103-Htt-EGFP aggregates (FIG. 4).

[0531] Poly(Q) Toxicity & Viability Analysis. Viability assays were performed as described before (Aiken et al., 2004). PC12 cells that stably express the inducible poly(Q)103-Htt-EGFP were grown in culture. Ponasterone A (Life Technologies), an ecdysone analog, was added to 10 μΜ final concentration to induce transgene expression, and formation of puncta was examined and confirmed using the Eclipse 200 fluorescent microscope (Nikon). Cell viability was analyzed 48 hrs later by measuring ATP content with CellTiter-Glo. The parental WT-PC12A cells that do not express the poly(Q)103-Htt-EGFP were used as the negative control to exclude the small molecules that could enhance viability in general. [0532] Effects on Toxic Protein Aggregation. In an established cellular model of

Huntington's disease (HD), 4 molecules (Gr-IA, Gr-lC, Gr-6B and Gr-7C) consistently increased the viability of PC12 cells upon the induction of toxic polyQ(103)-Htt-EGFP aggregates.

Example 9. Lifespan modulating compounds

[0533] Hydrogen peroxide resistance on C. elegans. In two independent trials, 54 small molecules were tested and found that at least 3 (Gr-7A, 015 and 017; 2 of 2 trials) could protect C. elegans from hydrogen peroxide of lethal dose. [0534] Hydrogen peroxide resistance. In two independent trials, we tested our 54 small molecules and found that at least 3 (Gr-7A, 015 and 017; 2 of 2 trials) could protect C. elegans from hydrogen peroxide of lethal dose (Table 12). This appeared to be rather surprising.

However, our molecules were isolated with human cells, while their pharmacological kinetics and dynamics could be totally different in between human cells and worms. Moreover, stress resistance at the cellular level and organismal level may not be perfectly correlated with each other.

[0535] Lifespan extension on C. elegans. To test the molecules in more diverse experimental scope, different assay conditions were used, (i.e. in liquid or on plate, non-irradiated or UV- irradiated bacteria, FuDR-treated or genetically-induced sterile animals). In multiple

independent experiments, 12 of 38 small molecules (Gr-IE, Gr-3A, Gr-3B, Gr-3C, Gr-4D, Gr- 6C, Gr-7A, 012, 013, 014, 017, and 023) could extend animal's lifespan (in at least 3 to 4 trials) (from -10% to -50%) (Tables la-lf). Of these, 014 is an identified PARP inhibitor (Mouchiroud et al., 2013). Furthermore, the chalcone Gr-4D and another orphan compound 013 consistently produced significant life-extending effects (Gr-4D, 24.0%; 013, 18.2%; average increase) in 4 or more trials.

[0536] In this study, we have screened for a cellular phenotype that is common to cells from many long-lived animal mutants, and from long-lived species of mammals and birds: resistance to multiple forms of environmental stress. We screened 104, 121 small molecules for their ability to protect primary human fibroblasts from a lethal dose of hydrogen peroxide, and then retested our top -60 hits for their ability to protect cells from the DNA-damaging agent MMS and the heavy metal cadmium. Many of these compounds conferred resistance to multiple stressors, and a number inhibited TOR activity and appeared to affect FOX03 and/or RF2 activities, and/or extended C. elegans ' lifespan (see the summary in Table 4). [0537] Table 4 is a summary for characterization of screen hits. 38 "core set" small molecules are listed and are assigned a score, based on the result for each individual characterization. From our small molecule screen for H ₂ 0 ₂ -resi stance, we isolated 61 top hits. Of these, 38 repurchased molecules were further validated and analyzed as the "core set" in multiple phenotypical assays that have been shown to be longevity-related in experimental systems (including animals).

Specifically, a 2-point score was assigned to the most well-known and prominent longevity- related phenotypes, such as multiplex resistance, activation of FOX03 and/or RF2, and down- regulation of mTOR. Small molecules were also analyzed for their ability to extend C. elegans ' lifespan in 4 to 6 independent trials, and the lifespan score scale is from 0 to 2: 0 for no obvious effects, 1 for lifespan extension observed in 2 trials, 2 for observed in more than 2 trials. Certain molecules appeared to have DNA-damaging effects and/or potential cell-toxicity in cultured human cells, and they receive a negative point.

[0538] No observations were made regarding the obvious reduction in pumping rates for worms treated with the life-extending molecules. Consistent with this, these animals did not appear to be pale, a feature that is often seen in calorically restricted animals.

Example 10. Proliferation modulating compounds

[0539] To understand to what extent these molecules could adversely affect cells under normal conditions, applicants analyzed the small molecule's effects on two DNA damage-associated cellular markers: phosphorylated histone variant γΗ2Α.Χ and tumor protein p53 binding protein 1 (TP53BP1). γΗ2Α.Χ is required for checkpoint-mediated cell cycle arrest and DNA repair following double-stranded DNA breaks, and phosphorylation of γΗ2Α.Χ by a group of PI3K-like kinases (ATM, ATR, and DNA-PK) occurs rapidly in response to DNA damages (Perez-Cadahia et al., 2010). Likewise, in response to DNA damages, TP53BP1 is phosphorylated and translocated into the nucleus, and retention of TP53BP1 at DNA breaks requires phosphorylated γΗ2Α.Χ (Panier and Boulton, 2014). Applicants found that 10 small molecules (Gr-1 A, Gr-lC, Gr-ID, Gr-IF (these 4 belong to one structural class), Gr-3A, Gr-3C, Gr-6C, 021 and 027) increased the percentage of both γΗ2Α.Χ- and TP53BPl-positive cells under the assayed conditions in multiple independent experiments (Tables la-lf). Consistent with these results, of these, 4 molecules (Gr-lC, Gr-ID, Gr-IF and 021) increased the percentage of propidium iodide-positive death cells under normal conditions (Gr-lC, 3.5±1.3%, P = 0.002; Gr-ID, 4.2±1.4%, = 0.001; Gr-IF, 3.3±0.8%, P = 3.26E-14; and 021, 1.1±0.4%, P = 0.008; vs.

control, 0.4±0.2%). Besides, Pi-positive fraction was also increased for WI-38 cells treated with another 7 small molecules (Gr-IB, 1.0%±0.3%, P = 0.006; Gr-IG, 7.1%±1.1%, P = 2.09E-05; Gr-7B, 3.6%±0.7%, P = 8.77E-05; Oi l, 1.9%±0.7%, P = 0.004; 015, 3.8%±0.7%, P = 5.30E- 05; O20 0.7%±0.3%, P = 0.030; and 023, 2.6%±1.4%, P = 0.011), while these did not appear to increase both γΗ2Α.Χ and TP53BP1 foci in treated cells. Applicants did not observe obvious reduction in viability of WI-38 cells that had been incubated up to 5 days with our molecules (for example, of 11 analyzed, Gr-lC, Gr-ID, Gr-IE, Gr-6A, Gr-7A, 01, Oi l, 012, 014, O20 and 022: Gr-lC and Gr-ID showed some toxicity under conditions tested.

[0540] In this case, by inducing modest level of stress, small molecules may protect cells from H ₂ O ₂ through "hormesis" mechanism. However, such type of small molcules could result in increased DNA damages, which elevate the risk of malignant transformation when affected cells do not undergo senescence and apoptosis. But, even if so, these DNA-damaging small molecules could also be interesting, as they may act like certain cytotoxic agents (e.g., doxorubicin) and produce toxicity on highly proliferative tumor cells in vivo.

[0541] Longterm proliferation assay. Applicants introduced molecules (at lOuM final concentration) to WI-38 fibroblasts and then assayed cell viability (through ATP measurement) everyday, during a course of 5 days of continuous treatment. At least 14 of 38 molecules, including Gr-IA, Gr-IB, Gr-IF, Gr-3A, Gr-3B, Gr-3C, Gr-6C, Gr-7A, Gr-7B, Gr-7C, Oi l, 021, 023 and 027, could reduce the ATP content by more than 40% after 5 days of continuous incubation. These data suggested potential anti-proliferative activity and/or cell toxicity for these molecules under conditions tested. Applicants also examined the morphology and scored cell death (propidium iodide staining) for cells treated with the above molecules. Of these 14 molecules, some appeared to cause cell toxicity. For Gr-IB, Gr-3A, Gr-3B, Gr-6C, Gr-7C, Oi l, 021 & 027, there were less cells, and more cells scored positive for propidium iodide. Gr-7A, Gr-7B & 023 : many cells are dead and necrotic. Rapamycin (5uM), a potent inhibitor of mTOR, reduced the ATP content by more than 50%, yet did not significantly increase the fraction of PI- positive dead cells under the conditions tested. Many Group 1 molecules scored positive for DNA-damaging markers (phosphorylation of H2AX and 53BP1), and Group 7 molecules significantly reduce the phosphorylation of RPS6 and exerted toxicity on the HTB-178 lung tumor cell line. Furthermore, preliminary analysis with comet assay, which assesses DNA damages by assaying the electrophoresis behavior of DNA, indicated that, at least Gr-7A significantly increased the fraction of damaged DNA with long comet tails. Despite the observed long-term toxicity, these molecules are still interesting as they may act as anti-tumor agents in vivo, should they have more pronounced cytotoxicity on highly proliferative tumor cells. When cells were incubated with these molecules for ~24hrs and then subject to hydrogen peroxide for 3hrs, these molecules are all protective. Of the 38 core hits, a few small molecules, including Gr- IA, Gr-3A, Oi l, 015, O20, 023 and 027, may have some cell toxicity and/or DNA-damaging effects under certain conditions. Some of these small molecules may be toxic by themselves under certain conditions, but by inducing protective mechanisms, they may trigger "hormesis" and therefore protect cells from oxidative stress. [0542] Lifespan Assays Methods. Liquid culture-based lifespan assays were performed, following the protocol as descrbied before (Solis and Petrascheck, 2011). Briefly, newly hatched wild-type N2 worms were fed ampicillin-resistant OP50 bacteria and treated with small molecules (67 μΜ final concentration, 0.2% DMSO) at the young adult stage. FUdR was used to block progeny production. The molecules were analyzed in 96-well plates, with 4 wells for each small molecule. Multiple control wells with DMSO (0.2% final concentration) were included. Likewise, small molecules were also analyzed for their ability to extend lifespan on solid agar, following procedures as described before (Cabreiro et al., 2013). Hypochlorite-synchronized temperature-sensitive sterile mutants, CF4059, (fer-15(b26)II rol-6(su 1006)11; fern- 1 (he 17)1 V), were raised on large agar plates seeded with OP50 bacteria at 25°C. Day 1 adults were transferred onto mini-plates, seeded with OP50 bacteria (UV-irradiated, kanamycin-treated) and supplemented with small molecules (-60 μΜ final concentration, 0.2% DMSO). Worms were scored every other day. Cumulative survival was analyzed using the STATA software (log-rank test). The small molecules were tested (at 67 μΜ) for their ability to confer H ₂ 0 ₂ -resistance. The worms were treated with the small molecules in liquid, with H ₂ 0 ₂ (500 μΜ final concentration) added on day 4 of adulthood, and scored for viability every day.

