WO2015006615A1 - Anticancer agents - Google Patents

Abstract

Provided herein, inter alia, are compounds and methods for treating cancer.

Description

ANTICANCER AGENTS

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61/844,738 filed July 10, 2013 which is hereby incorporated by reference in its entirety 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 number GM25439 awarded by the National Institutes of Health. The Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] Cancers affect many people each year, and access to novel cancer therapeutics or understanding of their mechanisms of action offer new potential treatments. Thus there is need in the art for novel therapeutics. Provided herein are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

[0004] Provided herein, inter alia, are compositions and methods for treating cancer. In one aspect is a compound having the formula:

[0005] In the formulae above, R¹ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, - C(0)R^1A, -OR^1A, -NR^1AR^1B, -C(0)OR^1A, -C(0)NR^1A R^1B, -N0₂, -SR^1A, -S(0)„iR^1A, - S(0)„iOR^1A, -S(0)„iNR^1AR^1B, -NHNR^1AR^1B, -ONR^1AR^1B, -NHC(0)NHNR^1AR^1B, 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. R² is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^2A, -OR^2A, -NR^2AR^2B, -C(0)OR^1A, -C(0)NR^2AR^2B, -N0₂, -SR^2A, -S(0)„₂R^2A, - S(0)_n20R^2A, -S(0)„iNR^2AR^2B, -NHNR^2AR^2B, -ONR^2AR^2B, -NHC(0)NHNR^2AR^2B, 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. R³ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^3A, -OR^3A, -NR^3AR^3B, -C(0)OR^3A, -C(0)NR^3AR^3B, -N0₂, -SR^3A, -S(0)„₃R^3A, - S(0)_Il3OR^3A, -S(0)„₃NR^3AR^3B, -NHNR^3AR^3B, -ONR^3AR^3B, -NHC(0)NHNR^3AR^3B, 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. R⁴ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^4A, -OR^4A, -NR^4AR^4B, -C(0)OR^4A, -C(0)NR^4AR^4B, -N0₂, -SR^4A, -S(0)_n4R^4A, - S(0)_n4OR^4A, -S(0)_n4NR^4AR^4B, -NHNR^4AR^4B, -ONR^4AR^4B, -NHC(0)NHNR^4AR^4B, 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. R⁵ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^5A, -OR^5A, -NR^5AR^5B, -C(0)OR^5A, -C(0)NR^5AR^5B, -N0₂, -SR^5A, -S(0)„₅R^5A, - S(0)„₅OR^5A, -S(0)„₅NR^5AR^5B, -NHNR^5AR^5B, -ONR^5AR^5B, -NHC(0)NHNR^5AR^5B, 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. R⁶ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^6A, -OR^6A, -NR^6AR^6B, -C(0)OR^6A, -C(0)NR^6AR^6B, -N0₂, -SR^6A, -S(0)„₆R^6A, - S(0)„₆OR^6A, -S(0)„₆NR^6AR^6B, -NHNR^6AR^6B, -ONR^6AR^6B, -NHC(0)NHNR^6AR^6B, 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. R⁷ is independently hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^7A, -OR^7A, -NR^7AR^7B, -C(0)OR^7A, -C(0)NR^7AR^7B, -N0₂, -SR^7A, - S(0)„₇R^7A, -S(0)„₇OR^7A, -S(0)„₇NR^7AR^7B, -NHNR^7AR^7B, -ONR^7AR^7B, -NHC(0)NHNR^7AR^7B, 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. L¹ and L² are independently -0-, - C(0)0-. -C(0)NH-, -NH-. -S-, substituted or unsubstituted alkylene, substituted or

unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. The symbols nl, n2, n3, n4, n5, n6 and n7 are independently 1 or 2. The symbol n is 1, 2, 3, 4 or 5. The symbol m is 1 or 2. R^1A, R^1B, R^2A, R^2B, R^3A, R^3B, R^4A, R^4B, R^5A, R^5B, R^6A, R^6B, R^7A, R^7B are independently hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, - S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, - NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, -Si(CH₃)₃ 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. The compound is not actinophyllic acid or its methyl ester. [0006] Provided herein are pharmaceutical compositions. In one aspect is a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a compound (e.g. formula (I), (II), (III), (IV), (V), or a compound of Table 1) as described herein.