Table 1A. Index, SMDC ID, Cmpd ID, Structure and Group Hit Structure (it will be understood that the R moieties (e.g., Rl, R2, R3) shown in the Group Hit Structures of Table 1A do not necessarily correspond to the R moieties (e.g., R ¹ , R ² , R ³ ) of the compounds described herein (e.g., in the Compound section above). It will be further understood that the formulae of the Group Hit Structures may be embodiments of the compounds described herein (e.g., in aspects or embodiments of the Compound section above) wherein a person of ordinary skill will readily recognize which R moieties of the Group Hit Structures correspond to which R moieties described in the Compound section when a Group Hit Structure is fit to a formulae of the Compound section above).

ı92

ı93

ı94

ı95

ı96

ı97

ı98

ı99

200

201

202

203

205

206

207

208 [0543] Table IB. Screening Compounds, a Screen 1 : Screening, at lOuM (viability assay by ATP measurement, normalized fold-change shown, >= 2.5); b Screen 2: Dose response, at lOuM (viability assay by ATP measurement, normalized fold-change shown, >= 1.5);c Screen 3 : Dose response, at 20uM (viability assay by ATP measurement, normalized fold-change shown).

43 178510 09 3.05 1.11 1.59 14.2

44 41334 O10 3.12 1.83 2.32 9.5

45 157343 on 3.42 6.71 3.00 4.4

46 122572 012 3.82 5.74 9.57 1.0

47 30228 013 4.21 1.50 2.09 10.1

48 38610 014 4.24 2.32 3.77 12.5

49 29424 015 4.60 1.57 2.32 20.0

50 194820 016 4.96 0.93 1.88 20.0

51 157154 017 4.97 1.96 2.22 8.5

52 31883 018 5.33 1.73 2.22 9.8

53 47511 019 6.45 1.28 1.34 20.0

54 39793 O20 8.90 1.41 1.82 12.9

55 128071 021 10.24 1.59 8.46 18.1

56 115873 022 14.30 3.28 5.11 20.0

57 165151 023 15.73 2.82 1.44 4.9

58 184478 024 18.69 27.09 30.94 7.5

59 119430 025 40.54 34.84 43.28 8.5

60 49713 026 45.06 1.05 0.68 20.0

61 34215 027 48.52 10.45 43.23 12.7

62 43877 028 58.35 46.91 41.23 5.4

63 29261 029 24.70 4.10 44.54 15.3

64 155615 O30 2.59 2.03 2.14 4.2

65 160962 031 3.22 2.00 2.68 10.6

[0544] Table 1C. Cellular Assays, d Assay: H202-resistant (If scored NO, possibly due to repeated freezing/thawing that compromise the stocks); e Assay: Cadmium-resistant; f Assay: MMS-resistant; g Assay: H202- & Cd-resistant; h Assay: Triple resistant; i Assay: H ₂ O ₂ - resistant, at 10 uM, human dermal fibroblast (HDF) primary cells; j Assay: H ₂ 0 ₂ -resistant, at 10 uM, validated by propidium iodide (PI) cell-death imaging (w/ H ₂ 0 ₂ , 3hrs/4hrs/5hrs).* indicates partial.

Cellular Assays

Cmpd Assay Assay Assay Assay Assay Assay Assay

SMDC ID ID 1(d) 2(e) 3(f) 4(g) 5(h) 6(i) ⁷ <j)

43368 Gr-IA YES YES YES YES YES YES YES

45705 Gr-IB YES YES NO * YES YES YES YES

34365 Gr-lC YES YES NO YES NO YES YES

43139 Gr-ID YES YES YES YES YES YES YES

45496 Gr-IE YES YES NO * YES YES YES YES

44811 Gr-IF YES YES YES YES YES YES YES

44542 Gr-IG YES YES NO YES NO YES YES

152226 Gr-2A YES YES YES YES YES YES NO

29688 Gr-2B YES YES YES YES YES YES NO

30271 Gr-2C YES YES YES YES YES YES NO

164559 Gr-2D N/A N/A N/A N/A N/A - -

182737 Gr-2E YES YES NO YES NO YES NO 29031 Gr-3A YES YES YES YES YES YES YES

28636 Gr-3B NO NO NO NO NO YES YES

29041 Gr-3C NO NO NO NO NO YES YES

118836 Gr-3D N/A N/A N/A N/A N/A - -

29513 Gr-4A YES YES NO YES NO YES YES

33179 Gr-4B YES YES YES YES YES YES YES

32955 Gr-4C YES YES YES YES YES YES YES

28213 Gr-4D YES YES YES YES YES YES YES

158211 Gr-5A NO NO NO NO YES YES

158201 Gr-5B NO NO NO NO NO YES YES

158206 Gr-5C NO NO NO NO NO YES NO

158125 Gr-5D YES YES YES YES YES YES YES

50328 Gr-6A YES YES YES YES YES YES YES

150533 Gr-6B YES YES YES YES YES YES YES

162159 Gr-6C NO NO NO NO NO YES YES

152946 Gr-7A YES YES NO YES NO YES YES

152936 Gr-7B YES YES NO YES NO YES YES

152926 Gr-7C YES YES NO YES NO YES YES

39959 01 YES YES NO YES NO YES YES

169199

02 N/A N/A N/A N/A N/A - - N/A

127091 03 YES YES YES YES YES YES NO

194447 04 YES YES YES YES YES YES NO

151482 05 YES YES YES YES YES YES NO

166246 06 YES YES NO YES NO YES YES

148098 07 YES YES YES YES YES YES NO

173384 08 NO NO NO NO NO YES NO

178510 09 YES YES YES YES YES NO NO

41334 O10 YES YES NO YES NO YES YES

157343 Oi l YES YES NO YES NO YES YES

122572 012 NO NO* NO NO NO YES YES

30228 013 YES YES YES YES YES YES YES

38610 014 YES YES YES YES YES YES YES

29424 015 YES YES NO YES NO YES YES

194820 016 NO NO NO NO NO YES NO

157154 017 NO NO NO NO NO YES YES

31883 018 YES YES YES YES YES NO YES

47511 019 NO N/A N/A N/A NO YES NO

39793 O20 YES YES YES YES YES YES YES

128071 021 NO NO NO NO YES YES

115873 022 YES YES YES YES YES YES YES

165151 023 YES YES NO YES NO YES YES

184478 024 YES YES YES YES YES YES NO

119430 025 NO N/A N/A N/A NO YES NO

49713 026 NO N/A NO NO NO NO NO

34215 027 YES YES N/A YES YES YES YES

43877 N/A 028 N/A N/A N/A N/A N/A - -

29261 N/A 029 N/A N/A N/A N/A N/A - - 155615

O30 N/A N/A N/A N/A N/A - - N/A

160962

031 N/A N/A N/A N/A N/A - - N/A

[0545] Table ID. Cellular Assays, k Assay: Without H ₂ 0 ₂ , at 10 uM, PI cell-death imaging (indicating potential toxicity);l Assay: Score positive for both H2A.X & 53BP1, at lOuM

(indicating potential DNA-damaging effects);m Assay: Induction of FOX03 -regulated genes (5 analyzed), at lOuM (2012 Jul. qPCR analysis) (normalized fold-change and p value shown);n Assay: Potential FOX03 Activation (>= 2 target genes induced, by >=1.5-fold);o Assay:

Induction of NRF2-regulated genes (4 analyzed), at lOuM (2012 Jul. qPCR analysis) (normalized fold-change and p value shown);p Assay: Potential NRF2 Activation (>= 2 target genes induced, by >=1.5-fold);q Assay: mTOR down-regulation by p-RPS6 assays, at 5uM, lOuM & 20uM.

[0546] Table IE. Cellular Assays, r Assay: Potential autophagy induction by LC3A/B puncta assays, at lOuM & 20uM;s Assay: FOX03 -dependency for H ₂ O ₂ -resistance, at 10uM;t Assay: NRF2-dependency for H ₂ O ₂ -resistance, at 10uM;u Assay: FOX03 -dependency for target gene induction, at 10uM;v Assay: NRF2-dependency for target gene induction, at 10uM;w Assay: Huntington's poly-Q toxicity attenuation, at 10uM;x Assay: Potential killing effects on HTB-178 tumor cells (EGFR+ & PIK3CA+ & RBI- & TP53-) at lOuM.

Cel ular Assays

Cmpd Assay Assay Assay Assay Assay Assay Assay

SMDC ID ID 15(r) 16(s) 17(t) 18(u) 19(v) 20(w) 21(x)

43368 Gr-IA YES NO YES YES NO

45705 Gr-IB NO NO NO NO NO

34365 Gr-lC YES NO NO YES NO

43139 Gr-ID YES NO NO NO NO 45496 Gr-1E NO NO NO NO NO

44811 Gr-IF NO NO NO NO NO

44542 Gr-IG YES NO NO NO NO

152226 Gr-2A NO NO NO NO NO

29688 Gr-2B NO NO NO NO NO

30271 Gr-2C NO NO NO NO NO

164559 Gr-2D - - - - - - -

182737 Gr-2E NO NO YES NO NO

29031 Gr-3A NO NO NO NO NO

28636 Gr-3B NO NO NO NO NO

29041 Gr-3C NO NO NO NO NO

118836 Gr-3D - - - - - - -

29513 Gr-4A NO NO NO NO NO

33179 Gr-4B NO NO NO NO NO

32955 Gr-4C NO NO NO NO NO

28213 Gr-4D NO NO NO NO NO

158211 Gr-5A NO NO NO NO NO

158201 Gr-5B NO NO NO NO NO

158206 Gr-5C NO NO NO NO NO

158125 Gr-5D NO NO NO NO NO

50328 Gr-6A NO NO NO NO NO

150533 Gr-6B NO NO YES YES NO

162159 Gr-6C NO NO NO NO NO

152946 Gr-7A NO YES YES NO YES

152936 Gr-7B NO NO YES NO YES

152926 Gr-7C NO YES YES YES NO

39959 01 NO NO YES NO NO

169199 02 - - - - - - -

127091 03 NO NO NO NO NO

194447 04 NO NO YES NO NO

151482 05 NO NO NO NO NO

166246 06 NO NO NO NO NO

148098 07 NO NO NO YES NO

173384 08 NO NO NO NO NO

178510 09 NO NO NO NO NO

41334 O10 NO NO NO NO NO

157343 Oi l YES NO NO NO NO

122572 012 NO NO NO NO NO

30228 013 NO NO NO NO NO

38610 014 NO NO NO NO NO

29424 015 NO YES YES NO NO

194820 016 NO NO NO NO NO

157154 017 NO NO NO NO NO

31883 018 NO NO YES NO NO

47511 019 NO NO NO NO NO

39793 O20 NO YES YES NO NO

128071 021 NO NO YES NO NO

115873 022 NO NO YES NO NO

165151 023 YES NO YES NO NO

184478 024 NO NO NO NO NO 119430 025 NO NO NO NO NO

49713 026 NO NO YES NO NO

34215 027 NO NO NO NO YES

43877 N/A 028 - - - - -

29261 N/A 029 - - - - -

155615

O30 - - - - - N/A

160962

031 - - - - - N/A

[0547] Table IF. C. elegans Assays, y Assay: Potential killing effects on HTB-178 tumor cells (EGFR+ & PIK3CA+ & RBI- & TP53-) at lOuM; z Assay: Lifespan assay in liquid, at 66uM, 1.0Χ10 ^Λ 9 bacteria/ml, wild type + FuDR (2012 Jul.) (p<0.05 highlighted); aa Assay: Lifespan assay in liquid, at 66uM, 2.5X10 ^A 9 bacteria/ml, wild type + FuDR (p<0.05

highlighted); ab Assay: Lifespan assay on plates, at 66uM, 2.0X10 ^A 10 bacteria/ml, CF512 worms, no FuDR (p<0.05 highlighted); ac Assay: Lifespan assay on plates, at 66uM, 1.0X10 ^A 11 bacteria/ml, CF512 worms, no FuDR (p<0.05 highlighted); ad Assay: Lifespan assay on plates, at 66uM, 2.0Χ10 ^Λ 10 bacteria/ml, CF512 worms, no FuDR (p<0.05 highlighted); ae Assay: Lifespan assay on plates, at 66uM, 1.0X10 ^A 11 bacteria/ml, CF512 worms, no FuDR (p<0.05 highlighted).

C. elegans Assays

Cmpd Assay Assay Assay Assay Assay Assay Assay

SMDC ID ID Hy) 2(z) 3(aa) 4(ab) 5(ac) 6(ad) 7(ae)

1st,

YES;

43368 Gr-IA -1.3% +0.2% +14.2% N/A N/A N/A

2nd,

NO.

45705 Gr-IB NO +12.9% +8.0% +15.1% N/A N/A N/A

34365 Gr-lC NO +14.4% +1.7% +14.7% N/A N/A N/A

43139 Gr-ID NO +18.2% -0.5% +10.5% N/A N/A N/A

45496 Gr-IE NO +17.4% +6.3% +13.8% N/A N/A N/A

44811 Gr-IF NO +22.3% +0.6% +11.3% N/A N/A N/A

44542 Gr-IG NO +1.3% +10.2% +24.7% +5.8% N/A N/A

152226 Gr-2A NO +22.7% +10.8% +11.4% N/A N/A N/A

1st,

YES;

29688 Gr-2B +2.5% -1.1% +14.1% N/A N/A N/A

2nd,

NO.

30271 Gr-2C NO +15.3% +0.1% +7.6% N/A N/A N/A

164559 Gr-2D - - - - - - -

1st,

YES;

182737 Gr-2E +3.3% +4.0% +9.7% N/A N/A N/A

2nd,

NO.

29031 Gr-3A NO +33.4% +14.2% +16.3% +8.4% N/A N/A 1st,

YES;

28636 Gr-3B +13.7% +12.5% +8.1% N/A N/A N/A

2nd,

NO.

29041 Gr-3C NO +18.9% +11.9% +8.0% N/A N/A N/A

118836 Gr-3D - - - - - - -

29513 Gr-4A NO -21.4% +1.2% -0.1% N/A N/A N/A

33179 Gr-4B NO +8.1% + 14.5% +10.7% N/A N/A N/A

32955 Gr-4C NO -14.9% +3.1% -1.7% N/A N/A N/A

1st,

YES;

28213 Gr-4D +50.8% +9.0% +22.2% +11.3% +39.4% +11.1%

2nd,

NO.

1st,

YES;

158211 Gr-5A +25.8% -1.4% -8.3% N/A N/A N/A

2nd,

NO.

158201 Gr-5B NO +37.2% +2.0% +1.7% N/A N/A N/A

158206 Gr-5C NO +32.6% +1.6% -6.9% N/A N/A N/A

158125 Gr-5D NO +29.5% +5.8% -5.3% N/A N/A N/A

1st,

YES;

50328 Gr-6A +5.5% +6.8% +16.9% -2.7% N/A N/A

2nd,

NO.

150533 Gr-6B NO +3.0% +0.2% +20.6% -1.3% N/A N/A

162159 Gr-6C NO +20.5% +12.4% +9.4% N/A N/A N/A

1st,

YES;

152946 Gr-7A +40.6% +16.2% +13.9% +2.7% N/A N/A

2nd,

YES.

1st,

YES;

152936 Gr-7B +1.3% +3.5% +14.9% N/A N/A N/A

2nd,

NO.

152926 Gr-7C NO -29.1% +10.1% -41.6% N/A N/A N/A

39959 01 NO +1.8% -1.7% +22.1% -2.2% N/A N/A

169199 02 - - - - - - -

127091 03 NO +14.1% +14.8% +15.9% +12.0% +8.7% +1.4%

194447 04 NO +26.3% +8.0% +18.5% -0.9% N/A N/A

151482 05 NO +48.9% +18.9% +46.2% +46.3% +10.2% +32.0%

1st,

YES;

166246 06 +28.3% +10.3% +3.9% N/A N/A N/A

2nd,

NO.

148098 07 NO +19.7% +26.0% +33.7% +10.2% +5.8% -10.5%

1st,

YES;

173384 08 +6.6% +3.8% +10.0% N/A N/A N/A

2nd,

NO.

178510 09 1st, +6.6% +1.3% -0.3% N/A N/A N/A YES;

2nd,

YES.

41334 O10 NO +5.9% -6.2% +9.5% N/A N/A N/A

1st,

YES;

157343 Oi l +14.9% +6.0% +21.0% +9.0% N/A N/A

2nd,

NO.

1st,

YES;

122572 012 +36.8% +9.6% +6.6% N/A N/A N/A

2nd,

NO.

1st,

YES;

30228 013 +32.7% +10.3% +27.3% +15.0% +8.4% + 15.3%

2nd,

NO.

38610 014 NO +13.7% +5.8% +11.3% N/A N/A N/A

1st,

YES;

29424 015 +38.0% +6.6% +14.6% N/A N/A N/A

2nd,

YES.

1st,

YES;

194820 016 +16.8% +11.4% +19.7% +9.8% +9.9% +12.1%

2nd,

YES.

1st,

YES;

157154 017 +1.7% +22.6% +19.7% +17.8% +15.2% +20.8%

2nd,

YES.

31883 018 NO +22.1% +11.8% +3.8% N/A N/A N/A

47511 019 NO - - - - - -

39793 O20 NO +18.8% +3.4% +11.3% N/A N/A N/A

128071 021 NO +7.9% -0.5% +12.2% N/A N/A N/A

115873 022 NO -24.5% -2.3% -52.8% N/A N/A N/A

1st,

YES;

165151 023 +36.2% +17.4% +21.6% -0.3% N/A N/A

2nd,

NO.

184478 024 NO +13.0% +2.3% N/A N/A N/A N/A

119430 025 NO - - - - - -

49713 026 NO +23.9% +4.6% +27.1% +8.3% N/A N/A

34215 027 NO -35.1% -17.8% -69.3% N/A N/A N/A

43877 028 - - - - - - -

29261 029 - - - - - - -

155615 O30 - - - - - - -

160962 031 - - - - - - -

[0548] Table 2. Target Summary, a Target competency: Human Protein Targets (confirmed)/ Protein Targets (confirmed)/ Total Protein Targets/ Total BioAssays - query on PubChem.

[0549] Table 3. Summary of 20 compounds. A = Cadmium resistant; B = MMS resistant; C = H202- & Cd-resistant; D = Triple resistant; E = Potential FOX03 Activation; F= Potential RF2 Activation; G = mTOR down-regulation; H = Potential Autophagy Induction; I = FOX03- dependency for H ₂ 0 ₂ -resi stance; J = RF2-dependency for H ₂ 0 ₂ -resistance; K = Huntington's poly-Q toxicity attenuation; L = H ₂ 0 ₂ -resi stance in worms; M = Lifespan-extending scores in worms; N = Sum of Positive Scores; O = Potential toxicity; P = Potential DNA-damaging; Q = Sum of Negative Scores.

[0550] Table 4. Summary of 38 core scores. A = Cadmium resistant; B = MMS resistant; C = H202- & Cd-resistant; D = Triple resistant; E = Potential FOX03 Activation; F= Potential

NRF2 Activation; G = mTOR down-regulation; H = Potential Autophagy Induction; I = FOX03- dependency for H ₂ 0 ₂ -resi stance; J = NRF2-dependency for H ₂ 0 ₂ -resistance; K = Huntington's poly-Q toxicity attenuation; L = H ₂ 0 ₂ -resi stance in worms; M = Lifespan-extending scores in worms; N = Sum of Positive Scores; O = Potential toxicity; P = Potential DNA-damaging; Q = Sum of Negative Scores.

[0551] Table 5. List of 38 "core set" small molecule hits, some of which increased the resistance to other stress conditions, including heavy metal cadmium and DNA-damaging agent MMS. Note: asterisks indicate the loss of the ability of several small molecules to protect cells from H ₂ 0 ₂ , which could be due to compromised stability of compound assayed over time. 24 of the 54 repurchased compounds are not shown because: 1) Two orphan compounds (019 and 025) scored negatively in all tests, even the hydrogen peroxide retest, and were discarded. 2) the other twenty -two, including all Group 2 compounds that were confirmed to be PARP inhibitors, increased stress resistance, but did not score positive for the cell death-imaging assay.