[0007] Also provided herein are method of treating cancer in a subject in need thereof. In one aspect is a method of treating cancer in a subject in need thereof by administering an effective amount of a compound (e.g. formula (I), (II), (III), (IV), (V), or a compound of Table 1) as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1. Structures of primary hit compounds organized by potency in follow-up dose-response assays for cytotoxicity. Labels indicate library of origin (first line) and compound identifier or well location (second line). [0009] Figure 2. Structure of actinophyllic acid, 1227, and other synthetic intermediates and their analogs.

[0010] Figure 3. Cell viability of U937 cells treated with 10 μΜ cytotoxin (or 20 μΜ

Thapsigargin) assessed by flow cytometry (AnnV/PI) at various timepoints. [0011] Figure 4. Representative dose-response curves, average Hill Slope values and average Em_ax values for 1257 and doxorubicin (Dox) in a panel of cell lines. All dose-response curves were determined after 48 h incubation with alamar blue and fitted to a sigmoidal dose-response curve.

[0012] Figure 5. Representative dose-response curves, average Hill Slope values and average E_max values for a panel of cytotoxins in U937 cells. All dose-response curves were determined after 48 h incubation with alamar blue and fitted to a sigmoidal dose-response curve.

[0013] Figure 6. Cell phase distribution of U937 cells treated with either DMSO or 6 μΜ 1257 for 20 h, assessed by flow cytometry (PI).

[0014] Figure 7. Cell cycle analysis of U937 cells arrested at G2/M with 80 ng/mL nocodazole for 16 h, followed by treatment with DMSO of 4 μΜ 1257 for 16 h, cell aliquots removed and fixed at indicated time, cell cycle assessed by flow cytometry (PI).

[0015] Figure 8. Dot plots of propidium iodide fluorescence vs Annexin V-FITC fluorescence of U937 cells treat for 16 h with either DMSO or 4 μΜ 1257.

[0016] Figure 9. Apoptosis pathways and relevant tool compounds. [0017] Figure 10. Percent protection against cell death induced by 1257 provided by various apoptosis-preventing agents. U937 cells were pretreated with indicated concentration of protective agent for 2 h, 1257 was added at a final concentration of 9 μΜ, cells were incubated for an additional 3 h and viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m.

[0018] Figure 11. Viability of isogenic MEF cell lines after treatment with either DMSO or 15 μΜ 1257 for 3 h, with or without 2 h pre- incubation with 50 μΜ NS3694. Viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m.

[0019] Figure 12. Viability of isogenic MEF cell lines after treatment with either DMSO or 15 μΜ 1257 for 3 h. Viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m. [0020] Figure 13. Cell viability of isogenic Jurkat cell lines after treatment with 1257 +/- necrostatin-1, SP600125, or QVD-OPh. Viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m.

[0021] Figure 14. Percent protection against cell death induced by 1257 provided by various necrosis -preventing agents. U937 cells were pretreated with indicated concentration of protective agent for 2 h, 1257 was added at a final concentration of 9 μΜ, cells were incubated for an additional 3 h and viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m.

[0022] Figure 15. ER stress pathways and relevant tool compounds.

[0023] Figure 16. Percent protection against cell death induced by 1257 provided by various ER stress-preventing agents. U937 cells were pretreated with indicated concentration of protective agent for 2 h, 1257 was added at a final concentration of 9 μΜ, cells were incubated for an additional 3 h and viability was assessed by flow cytometry (AnnV/PI); n=3, s.e.m.

[0024] Figure 17. Mode of action upon and structure of PP1/GADD34 inhibitor salubrinal.

[0025] Figure 18. Western blots of apoptotic events in lysates of U937 cells treated with 9 μΜ 1257 with or without 50 μΜ NS3694, 75 μΜ salubrinal, or 10 μΜ QVD-OPh, and 1 μΜ staurosporine as an apoptotic control.

[0026] Figure 19. Western blots for PARP-1 and actin in lysates of U937 cells treated with 9 μΜ 1257 with or without 10 μΜ QVD-OPh (QVD) or 75 μΜ salubrinal (Sal), or 1 μΜ staurosporine (STS) as an apoptotic control. [0027] Figure 20. Western blots for ER stress markers in lysates of U937 cells treated with 9 μΜ 1257 with or without 75 μΜ salubrinal (Sal).

[0028] Figure 21. Western blots for phosphorylated and total eIF2a in lysates of U937 cells treated with 1 μΜ tunicamycin for 4-24 h.