01 YES YES NO YES NO

06,

phenolic

YES YES NO YES NO

mannich

- PAINS

O10 YES YES NO YES NO on YES YES NO YES NO

012 YES YES NO YES NO

013 YES NO NO NO NO

014 YES YES NO YES NO

015,

enones - YES (*) NO NO NO NO PAINS

017 YES NO NO NO NO

018 YES NO NO NO NO

020 YES YES NO YES NO

021,

rhodanin

YES NO NO NO NO

es - PAINS

022 YES YES YES YES YES

023,

enones,

YES (*) NO NO NO NO

catechols

- PAINS

027 YES YES NO YES NO

[0552] Table 6. Effects of small molecules on F0X03- and NRF2-regulated genes and analysis of the requirement for F0X03 and NRF2 to promote H ₂ 0 ₂ -rei stance. Small molecules (at 10 μΜ, n = 4) were introduced to WI-38 cells for 24 hrs and then analyzed by qPCR assays to address their effects on the expression levels of F0X03- and NRF2-regulated genes. Relative levels were normalized to the genes B2M (summary of normalized fold changes for genes analyzed is shown, Student's t-test), PPIA and GAPDH (see Table 15 for additional details). To ask whether small molecules require F0X03 and/or NRF2 to increase the resistance to H ₂ 0 ₂ , F0X03 or NRF2 was first knocked down in WI-38 cells, and then cell viability was assayed following small molecule incubation and H ₂ 0 ₂ stress treatment. Small molecules were analyzed in three independent gene knockdown experiments (1 & 2, with H ₂ 0 ₂ only; 3 with and without H ₂ 0 ₂ ). Dependency on F0X03 or NRF2 is scored when the H ₂ 0 ₂ -resi stance capacity of a given small molecule was reduced by at least 50% upon gene knockdown, and partial dependency is scored when it falls in between 25% and 50%. A = Summary of effects on F0X03- regulated genes, at lOuM; B = Summary of effects on NRF2- regulated genes, atlOuM; C = F0X03- dependency for H202- resistance, at lOuM (experiment 1 & 2) - with H202; D = F0X03- dependency for H202- resistance, at lOuM (experiment 3) - with & without H202; E = NRF2- dependency for H202-resi stance, at lOuM (experiment 1 & 2) -with H202; F = NRF2- dependency for H202-resi stance, at lOuM (experiment 3) - with & without H202.

2.07, p>0.05 partial.

partial. HMOX1 YES

12.86, (note:

TXNIP 0.07, p<0.05; yet

023, p<0.001; GCLC 0.67, 1st, viability enones, SOD2 2.04 p<0.01; YES; of non-

NO YES

catechols - p<0.01; NQOl 0.48, 2nd, stressed

PAINS GADD45 p<0.001; YES. cells,

7.22, p<0.01 GSTMl reduced

0.60, by p<0.001 40%)

SESN1 HMOX1

027 NO N/A NO N/A

1.54, p<0.05 1.71, p<0.05

[0553] Table 7. Small molecules extend C. elegans ' lifespan, and a few also promoted H ₂ 0 ₂ - resistance. Multiple independent trials were conducted to analyze the effects of small molecules (at 60 μΜ final concentration, 0.3% DMSO) on lifespan. Trial 1 (1.0Χ10 ^Λ 9 bacteria/ml) & 2 (2.5Χ10 ^Λ 9 bacteria/ml): wild type, with FuDR; Trial 3 (2.0Χ10 ^Λ 10 bacteria/ml, 100 μΐ) & 4 (1.0X10 ^A 11 bacteria/ml, 100 μΐ) (UV-irradiated, plus kanamycin), on plate, CF512 temperature- sensitive sterile mutant animals, no FuDR; Confirmative trials 5 (2.0X10 ^A 10 bacteria/ml, 100 μΐ) & 6 (1.0X10 ^A 11 bacteria/ml, 100 μΐ), same as trials 3 or 4, three molecules analyzed. Compared with control animals, relative changes of mean lifespan are shown (color code indicate statistical significant differences). Similarly, H ₂ 0 ₂ -resi stance assays were conducted for all the small molecules in liquid (60 μΜ final concentration) and molecules that scored positive in two independent experiments are reported. A = Trial 1, in liquid, wild type, with FuDR; B = Trial 2, in liquid, wild type, with FuDR; C= Trial 3, on plate, temperature-sensitive sterile animals, without FuDR; D = Trial 4, on plate, temperature-sensitive sterile animals, without FuDR (11 analyzed); E = Trial 5, on plate, temperature-sensitive sterile animals, without FuDR (3 analyzed); F= Trial 6, on plate, temperature-sensitive sterile animals, without FuDR (3 analyzed); G = H202- resistance assay, in liquid, wild type, with FuDR. 1st,

Group 1 : 7 YES;

-1.3% +0.2% +14.2% N/A N/A N/A

hits (Gr-IA) 2nd,

NO.

Gr-IB +12.9% +8.0% +15.1% N/A N/A N/A NO

Gr-lC +14.4% +1.7% +14.7% N/A N/A N/A NO

Gr-ID +18.2% -0.5% +10.5% N/A N/A N/A NO

Gr-IE +17.4% +6.3% +13.8% N/A N/A N/A NO

Gr-IF +22.3% +0.6% +11.3% N/A N/A N/A NO

Gr-IG +1.3% +10.2% +24.7% +5.8% N/A N/A NO

Group 3 : 4

hits (3 +33.4% +14.2% +16.3% +8.4% N/A N/A NO available)

1st, YES;

Gr-3B +13.7% +12.5% +8.1% N/A N/A N/A

2nd, NO.

Gr-3C +18.9% +11.9% +8.0% N/A N/A N/A NO

Group 4: 4

hits

-21.4% +1.2% -0.1% N/A N/A N/A NO (chalcones)

(Gr-4A)

Gr-4B +8.1% +14.5% +10.7% N/A N/A N/A NO

Gr-4C -14.9% +3.1% -1.7% N/A N/A N/A NO

1st, YES;

Gr-4D +50.8% +9.0% +22.2% + 11.3% +39.4% +11.1%

2nd, NO.

Group 5 : 4 1st, hits (3 YES;

+25.8% -1.4% -8.3% N/A N/A N/A validated) 2nd, (Gr-5A) NO.

Gr-5B +37.2% +2.0% +1.7% N/A N/A N/A NO

Gr-5D +29.5% +5.8% -5.3% N/A N/A N/A NO

1st,

Group 6:

YES; 3 hits (Gr- +5.5% +6.8% +16.9% -2.7% N/A N/A

2nd, 6A)

NO.

Gr-6B +3.0% +0.2% +20.6% -1.3% N/A N/A NO

Gr-6C,

rhodanines - +20.5% +12.4% +9.4% N/A N/A N/A NO PAINS 1st,

Group 7: 3 YES;

+40.6% +16.2% +13.9% +2.7% N/A N/A hits (Gr-7A) 2nd,

NO.

1st, YES;

Gr-7B +1.3% +3.5% +14.9% N/A N/A N/A

2nd, NO.

Gr-7C -29.1% +10.1% -41.6% N/A N/A N/A NO

01 +1.8% -1.7% +22.1% -2.2% N/A N/A NO

06, 1st, phenolic YES; mannich - +28.3% +10.3% +3.9% N/A N/A N/A

2nd, PAINS NO.

O10 +5.9% -6.2% +9.5% N/A N/A N/A NO

1st, on YES;

+14.9% +6.0% +21.0% +9.0% N/A N/A

2nd, NO.

1st, YES;

012 +36.8% +9.6% +6.6% N/A N/A N/A

2nd, NO.

1st, YES;

013 +32.7% +10.3% +27.3% + 15.0% +8.4% +15.3%

2nd, NO.

014 +13.7% +5.8% +11.3% N/A N/A N/A NO

1st,

015,

YES; enones - +38.0% +6.6% +14.6% N/A N/A N/A

2nd, PAINS YES.

1st, YES;

017 +1.7% +22.6% +19.7% + 17.8% +15.2% +20.8%

2nd, YES.

018 +22.1% +11.8% +3.8% N/A N/A N/A NO

020 +18.8% +3.4% +11.3% N/A N/A N/A NO

021,

rhodanines

+7.9% -0.5% +12.2% N/A N/A N/A NO

PAINS

022 -24.5% -2.3% -52.8% N/A N/A N/A NO

023, 1st, enones, +36.2% +17.4% +21.6% -0.3% N/A N/A YES; catechols - 2nd, PAINS NO.

027 -35.1% -17.8% -69.3% N/A N/A N/A NO

[0554] Table 8. Summary for characterization of screen hits. 38 "core set" small molecules are listed and are assigned a score, based on the result for each individual characterization. From our small molecule screen for H ₂ 0 ₂ -resistance, we isolated 61 top hits. Of these, 38 repurchased molecules were further validated and analyzed as the "core set" in multiple phenotypical assays that have been shown to be longevity-related in experimental systems (including animals).

Specifically, a 2-point score was assigned to the most well-known and prominent longevity- related phenotypes, such as multiplex resistance, activation of FOX03 and/or NRF2, and down- regulation of mTOR. Small molecules were also analyzed for their ability to extend C. elegans ' lifespan in 4 to 6 independent trials, and the lifespan score scale is from 0 to 2: 0 for no obvious effects, 1 for lifespan extension observed in 2 trials, 2 for observed in more than 2 trials. Certain molecules appeared to have DNA-damaging effects and/or potential cell-toxicity in cultured human cells, and they receive a negative point. A = Cadmium resistant; B = MMS resistant; C = H202- & Cd-resistant; D = Triple resistant; E = Potential FOX03 Activation; F= Potential NRF2 Activation; G = mTOR down-regulation; H = Potential Autophagy Induction; I = FOX03- dependency for H ₂ 0 ₂ -resi stance; J = NRF2-dependency for H ₂ 0 ₂ -resistance; K = Sestrin induction; L = PARP inhibition; M = Huntington's poly -Q toxicity attenuation; N = H202- resistance in woms; O = Life span- extending scores in worms; P = Sum of Positive Scores; Q = Potential toxicity; R = Potential DNA damaging; S = Sum of Negative scores.