[0029] Figure 22. TEM images of cytotoxin-treated U937 cells, 4,000X. 5 million cells per sample were treated with protective agent (75 μΜ salubrinal, 10 μΜ QVD-OPh, or 50 μ LNS3694) for 2 h before 1257 (final concentration of 9 μΜ) was added with mixing, then incubated for 1 h. For controls, cells were treated with either DMSO, 10 μΜ thapsigargin, or 10 μΜ staurosporine for 4 h. Cells were harvested at the indicated times, washed 6x with PBS, suspended in Karnovsky's fixative. Endoplasmic reticula are indicated with arrows. [0030] Figure 23. TEM images of cytotoxin-treated U937 cells, 15,000X. 5 million cells per sample were treated with 75 μΜ salubrinal for 2 h before 1257 (final concentration of 9 μΜ) was added with mixing, then incubated for 1 h. For controls, cells were treated with either 10 μΜ thapsigargin or staurosporine for 4 h. Cells were harvested at the indicated times, washed 6x with PBS, suspended in Karnovsky's fixative and submitted to Dr. Lou Ann Miller for further sample preparation and processing.

[0031] Figure 24. Cytosolic stain set images of control and 1257-treated HeLa cells. Blue = DNA; red = actin; green = tubulin; cyan = phospho-H3.

[0032] Figure 25. Nuclear stain set images of control and 1257-treated HeLa cells. Blue = DNA; Magenta = phospho-H3 ; Cyan = EdU.

[0033] Figure 26. Heat map analysis of transcript levels in GEM-1 treated cells, 1257 treated cells, and corresponding DMSO treated cells.

[0034] Figure 27. Western blot analysis of TXNIP protein levels in U937 cells upon treatment with 1257. [0035] Figure 28. Structure of terfenadine.

[0036] Figure 29. Depiction of expected shRNA screen results: plot of shRNA construct abundance in treated cells vs. control cells. Enriched shRNA constructs (green, circled) should correspond to proteins critical for compound-induced cell death. Depleted constructs and those with no change are less informative in this experiment. [0037] Figure 30. Viability of MiaPaca-2 cells after treatment with 12.5 μΜ 1257 with or without a 2 h pre-treatment with 100 μΜ salubrinal, assessed by flow cytometry (AnnV/PI), n=3, s.e.m.

[0038] Figure 31. Schematic of nested PCR steps for isolation and amplification of shRNA inserts from genomic DNA (gDNA) of surviving MiaPaca-2 cells. WPRE = Woodchuck hepatitis virus posttranscriptional regulatory element; LTR = long terminal repeat.

[0039] Figure 32. Dose-response hemolysis (red) and Hs578t cytotoxicity (blue) curves for

1257 and related active analogs. IC5₀ values for each activity are indicated on each graph.

Compound was incubated with washed erthrocytes for 2 h at 37 °C, then centrifuged to pellet cells and cellular debris, the supernatent was removed and absorbance at 540 nm was measured to determine the relative amounts of released hemoglobin. [0040] Figure 33. Representative dose-response curves, average Hill Slope values and average Em_ax values for 1258 in 4T1 and Hs578t cell lines. All dose-response curves were determined after 48 h incubation with alamar blue and fitted to a sigmoidal dose-response curve.

[0041] Figure 34. Protection provided by salubrinal when U937 cells are treated with 1258. U937 cells were pre-incubated with 100 μΜ salubrinal for 2 h, then 30 μΜ 1258 was added cell viability was assessed after 3 h by flow cytometry (AnnV/PI).

[0042] Figure 35. Scheme to prepare Actinophyllic acid (1).

[0043] Figure 36. Scheme to prepare Compounds 16-20.

[0044] Figure 37. Scheme to prepare Compounds 5-7 and 21-24.

DETAILED DESCRIPTION OF THE INVENTION

[0045] 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. [0046] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0047] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C1₀ means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, (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-). [0048] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH₂CH₂CH₂CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred 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.

[0049] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom 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, B, As, 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. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH₂-CH₂-0-CH₃, -CH₂-CH₂-NH-CH₃, -CH2-CH₂-N(CH₃)-CH3, - CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH₃, -CH2-CH₂-S(0)2-CH₃, -CH=CH-0-CH₃, -Si(CH₃)₃, - CH₂-CH=N-OCH₃, -CH=CH-N(CH₃)-CH₃, -0-CH₃, -0-CH₂-CH₃, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃ and -CH₂-0-Si(CH₃)₃.

[0050] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH₂-CH₂-S-CH₂-CH₂- and -CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,

alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)₂R'- represents both -C(0)₂ '- 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)NR', -NR'R", -OR', -SR, and/or -S0₂R. 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. [0051] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heteroalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 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.

[0052] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0053] 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.

[0054] 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, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5 -isoquinolyl, 2-quinoxalinyl, 5 -quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be a -O- bonded to a ring heteroatom nitrogen.

[0055] A "fused ring aryl-heterocycloalkyl" is an aryl fused to a heterocycloalkyl. A "fused ring heteroaryl-heterocycloalkyl" 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 aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring

heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein. Fused ring aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be named according to the size of each of the fused rings. Thus, for example, 6,5 aryl-heterocycloalkyl fused ring describes a 6 membered aryl moiety fused to a 5 membered heterocycloalkyl. Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.

Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0056] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0057] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0058] 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', -NR'R", -SR, -halogen, - SiR'R'R'", -OC(0)R, -C(0)R, -C0₂R, -CONRR", -OC(0)NR'R", -NR"C(0)R, -NR-

C(0)NR"R", -NR"C(0)₂R', -NR-C(NRR"R")=NR"", -NR-C(NR'R")=NR", -S(0)R', -S(0)₂R', - S(0)₂NRR", -NRS0₂R, -NRTWR", -ONRR", -NR'C=(0)NR"NR"R"", -CN, -N0₂, - NRS0₂R", -NRC=(0)R", -NR'C(0)-OR", -NROR", 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, -NR'R" includes, but is not limited to, 1 -pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF₃ and -CH₂CF₃) and acyl (e.g., -C(0)CH₃, -C(0)CF₃, -C(0)CH₂OCH₃, and the like). [0059] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR, -halogen, - SiR'R'R'", -OC(0)R, -C(0)R, -C0₂R, -CONRR", -OC(0)NR'R", -NR"C(0)R, -NR- C(0)NR"R", -NR"C(0)₂R', -NR-C(NRR"R")=NR"", -NR-C(NR'R")=NR", -S(0)R', -S(0)₂R', - S(0)₂NRR", -NRS0₂R, -NRTWR", -ONRR", -NR'C=(0)NR"NR"R"", -CN, -N0₂, -R', -N₃, -CH(Ph)₂, fluoro(Ci-C₄)alkoxy, and fluoro(Ci-C₄)alkyl, -NRS0₂R", -NRC=(0)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound 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.

[0060] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0061] 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.

[0062] 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-(CH₂)_r-B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O) -, - S(0)₂-, -S(0)₂NR'-, or a single bond, and r is an integer 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-, -NR-, -S-, -S(O)-, -S(0)₂-, or -S(0)₂NR'-. The substituents R, R, R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0063] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), Arsenic (As), and silicon (Si). [0064] A "substituent group," as used herein, means a group selected from the following moieties:

(A) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S0₂C1, -S0₃H, - S0₄H, -S0₂NH₂, -NH H₂, -ONH₂, -NHC=(0)NH H₂, -NHC=(0) NH₂, -NHS0₂H, - NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

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

(i) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S0₂C1, -SO₃H, -

SO₄H, -S0₂NH₂, -NHNH₂, -ONH₂, -NHC=(0)NHNH₂, -NHC=(0) NH₂, -NHS0₂H, - NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

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

(a) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S0₂C1, - SO₃H, -SO₄H, -S0₂NH₂, -NHNH₂, -ONH₂, -NHC=(0)NHNH₂, _NHC=(0) NH₂, - NHS0₂H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted

heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF₃, -CN, -OH, -NH₂, - COOH, -CONH₂, -NO₂, -SH, -S0₂C1, -SO3H, -SO₄H, -S0₂NH₂, -NHNH₂, -ONH₂, -NHC=(0)NHNH₂, -NHC=(0) NH₂, -NHS0₂H, -NHC= (O)H, -NHC(0)-OH, -

NHOH, -OCF3, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0065] 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-C₂o 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, and each substituted or unsubstituted heterocycloalkyl is a substituted or

unsubstituted 3 to 8 membered heterocycloalkyl.

[0066] 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 Q-Cg 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, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.

[0067] 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. [0068] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C2₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered

heterocycloalkyl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C2₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, and/or each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0069] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs 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, and/or each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs 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, and/or each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene.

[0070] 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.

[0071] 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. [0072] 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.

[0073] 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. [0074] 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, generally recognized as stable by those skilled in the art, are within the scope of the invention.