Gr-

1 0 1 0 0 0 0 0 0 0 1 0 0 0 1 4 1 1 2 1F

Gr-

1 0 1 0 0 0 0 1 0 0 0 0 0 0 1 4 0 0 1 1G

Gr-

1 0 1 0 0 0 0 0 0 0 0 0 0 0 2 4 0 1 1

3A

Gr-

0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 1 0 0 3B

Gr-

0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 1 1 2

3C

Gr-

1 0 1 0 0 2 0 0 0 0 0 0 0 0 0 4 0 0 0

4A

Gr-

1 0 1 0 0 2 0 0 0 0 0 0 0 0 1 5 0 0 0 4B

Gr-

0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 2 0 0 0 4C

Gr-

1 0 1 0 0 2 0 0 0 0 1 0 0 0 2 7 0 0 0 4D

Gr-

1 0 1 0 0 2 0 0 0 0 0 0 0 0 0 4 0 0 0

5A

Gr-

0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 2 0 0 0 5B

Gr-

0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 2 0 0 0 5D

Gr-

1 1 1 2 0 0 0 0 0 0 0 1 0 0 0 6 0 0 0

6A

Gr-

1 0 1 0 0 2 0 0 0 1 0 0 1 0 0 6 0 0 0 6B

Gr-

0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 1 1 2

6C

Gr-

0 0 0 0 2 0 2 0 1 1 0 0 0 1 2 9 1 0 1

7A

Gr-

0 0 0 0 0 0 2 0 0 1 0 0 0 0 0 3 1 0 1 7B

Gr-

0 0 0 0 2 2 2 0 1 1 0 0 1 0 0 9 1 0 1 7C

01 1 0 1 0 0 0 0 0 0 1 0 1 0 0 0 4 0 0 0 06 1 0 1 0 0 2 0 0 0 0 0 0 0 0 1 5 0 0 0

O10 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 on 1 0 1 0 0 0 0 1 0 0 1 0 0 0 1 5 1 0 1

012 1 0 1 0 2 0 0 0 0 0 0 0 0 0 2 7 0 0 0

013 0 0 0 0 0 2 0 0 0 0 0 0 0 0 2 4 0 0 0

014 1 0 1 0 0 0 0 0 0 0 0 1 0 0 2 5 0 0 0

015 0 0 0 0 0 2 0 0 1 1 0 0 0 1 1 6 0 0 0

017 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 3 0 0 0

018 0 0 0 0 0 2 0 0 0 1 0 0 0 0 1 4 0 0 0

020 1 0 1 0 0 2 0 0 1 1 1 0 0 0 1 8 0 0 0

021 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 2 1 1 2

022 1 1 1 2 0 0 0 0 0 1 0 1 0 0 0 7 0 0 0

023 0 0 0 0 2 0 0 1 0 1 0 0 0 0 2 6 1 0 1

027 1 0 1 0 0 0 2 0 0 0 1 0 0 0 0 5 1 1 2

[0555] Table 9. PubChem database queries indicate that at least 11 small molecules had been identified in multiple screens with confirmed human protein targets. Shown are the potential targets, which upon knocking down, may recapitulate the oxidative stress-resistance phenotype of our small molecules. Human Protein Targets (confirmed)/ Protein Targets (confirmed)/ Total Protein Targets/ To 11/23/446/653 for Gr-IF; 21/25/285/423 for Gr-3A (note Gr-3A =

AC1LE0RR); 39/44/482/772 for Gr-3B; 3/7/27/39 for Gr-3C; tal BioAssays - query on PubChem 32/41/473/700 for Gr-4D; 41/52/4N78/718 for Gr-7C; 9/15/361/498 for 06 (note phenolic mannich - PAINS); 10/19/363/521 for 013; 1/1/421/581 for 014; 1/1/1/1 for 018; 8/11/395/561 for 022.

[0556] Table 10 (related to Table 5). Dose response and cell death imaging analysis of library compounds identified in the screen. 209 candidate hits were cherry-picked from the screen library and retested at six different final concentrations (0.6 μΜ, 1.25 μΜ, 2.5 μΜ, 5 μΜ, 10 μΜ and 20 μΜ) to examine their ability to promote H ₂ 0 ₂ -resistance of WI-38 cells. Dose response curves and derived EC50 values are shown. This table includes the data for the 38 "core set" hits, including 23 that belong to 6 structural groups and 15 orphans. Potential pan assay interference compounds are also indicated. Cells pre-treated with these molecules (at 1.25 μΜ and 10 μΜ) were also analyzed by propidium iodide imaging to examine cell death upon 3.5 hours of H ₂ 0 ₂ treatment. For DMSO pre-treated controls (n = 30), the percentages of Pi-positive cells were 23.7% ± 6.9% (average ± standard deviation, 1.25 μΜ assay plate) and 27.4% ± 6.5% (average ± standard deviation, 10 μΜ assay plate). 107 hits were found to reduce [by one (*), two (**) or three (***) standard deviations] the percentage of Pi-positive dead cells. Certain effective small molecules could have been missed in the imaging assays, as false negatives could arise due to potential stability issue of the library compounds. Note that significant reduction of performance (fold change < 1.50, highlighted in red) and high EC50 values were observed in certain cases.

[0557] Table 11 (related to Table 5). Cell death-imaging analysis and effects on primary HDF cells for repurchased small molecules. Repurchased small molecules were analyzed first by LC-

MS for quality check. Except for three molecules (Gr-6A, 012 and 017 - these molecules also protected human cells from H ₂ 0 ₂ and were included for subsequent analyses), their masses matched with predicted values. Potential pan assay interference compounds are also indicated.

Consistent with the results of ATP assay for cell viability, the 38 "core set" small molecules reduced the fraction of propidium iodide-positive cells upon H ₂ 0 ₂ stress treatment (n = 6 for each molecule, Student's t-test, three consecutive time points - 3 hrs, 4 hrs and 5 hrs of H ₂ 0 ₂ treatment). Representative data, normalized fold-changes for ATP measurements and Pi-positive fractions, are shown for at least three independent experiments. Small molecules were also analyzed in primary human dermal fibroblasts (HDFs, from multiple donors), along with the WI- 38 cells, and found to protect these primary cells from H ₂ 0 ₂ . A = Mass match/quality check by LC-MS; B = No H ₂ 0 ₂ stress treatment, at lOuM (fold change); C = Percentage of propidium iodide-positive dead cells (no H202 stress treatment), at lOuM (Negative control:

0.41%±0.23%); D = H202 stress treatment (3 hrs), at lOuM (fold change); E = Percentage of propidium iodide-positive dead cells (under H202 stress treatment, 3 hrs/4 hrs/5 hrs), at lOuM (Negative control: 3 hrs, 5.44%±0.79 %; 4 hrs, 16.81%±1.42%; 5 hrs, 22.50%±1.53%); F = Experiment 1, WI-38 cells (under H202 stress treatment), at lOuM (fold change); G =

Experiment 1, HDF cells (under H202 stress treatment), at lOuM (fold change); H = Experiment 2, WI-38 cells (under H202 stress treatment), at lOuM (fold change); I = Experiment 2, HDF cells (under H202 stress treatment), at lOuM (fold change).

22

1.13%

±0.40 % ,

p=1.29E-

12;

0.69%

2.56%

±0.12

1.0 ±0.51 %, 11.1 27.1 60.4

013 OK .96 2.70

9 %, 1

p=6.36E- 8 6 9 p=0.00

2 21;

7.03%

±2.03 % ,

p=5.68E- 07

3.80%

±1.03%,

p=0.009;

0.41%

18.17%

±0.22

1.1 ±2.12%,

014 OK 2.73 7.50 2.87 3.96 4.73

1 %, p=0.187;

p=0.86

25.64%

3

±1.19%,

p=3.00E- 04

4.04%

±1.09%,

3.76% p=0.023;

015, ±0.68 4.40%

0.9 %, ±0.59%,

enones - OK p=5.30 1.25 p=2.38E- 2.92 0.57 6.45 1.77

8

E- 18;

PAINS 6.06%

05 ±1.10%,

p=2.12E- 12

0.80%

±0.24 % ,

p=1.65E- 16;

0.56%

2.83%

±0.25

1.0 ±0.40 % , 20.9 48.5

017 70 2.45 3.35

6 %, 3.

p=2.33E- 8 3 p=0.29

1 21;

10.53%

±1.69%,

p=3.43E- 07

018 OK 0.9 0.36% 4.32 3.66% 1.79 72.4 26.9 1.27 p=7.76E- 09

0.55%

±0.25 % ,

p=6.55E-

17;

0.50%

0.82%

Expe ±0.17

0.7 ±0.36 % , 181. 18.2 46.0

027 cted %, 8.45 7.68

5 p=1.64E- 60 0 6 mass p=0.44

22;

2

1.07%

±0.41 % ,

p=1.25E- 24

[0558] Table 12 (related to Table 5). Certain identified small molecules increased the resistance to multiple stressors, including H ₂ 0 ₂ , heavy metal CdCl ₂ and MMS. Repurchased small molecules were analyzed for their ability to protect WI-38 cells from, besides H ₂ 0 ₂ , CdCl ₂ and MMS. Normalized fold-changes for ATP measurements are shown. 21 molecules increased the cellular resistance for both H ₂ 0 ₂ and cadmium only, and another 2 promoted the resistance to all stressors analyzed (at 10 μΜ final concentration representative data from two independent trials are shown). Fold changes less than 1.5 are highlighted, and asterisks (*) indicate compromised ability of several small molecules to protect cells from H ₂ 0 ₂ , which could be due to stability issue of compound assayed.

Gr-1G YES YES NO YES NO

Group 3 : 4 YES YES NO YES NO hits (3

available)

(Gr-3A)

Gr-3B YES NO NO NO NO

Gr-3C YES NO NO NO NO

Group 4: 4 YES YES NO YES NO hits

(chalcones)

(Gr-4A)

Gr-4B YES YES NO YES NO

Gr-4C YES NO NO NO NO

Gr-4D YES YES NO YES NO

Group 5: 4 YES YES NO YES NO hits (3

validated)

(Gr-5A)

Gr-5B YES NO NO NO NO

Gr-5D YES (*) N/A N/A N/A N/A

Group 6: YES YES YES YES YES 3 hits (Gr- 6A)

Gr-6B YES YES NO YES NO

Gr-6C, YES (*) N/A N/A N/A N/A rhodanines

- PAINS

Group 7:3 YES (*) NO NO NO NO hits (Gr- 7A)

Gr-7B YES (*) NO NO NO NO

Gr-7C YES NO NO NO NO

01 YES YES NO YES NO

06, YES YES NO YES NO phenolic mannich

PAINS -

O10 YES YES NO YES NO

Oi l YES YES NO YES NO

012 YES YES NO YES NO

013 YES NO NO NO NO

014 YES YES NO YES NO

YES (*) NO NO NO NO enones - PAINS

017 YES NO NO NO NO

018 YES NO NO NO NO

020 YES YES NO YES NO

021, YES NO NO NO NO rhodanines

- PAINS

022 YES YES YES YES YES

023, YES (*) NO NO NO NO enones,

catechols - PAINS

027 YES YES NO YES NO

Gr-1D 11.24 3.14 1.16 7.36 3.84 2.31

Gr-IE 52.76 6.69 0.72 18.85 8.82 1.21

Gr-IF 46.70 6.65 0.74 2.44 4.80 2.07

Gr-IG 14.33 3.81 1.32 11.12 7.21 1.89

Group 3 : 4 2.36 1.93 1.00 1.81 1.64 0.86 hits (3

available)

(Gr-3A)

Gr-3B 4.78 2.10 1.72 3.62 2.88 1.33

Gr-3C 19.06 0.06 1.06 1.79 0.40 0.84

Group 4: 4 2.86 1.98 0.95 2.08 1.66 1.52 hits

(chal cones)

(Gr-4A)

Gr-4B 2.52 2.00 1.22 2.15 1.52 1.54

Gr-4C 2.96 1.07 1.24 2.10 1.19 1.61

Gr-4D 4.78 2.10 1.72 3.62 2.88 1.33

Group 5 : 4 2.53 4.12 0.83 2.22 2.40 1.49 hits (3

validated)

(Gr-5A)

Gr-5B 1.63 1.29 1.13 2.00 1.36 1.36

Gr-5D N/A N/A N/A N/A N/A N/A

Group 6: 2.64 2.46 2.20 2.85 2.36 7.20 3 hits (Gr- 6A)

Gr-6B 27.64 5.07 2.12 1.90 2.65 1.22

Gr-6C, N/A N/A N/A N/A N/A N/A rhodanines

- PAINS

Group 7:3 1.04 0.07 0.96 0.76 0.14 2.21 hits (Gr- 7A)

Gr-7B 1.41 0.12 0.39 1.21 0.26 1.45 Gr-7C 2.18 1.31 1.14 2.41 0.97 1.39

01 1.52 1.84 1.20 1.57 1.86 4.96

06, 1.93 2.18 0.81 1.12 2.05 0.79 phenolic

mannich

PAINS -

O10 4.75 2.73 1.08 2.45 2.00 4.08 on 3.53 3.78 0.97 2.10 2.80 4.20

012 2.89 1.36 0.78 3.42 1.59 2.00

013 2.34 1.27 1.11 1.84 1.55 2.24

014 2.03 2.20 0.84 2.37 2.69 3.45

015, 1.07 0.18 0.16 0.41 0.57 0.38 enones - PAINS

017 2.03 0.95 0.86 1.77 1.35 5.33

018 2.16 1.50 1.11 1.22 1.24 1.48

020 3.13 6.37 2.17 1.25 4.00 1.46

021, 2.87 0.03 0.74 2.39 0.04 0.94 rhodanines

- PAINS

022 6.38 5.61 3.22 8.06 14.65 14.83

023, 1.10 0.69 1.04 0.95 0.64 1.28 enones,

catechols - PAINS

027 15.17 1.68 0.74 2.10 1.89 2.45

[0559] Table 13. Long-term effects of small molecules on cell viability. 38 "core set" molecules were analyzed in two batches (31, 2 - confirmed to increase H ₂ 0 ₂ -resi stance) and assayed for their effects on cell viability upon prolonged incubation (at 10 μΜ final concentration, n = 6 for each molecule, and mean standard deviation across the whole assay is -5.9%). Luminescence signals for ATP measurements are shown. Rapamycin, as the control, delayed cell proliferation and significantly reduced ATP levels. Batch 1 : cell viability assay by ATP measurment (day-O, before adding small molecules, luminescence = 320956 ±24708).

017 507143 33431 697351 34985 849445 19518

018 453443 28307 639628 53472 693776 20125

O20 544305 47949 770055 55862 888893 68909

021 460366 22372 542268 22201 557236 13390

022 435891 12758 566145 28030 690403 24600

023 329880 22739 149226 10914 52831 7565

027 431303 9431 437195 14937 517210 20523 day-4 SD day-5 SD by day-5 Average Average normalized

DMSO 1017995 21520 1026775 41680 100.0% Ctrl

H20 1061361 45700 1035227 34100 100.8% Ctrl

Rapa 552160 23811 547771 22151 53.3% Ctrl

Gr-IA 878508 44735 943836 62968 91.9%

Gr-IB 977658 20676 1021113 53459 99.4%

Gr-lC 875881 107272 819655 6681 79.8%

Gr-ID 797305 63893 865168 40279 84.3%

Gr-IE 1038011 41115 1066135 33622 103.8%

Gr-IF 534298 43515 600633 71490 58.5%

Gr-IG 866631 39075 955703 48363 93.1%

Gr-4A 995321 40252 1019996 20027 99.3%

Gr-4C 769380 37494 813018 56651 79.2%

Gr-5A 1074220 51491 1082445 29904 105.4%

Gr-5B 1091073 33546 1104305 32623 107.6%

Gr-5D 1052285 38352 1110868 44999 108.2%

Gr-6A 1007061 22907 986943 33964 96.1%

Gr-6B 969598 36524 953988 43624 92.9%

Gr-6C 624471 8551 548865 22967 53.5%

Gr-7A 48480 5216 44670 5998 4.4%

Gr-7B 44298 4451 40768 4813 4.0% (*)

Gr-7C 72490 6038 127440 6576 12.4%

Ol 1101026 28418 977541 28798 95.2%

O10 1079863 23604 1066130 38115 103.8% Oil 642267 109087 633963 149645 61.7%

012 1128385 23641 1117938 25699 108.9%

013 947030 197216 992715 12546 96.7%

014 1074238 33242 1052551 29570 102.5%

015 904970 97039 761533 96306 74.2%

017 1073975 22442 1070851 24335 104.3%

018 825623 21298 760275 39450 74.0%

O20 997113 18011 926888 18796 90.3%

021 677875 34086 550651 28754 53.6%

022 840178 25679 805461 30549 78.4%

023 53125 7815 52771 7645 5.1%

027 634360 12988 587798 51143 57.2%

[0560] Table 13 cont'd: Batch 2: cell viability assay by ATP measurment (day-0, before adding small molecules, luminescence = 229312 ±17487).

[0561] Table 14. Induction of DNA-damaging markers by certain small molecules. WI-38 cells that had been treated with small molecules (10 μΜ, 24 hrs) were analyzed in two independent experiments by immuno-staining for two DNA-damaging markers, phosphorylated- γΗ2Α.Χ and phosphorylated-TP53BPl . Small molecules that induced both markers (in the absence of H ₂ 0 ₂ stress treatment) were scored positive for DNA-damaging. Normalized values for marker-positive fractions are shown (n = 3, Student t-test. In experiment 2, the marker- positive fractions of cells were - γΗ2Α.Χ-Ρ: DMSO, ~1.7±0.4% (n = 6); H ₂ 0 ₂ ~50.9±4.2% (n = 3); doxorubicin, ~16.9±2.1% (n = 6). TP53BP1-P: DMSO, ~1.0±0.2% (n = 6); H ₂ 0 ₂ ,

~45.8±5.1% (n = 3); doxorubicin, ~15.1±1.4% (n = 6).

Gr-3B 81.9%, 227.8%, 130.4%, 243.5%, 66.3%, NO p=0.030 p=0.001 p=0.091 p=0.023 p=0.152

Gr-3C 112.6%, 403.8%, 135.6%, 253.9%, 390.0%, YES p=0.285 p=0.014 p=0.001 p=0.023 p=0.015

Group 4: 4 80.2%, 75.0%, 105.3%, 154.6%, 286.8%, NO hits p=0.115 p=0.059 p=0.646 p=0.042 p=0.301

(chalcones)

(Gr-4A)

Gr-4B 116.3%, 140.2%, 150.5%, 117.9%, 435.0%, NO p=0.213 p=0.340 p=0.034 p=0.489 p=0.014

Gr-4C 107.7%, 135.1%, 149.7%, 179.3%, 443.7%, NO p=0.202 p=0.070 p=0.042 p=0.105 p=0.001

Gr-4D 103.2%, 49.6%, 123.2%, 136.3%, 387.5%, NO p=0.737 p=0.002 p=0.307 p=0.139 p=0.009

Group 5: 4 104.7%, 115.4%, 127.4%, 147.1%, 547.5%, NO hits (3 p=0.646 p=0.723 p=0.148 p=0.114 p=4.85E- validated) 05

(Gr-5A)

Gr-5B 100.3%, 127.8%, 167.7%, 222.8%, 540.3%, NO p=0.976 p=0.282 p=0.0003 p=0.015 p=7.85E- 09

Gr-5D 94.1%, 75.%, 111.9%, 145.0%, 479.8%, NO p=0.329 p=0.049 p=0.488 p=0.195 p=0.051

Group 6: 116.6%, 59.9%, 199.7%, 137.9%, N/A NO 3 hits (Gr- p=0.041 p=0.014 p=4.89E- p=0.050

6A) 07

Gr-6B 93.4%, 112.3%, 136.5%, 175.7%, 272.4%, NO p=0.680 p=0.295 p=0.009 p=0.029 p=0.071

Gr-6C, 181.3%, 300.3%, 43.0%, 289.7%, 440.3%, YES rhodanines p=0.012 p=0.002 p=6.99E- p=0.003 p=4.87E- - PAINS 06 05

Group 7:3 337.3%, 246.0%, 112.9%, 362.9%, 516.4%, YES hits (Gr- p=0.08 p=0.093 p=0.303 p=0.290 p=6.19E- 7A) (cells loss 09

during

preparation)

Gr-7B 694.7%, 348.2%, 74.0%, 31.3%, 4.2%, YES p=0.017 p=0.046 p=0.005 p=0.035 p=0.0002

(cells loss

during

prep., many

dead)

Gr-7C 132.1%, 135.2%, 82.9%, 196.3%, 368.8%, NO p=0.014 p=0.136 p=0.102 p=0.152 p=0.0001 01 101.9%, 104.4%, 216.5%, 142.9%, 335.6%, NO p=0.757 p=0.831 p=2.69E- p=0.051 p=0.0002

06

06, 122.4%, 87.7%, 129.9%, 86.3%, 537.7%, NO phenolic N.A. p=0.441 p=0.246 p=0.589 p=0.001 mannich - PAINS