[0075] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

[0076] 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 (³H), iodine- 125 (¹²⁵I), or carbon- 14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0077] The symbol " denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0078] Where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman decimal symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³

13 13 1 13 2 13 3 13 4 substituents are present, each R substituent may be distinguished as R , R , R , R , etc., wherein each of R^{13 1}, R^13'2, R^{13 3C}, R^13'4, etc. is defined within the scope of the definition of R¹³ and optionally differently.

[0079] Description of compounds of the present invention is 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.

[0080] 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, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et ah,

"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). 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.

[0081] 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. [0082] 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.

[0083] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein include those compounds that readily undergo chemical or enzymatic changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. [0084] 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.

[0085] 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.

[0086] 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. [0087] 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 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 is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. 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).

[0088] 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.

[0089] 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.

[0090] 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 effect 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. [0091] 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.

[0092] 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. [0093] "Control" or "control experiment" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0094] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0095] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0096] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. Inhibition may refer to reduction of a disease or symptoms of disease. Inhibition may refer to a reduction in the activity of a particular protein or nucleic acid target. Thus, inhibition includes, 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.

[0097] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.

[0098] The term "modulate" is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.

[0099] "Selective" or "selectivity" or the like of a compound refers to the compound's ability to discriminate between molecular targets. "Specific", "specifically", "specificity", or the like of a compound refers to the compound's ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.

[0100] "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.

[0101] 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.

[0102] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0103] The compositions disclosed herein 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 disclosed herein 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 Set 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, Am. J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions can also be delivered as nanoparticles.

[0104] Pharmaceutical compositions may include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is 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., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms. [0105] 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, 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.

[0106] The compounds and complexes described herein can be used in combination with one another, with other active drugs known to be useful in treating a disease (e.g. anti-cancer drugs) or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. [0107] 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, for example an anticancer agent as described herein. The compound of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the 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. anticancer agents).

[0108] Co-administration includes administering one active agent (e.g. a complex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g. anti- cancer agents). Also contemplated herein, are embodiments, where 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 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 embodiments, the active and/or adjunctive agents may be linked or conjugated to one another. In embodiments, the compounds and complexes described herein may be combined with treatments for cancer such as chemotherapy or radiation therapy. [0109] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by (in whole or in part) the substance or substance activity or function. [0110] "Patient," "subject," "patient in need thereof," and "subject in need thereof are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. [0111] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. Disease as used herein may refer to cancer.

[0112] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant or benign tumors found in mammals, including leukemia, carcinomas and sarcomas. Exemplary cancers include acute myeloid leukemia ("AML"), chronic myelogenous leukemia ("CML"), and cancer of the brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and prostate. Additional examples include, cervix cancers, stomach cancers, head & neck cancers, uterus cancers, mesothelioma, metastatic bone cancer, Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, 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, and neoplasms of the endocrine and exocrine pancreas.

[0113] 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). The murine leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity. It is believed that a compound that tests positive in the P388 cell assay will generally exhibit some level of anti-leukemic activity regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, including treating acute myeloid 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, and undifferentiated cell leukemia.

[0114] 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 which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent 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, and telangiectaltic sarcoma.

[0115] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent 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, and superficial spreading melanoma.

[0116] 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 which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, 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, and carcinoma villosum.

[0117] "Anti-cancer agent" is used in accordance with its plain and 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. An anti-cancer agent may be an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. [0118] Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI- 1040, PD035901, selumetinib/ AZD6244, GSK1 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), or 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, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,

LY294002, bortezomib, trastuzumab, BAY 1 1-7082, PKC412, PD184352, 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;

adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;

angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;

apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;

bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;

CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B;

combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol;

cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;

dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;

duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists;

etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;

galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;

idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;

isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin;

loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;

mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;

monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;

nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;

nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;

oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;

ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;

phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;

pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;

raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;

spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem- cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;

urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;

ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;

bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin;

carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;

cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;

enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;

estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II

(including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b;

interferon alfa-nl; interferon alfa-n3; interferon beta- la; interferon gamma- lb; iprop latin;

irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole

hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;

maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;

melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;

meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;

mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;

perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;

puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride;

spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone;

thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;

zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol.TM (i.e. paclitaxel), Taxotere.TM, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS- 10 and SC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21 -aminoepothilone B (i.e. BMS-310705), 21- hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-1 12378

(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS- 164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970

(Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L- Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC- 106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI- 138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),

Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T- 138026 (Tularik), Monsatrol, Inanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),

Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-1 10, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC- 12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-25041 1 (Sanofi)), 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 ^{U 1}ln, ⁹⁰Y, or ¹³¹I, 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, or the like.