O10 101.9%, 71.5%, 153.1%, 134.8%, 498.2%, NO p=0.875 p=0.110 p=0.0003 p=0.099 p=0.0004 on 83.1%, 91.2%, 151.7%, 154.0%, 560.5%, NO p=0.208 p=0.726 p=4.80E- p=0.011 p=4.53E- 05 08

012 106.0%, 88.0%, 113.4%, 141.7%, 523.2%, NO p=0.586 p=0.509 p=0.082 p=0.389 p=1.51E- 06

013 145.2%, 98.3%, 152.3%, 238.3%, 672.9%, NO p=0.054 p=0.874 p=0.003 p=0.019 p=0.009

014 115.9%, 85.3%, 221.4%, 159.0%, 254.4%, NO p=0.315 p=0.194 p=3.60E- p=0.289 p=0.017

07

015, 90.0%, 183.5%, 58.4%, 48.3%, 250.9%, NO enones - p=0.391 p=0.001 p=0.0002 p=0.029 p=0.068

PAINS

017 96.7%, 72.1%, 129.0%, 147.5%, 348.8%, NO p=0.613 p=0.055 p=0.117 p=0.067 p=0.033

018 364.1%, 142.7%, 137.1%, 183.1%, 450.0%, YES p=0.138 p=0.045 p=0.002 p=0.069 p=1.78E- (cells loss 08 during

preparation)

020 115.2%, 129.7%, 178.5%, 107.5%, 544.4%, NO p=0.377 p=0.085 p=0.003 p=0.543 p=4.26E- 05

021, 161.2%, 216.4%, 127.4%, 196.4%, 620.5%, YES rhodanines p=0.001 p=0.0001 p=0.049 p=0.065 p=3.27E- - PAINS 06

022 100.9%, 120.8%, 210.5%, 154.0%, 510.2%, NO p=0.855 p=0.355 p=0.0001 p=0.017 p=0.003

023, 79.9%, 325.5%, 33.4%, 42.4%, 13.2%, NO enones, p=0.033 p=0.029 p=2.39E- p=0.021 p=0.0001 catechols - 06

PAINS

027 122.2%, 337.5%, 26.1%, 241.0%, 379.2%, YES p=0.050 p=0.00002 p=6.33E- p=6.22E-06 p=0.003 07

[0562] Table 15 (related to Table 2 and Table 9). Analysis of small molecule effects on FOX03- and RF2-regulated genes, as well as the dependency on FOX03 or RF2 for molecules to promote H ₂ 0 ₂ -rei stance. qPCR analysis of selected, representative FOX03- and RF2-regulated genes was performed for WI-38 cells treated with small molecules (at 10 μΜ, n = 4) for 24 hrs. Relative expression levels (normalized by B2M), standard deviations and statistics (Student's t-test) are shown.

[0563] Table 15A-15D (related to Table 6). Analysis of small molecule effects on FOX03- and RF2-regulated genes, as well as the dependency on FOX03 or RF2 for molecules to promote H ₂ 0 ₂ -reistance. qPCR analysis of selected, representative FOX03- and RF2-regulated genes was performed for WI-38 cells treated with small molecules (at 10 μΜ, n = 4) for 24 hrs. Relative expression levels (normalized by B2M), standard deviations and statistics (Student's t- test) are shown.

[0564] Table 15 A. Summary of effects on FOX03 -regulated genes TXNIP, SOD2, and CAT.

CAT

1.31,

p<0.01;

Group 1 : DDB l

7 hits 1.36, 1.234 0.304 0.225 1.495 0.540 0.164 1.312 0.055 0.001 (Gr-IA) p<0.05;

SESNl

2.12,

p<0.01

TXNIP

1.94,

p<0.05;

CAT

Gr-IB 1.40, 1.938 0.523 0.034 1.211 0.392 0.362 1.397 0.058 0.000 p<0.01;

SESNl

1.30,

p<0.01

CAT

Gr-lC 1.44, 1.226 0.334 0.275 1.335 0.411 0.201 1.443 0.186 0.012 p<0.05

TXNIP

0.62,

p<0.05;

DDB l

Gr-ID 1.18, 0.621 0.235 0.040 1.423 0.515 0.199 0.953 0.256 0.747 p<0.05;

SESNl

1.73,

p<0.01 TXNIP

2.02,

p>0.05;

CAT

Gr-1E 1.45, 2.017 0.863 0.099 1.459 0.721 0.293 1.452 0.197 0.014 p<0.05;

SESNl

1.40,

p<0.01

CAT

1.35,

p<0.05;

Gr-IF 1.536 0.453 0.095 1.683 0.864 0.212 1.350 0.226 0.047

SESNl

2.00,

p<0.05

SOD2

0.76,

p<0.05;

CAT

Gr-IG 1.35, 1.026 0.384 0.921 0.756 0.045 0.026 1.352 0.159 0.013 p<0.05;

GADD45

A 0.60,

p<0.01

TXNIP

0.75,

Group 3 : p<0.05;

4 hits (3 CAT

availabl 0.87, 0.754 0.137 0.034 1.482 0.566 0.187 0.871 0.056 0.034 e) (Gr- p<0.05;

3A) SESNl

1.18,

p<0.05 Gr-3B NO 1.063 0.223 0.756 1.137 0.073 0.122 1.114 0.026 0.087

CAT

Gr-3C 0.87, 1.026 0.213 0.839 1.199 0.259 0.223 0.868 0.065 0.036 p<0.05

CAT

Group 4:

1.26,

4 hits

p<0.05;

(chalcon 0.819 0.059 0.100 0.980 0.026 0.744 1.264 0.068 0.029

DDB l

es) (Gr- 1.20,

4A)

p<0.05

Gr-4B NO 0.792 0.156 0.130 1.045 0.030 0.236 1.175 0.331 0.460

Gr-5B NO 1.201 0.209 0.148 1.129 0.256 0.394 1.422 0.443 0.151

TXNIP

Gr-5D 0.67, 0.669 0.100 0.001 1.125 0.168 0.238 1.273 0.212 0.074 p<0.01

Group 6: GADD45

3 hits A 0.79, 1.136 0.357 0.587 0.868 0.048 0.122 1.200 0.137 0.058 (Gr-6A) p<0.05

DDB l

Gr-6B 1.19, 0.861 0.197 0.486 1.141 0.092 0.127 1.109 0.088 0.139 p<0.05 TXNIP

0.57,

p<0.01;

Gr-6C,

GADD45

rhodanin

A 2.17, 0.568 0.115 0.001 1.008 0.187 0.943 1.126 0.329 0.509 es - p>0.10;

PAINS SESNl

1.42,

p<0.05

TXNIP

0.12,

p<0.001;

Group 7 SOD2

: 3 hits 1.78, 0.120 0.034 0.000 1.778 0.226 0.004 1.145 0.213 0.282 (Gr-7A) p<0.01;

GADD45

A 1.91,

p<0.01

TXNIP

0.26,

p<0.001;

Gr-7B 0.262 0.079 0.000 1.331 0.515 0.290 1.134 0.178 0.249

GADD45

A 2.07,

p>0.05

TXNIP

0.07,

p<0.001;

SOD2

2.67,

p<0.05;

CAT

Gr-7C 1.43, 0.068 0.012 0.000 2.677 0.727 0.018 1.433 0.156 0.006 p<0.01;

GADD45

A 10.86,

p<0.01;

DDB l

1.36,

p<0.05

GADD45

017 A 0.85, 0.801 0.081 0.070 0.997 0.045 0.965 1.107 0.059 0.274 p<0.05

TXNIP

018 0.30, 0.297 0.083 0.000 1.042 0.133 0.596 1.468 0.531 0.176 p<0.001

CAT

1.35,

p<0.01;

DDB l

O20 1.25, 1.121 0.315 0.614 1.086 0.069 0.297 1.348 0.105 0.003 p<0.05;

SESNl

1.73,

p<0.05

021,

SESNl

rhodanin

1.88, 0.900 0.097 0.164 1.121 0.192 0.302 1.305 0.329 0.160 es - p<0.05

PAINS GADD45

022 A 1.23, 0.742 0.232 0.235 1.017 0.102 0.845 1.045 0.056 0.452 p<0.01

TXNIP

0.07,

023, p<0.001;

enones, SOD2

catechol 2.04 0.071 0.013 0.000 2.036 0.317 0.006 0.890 0.275 0.497 s - p<0.01;

PAINS GADD45

7.22,

p<0.01

SESN1

027 1.54, 0.882 0.168 0.352 1.147 0.119 0.133 1.133 0.171 0.305 p<0.05

Table 15B. Summary of effects on FOX03 -regulated genes GADD45A, DDBl, and

Group 3 : 4

hits (3

1.396 0.452 0.178 0.969 0.189 0.769 1.181 0.083 0.020 available)

(Gr-3A)

Gr-3B 1.156 0.266 0.331 1.117 0.027 0.063 1.075 0.104 0.609

Gr-3C 1.160 0.263 0.320 0.985 0.232 0.908 1.090 0.034 0.108

Group 4: 4

hits

0.981 0.084 0.802 1.203 0.029 0.026 1.123 0.072 0.247 (chal cones)

(Gr-4A) Gr-4B 0.610 0.460 0.280 1.058 0.294 0.771 0.992 0.133 0.925

Gr-4C 1.233 0.122 0.023 1.507 0.030 0.000 1.423 0.232 0.046

Gr-4D 2.112 0.143 0.000 1.405 0.045 0.001 2.162 0.334 0.002

Group 5 : 4

hits (3

0.841 0.633 0.650 1.196 0.260 0.234 1.378 0.219 0.039 validated)

(Gr-5A) Gr-5B 0.808 0.546 0.534 1.255 0.405 0.300 1.365 0.302 0.094

Gr-5D 0.698 0.320 0.155 0.984 0.171 0.878 1.103 0.112 0.163

Group 6:

hits (Gr- 0.787 0.120 0.030 1.055 0.093 0.412 1.181 0.177 0.281 6A)

Gr-6B 1.263 0.239 0.112 1.192 0.089 0.020 1.248 0.295 0.246

Gr-6C,

rhodanines 2.167 0.864 0.144 1.215 0.398 0.363 1.418 0.240 0.038 - PAINS

Group 7 :

3 hits (Gr- 1.913 0.149 0.001 0.979 0.141 0.817 1.143 0.109 0.071 7A)

Gr-7B 2.069 1.122 0.153 1.310 0.375 0.197 0.952 0.133 0.537

Gr-7C 10.860 3.016 0.007 1.357 0.167 0.014 1.284 0.391 0.253

01 0.853 0.649 0.681 1.202 0.454 0.443 1.176 0.284 0.304

06,

phenolic

0.881 0.109 0.175 0.988 0.075 0.872 1.064 0.111 0.551 mannich - PAINS

O10 1.189 0.258 0.243 0.906 0.027 0.099 0.983 0.297 0.933 on 1.431 0.312 0.062 1.308 0.165 0.025 1.773 0.433 0.030

012 1.693 0.340 0.021 1.018 0.183 0.861 1.051 0.065 0.395

013 1.198 0.085 0.041 1.269 0.048 0.009 1.231 0.157 0.087

014 1.198 0.172 0.112 1.077 0.153 0.404 1.141 0.084 0.062

015,

enones - 2.715 0.554 0.007 1.168 0.087 0.065 0.679 0.120 0.018 PAINS 017 0.846 0.036 0.046 1.039 0.081 0.621 1.115 0.073 0.262

018 0.861 0.593 0.671 1.330 0.393 0.191 1.057 0.217 0.640

O20 1.039 0.041 0.456 1.253 0.121 0.017 1.728 0.432 0.035

021,

rhodanines 2.060 1.168 0.167 1.449 0.463 0.147 1.880 0.312 0.010 - PAINS 022 1.232 0.075 0.006 1.036 0.048 0.488 1.292 0.173 0.105

023,

enones,

7.216 2.072 0.009 1.261 0.351 0.236 0.799 0.195 0.129 catechols - PAINS

027 1.460 0.362 0.078 1.055 0.078 0.503 1.538 0.245 0.012

Table 15C Summary of effects on NRF2-regulated genes, HMOXl, GCLC, and

HMOXl,

Group 3 :

1.41,

4 hits (3

p<0.05;

available 1.413 0.231 0.031 1.008 0.120 0.927 1.369 0.092 0.002

NQOl

) (Gr- 1.37,

3A)

p<0.01

Gr-3B NO 1.041 0.201 0.818 1.097 0.135 0.491 1.071 0.135 0.518

Gr-3C NO 1.116 0.297 0.500 0.991 0.143 0.928 1.185 0.148 0.089

HMOXl

5.24,

Group 4: p<0.05;

4 hits NQOl

(chalcon 2.73, 5.239 2.485 0.042 1.183 0.180 0.234 2.731 0.262 0.000 es) (Gr- p<0.001;

4A) GSTMl

1.24,

p<0.05 HMOXl

1.73,

p<0.05;

NQOl

Gr-5B 1.94, 1.730 0.364 0.024 1.153 0.345 0.454 1.937 0.243 0.003 p<0.01;

GSTMl

1.27,

p<0.05

HMOXl

2.49,

p<0.01;

NQOl

Gr-5D 1.78, 2.492 0.269 0.001 0.886 0.233 0.428 1.782 0.084 0.000 p<0.001;

TXNIP

0.67,

p<0.01

Group 6:

3 hits NO 1.099 0.176 0.548 1.034 0.237 0.838 1.020 0.145 0.856 (Gr-6A)

HMOXl

1.88,

p<0.05;

Gr-6B 1.877 0.450 0.021 0.797 0.050 0.166 1.519 0.185 0.005

NQOl

1.52,

p<0.01 HMOXl

Gr-6C, 2.09,

rhodanin p<0.01;

2.086 0.233 0.009 0.331 0.058 0.000 0.870 0.092 0.058 es - GCLC

PAINS 0.33,

p<0.001

HMOXl

15.23,

p<0.01;

Group 7 GCLC

15.23

: 3 hits 0.60, 3.663 0.004 0.602 0.040 0.000 0.779 0.113 0.020

0

(Gr-7A) p<0.001;

NQOl

0.78,

p<0.05

HMOXl

54.15 17.90

Gr-7B 54.15, 0.010 1.804 0.649 0.087 1.411 0.437 0.156

3 1

p<0.05

HMOXl

28.05,

p<0.01;

GCLC

28.04

Gr-7C 2.27, 5.297 0.002 2.272 0.506 0.009 0.811 0.211 0.197

8

p<0.01;

GSTMl

0.78,

p<0.05 01 NO 1.255 0.318 0.208 1.209 0.558 0.514 1.082 0.243 0.553

HMOXl

06, 3.85,

phenolic p<0.001;

3.846 0.195 0.000 1.056 0.093 0.644 1.623 0.126 0.000 mannich NQOl

- PAINS 1.62,

p<0.001

O10 NO 0.755 0.096 0.166 0.933 0.083 0.598 0.937 0.120 0.549

NQOl

2.03,

on p<0.01;

1.069 0.305 0.713 1.333 0.220 0.070 2.027 0.329 0.004

GSTMl

1.30,

p<0.01

[0567] Table 15D. Summary of effects on NRF2-regulated gene GSTMl; and data for gene dependency for H ₂ 0 ₂ -resistance.

_l i ^{d fldh} No _r maeo can ^g ez l ^{id S} NDormaze

YES (note: viability of

Group 1 : 7

1st, NO; non-stressed hits (Gr- 2.527 1.413 0.119 NO NO

2nd, partial. cells, 1A)

reduced by

30%)

Gr-IB 2.003 0.779 0.081 NO N/A NO N/A

Gr-lC 1.773 0.697 0.112 NO N/A NO N/A

Gr-ID 1.170 0.161 0.146 NO N/A NO N/A Gr-1E 2.106 1.092 0.135 NO N/A NO N/A

YES (note: viability of non-stressed

Gr-IF 1.716 0.523 0.069 NO YES NO

cells, reduced by

50%)

1st, YES;

Gr-IG 0.948 0.188 0.671 NO N/A N/A

2nd, NO.

Group 3 : 4

hits (3

1.352 0.280 0.082 NO N/A NO N/A available)

(Gr-3A) Gr-3B 1.101 0.070 0.257 NO N/A NO N/A

Gr-3C 1.451 0.441 0.131 NO N/A NO N/A

Group 4: 4

hits

1.239 0.060 0.012 NO N/A NO N/A (chalcones)

(Gr-4A)

Gr-4B 1.147 0.123 0.163 NO N/A NO N/A

Gr-4C 1.631 0.231 0.006 NO N/A NO N/A

Gr-4D 1.517 0.239 0.014 NO Partial NO Partial

Group 5: 4

hits (3

1.153 0.103 0.063 NO N/A NO N/A validated)

(Gr-5A)

Gr-5B 1.269 0.140 0.020 NO N/A NO N/A

Gr-5D 1.165 0.107 0.053 NO N/A NO N/A

Group 6:

3 hits (Gr- 1.091 0.171 0.440 NO N/A NO N/A 6A)

1st, NO;

Gr-6B 1.218 0.137 0.067 NO NO YES

2nd, partial.

Gr-6C,

1st, NO;

rhodanines 0.914 0.087 0.223 NO N/A N/A

2nd, partial.

- PAINS YES (note:

viability of

Group 7 :

1st, partial; 1st, YES; non-stressed 3 hits (Gr- 1.089 0.091 0.220 YES

2nd, YES. 2nd, YES. cells, 7A)

reduced by

84%)

1st, partial;

Gr-7B 0.981 0.062 0.745 NO N/A N/A

2nd, partial.

YES (note: viability of

1st, YES; 1st, YES; non-stressed

Gr-7C 0.784 0.049 0.018 Partial

2nd, NO. 2nd, NO. cells, reduced by

60%)

1st, partial;

01 1.087 0.212 0.495 NO N/A N/A

2nd, partial.

06,

phenolic

0.965 0.092 0.662 NO N/A NO N/A mannich - PAINS

O10 1.031 0.115 0.733 NO N/A NO N/A

on 1.304 0.060 0.002 NO N/A NO N/A

012 1.208 0.136 0.063 NO N/A NO N/A

013 1.311 0.085 0.003 NO N/A NO N/A

014 1.531 0.448 0.095 NO N/A NO N/A

015,

1st, YES; 1st, YES;

enones - 0.995 0.120 0.952 YES YES

2nd, NO. 2nd, YES.

PAINS

017 1.122 0.089 0.143 NO N/A NO N/A

1st, NO;

018 1.522 0.134 0.001 NO YES YES

2nd, partial.

1st, NO; 1st, YES;

O20 1.364 0.281 0.075 YES YES

2nd, YES. 2nd, YES.

021,

1st, partial;

rhodanines 1.250 0.092 0.005 NO YES YES

2nd, NO.

- PAINS

1st, partial;

022 0.877 0.102 0.205 NO N/A N/A

2nd, partial.

YES (note:

yet viability

023,

of non- enones, 1st, YES;

0.595 0.079 0.000 NO YES stressed catechols - 2nd, YES.

cells, PAINS

reduced by 40%)

027 1.138 0.053 0.071 NO N/A NO N/A

[0568] Table 16 (related to Table 17). Several small molecules reduced the phosphorylated fraction of RPS6. We examined the effects of our molecules, at multiple doses (n = 4 for each dose), on the phosphorylation status of nbosomal protein S6, a downstream readout of mTOR activity, by In-Cell Western analyses. Rapamycin, as a control, substantially reduced the p-RPS6 fraction (analyzed at 1.25μΜ, 2.5μΜ, 5.0μΜ). For example, in Experiment 3, relative ratios of p-RPS/RPS are: DMSO control (pooled), 0.771±0.1 11 (average ± standard deviation, n = 12); rapamycin (pooled from three doses), 0.041±0.004. When normalized by the DMSO control, rapamycin treatment resulted in more than 90% reduction of phosphorylated fraction of RPS6. Small molecules that produced more than 40% reduction in p-RPS6 fraction in at least two of three experiments are scored as positive.

[0569] Table 17 (related to Table 8). Several small molecules induced the LC3A/B autophagy marker. By performing immuno-staining of the LC3A/B autophagic marker for WI-38 cells treated with small molecules, at least 6 small molecules (Gr-1 A, Gr-lC, Gr-ID, Gr-IG, Oi l and 023) were found to induce LC3 A/B puncta. Normalized change of nuclei numbers and LC3 A/B puncta intensity are shown and only the molecules that increased fold change by 2-fold or more in two independent experiments were scored positive. Other members of Group 1, including Gr- 1B, Gr-IE and Gr-IF, are also shown. Experiment 1 : rapamycin control, less cells, 83%, P < 0.05; Up, 174%, P >0.05 (n = 4).

[0570] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

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