[0119] "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.

[0120] "Cancer model organism", as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.

[0121] "Analog," or "analogue" are used in accordance with plain ordinary meaning within Chemistry and Biology and refer to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analogue is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

I. Compositions

[0122] Provided herein are compounds having the formula:

[0123] In the formulae above, R¹ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, - C(0)R^1A, -OR^1A, -NR^1AR^1B, -C(0)OR^1A, -C(0)NR^1A R^1B, -N0₂, -SR^1A, -S(0)„iR^1A, - S(0)„iOR^1A, -S(0)„iNR^1AR^1B, -NHNR^1AR^1B, -ONR^1AR^1B, -NHC(0)NHNR^1AR^1B, 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. R² is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^2A, -OR^2A, -NR^2AR^2B, -C(0)OR^1A, -C(0)NR^2AR^2B, -N0₂, -SR^2A, -S(0)„₂R^2A, - S(0)_n20R^2A, -S(0)„iNR^2AR^2B, -NHNR^2AR^2B, -ONR^2AR^2B, -NHC(0)NHNR^2AR^2B, 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. R³ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^3A, -OR^3A, -NR^3AR^3B, -C(0)OR^3A, -C(0)NR^3AR^3B, -N0₂, -SR^3A, -S(0)„₃R^3A, - S(0)_Il3OR^3A, -S(0)„₃NR^3AR^3B, -NHNR^3AR^3B, -ONR^3AR^3B, -NHC(0)NHNR^3AR^3B, 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. R⁴ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^4A, -OR^4A, -NR^4AR^4B, -C(0)OR^4A, -C(0)NR^4AR^4B, -N0₂, -SR^4A, -S(0)_n4R^4A, - S(0)_n4OR^4A, -S(0)_n4NR^4AR^4B, -NHNR^4AR^4B, -ONR^4AR^4B, -NHC(0)NHNR^4AR^4B, 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. R⁵ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^5A, -OR^5A, -NR^5AR^5B, -C(0)OR^5A, -C(0)NR^5AR^5B, -N0₂, -SR^5A, -S(0)„₅R^5A, - S(0)„₅OR^5A, -S(0)„₅NR^5AR^5B, -NHNR^5AR^5B, -ONR^5AR^5B, -NHC(0)NHNR^5AR^5B, 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. R⁶ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, - CN, -C(0)R^6A, -OR^6A, -NR^6AR^6B, -C(0)OR^6A, -C(0)NR^6AR^6B, -N0₂, -SR^6A, -S(0)„₆R^6A, - S(0)„₆OR^6A, -S(0)„₆NR^6AR^6B, -NHNR^6AR^6B, -ONR^6AR^6B, -NHC(0)NHNR^6AR^6B, 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. R⁷ is independently hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^7A, -OR^7A, -NR^7AR^7B, -C(0)OR^7A, -C(0)NR^7AR^7B, -N0₂, -SR^7A, - S(0)„₇R^7A, -S(0)„₇OR^7A, -S(0)„₇NR^7AR^7B, -NHNR^7AR^7B, -ONR^7AR^7B, -NHC(0)NHNR^7AR^7B, 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. L¹ and L² are independently -0-, - C(0)0-. -C(0)NH-, -NH-. -S-, substituted or unsubstituted alkylene, substituted or

unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. The symbols nl, n2, n3, n4, n5, n6 and n7 are independently 1 or 2. The symbol n is 1, 2, 3, 4 or 5. The symbol m is 1 or 2. R^1A, R^1B, R^2A, R^2B, R^3A, R^3B, R^4A, R^4B, R^5A, R^5B, R^6A, R^6B, R^7A, R^7B are independently hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, - S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, - NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, -Si(CH₃)₃ 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. The compound is not actinophyllic acid. The compound is not actinophyllic methyl-ester.

[0124] R¹ may be hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^1A, -OR^1A, - NR^1AR^1B, -C(0)OR^1A, -C(0)NR^1A R^1B, -N0₂, -SR^1A, -S(0)„iR^1A, -S(0)„iOR^1A, -S(0)„iNR^1AR^1B, -NHNR^1AR^1B, -ONR^1AR^1B, -NHC(0)NHNR^1AR^1B. R¹ may be 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. R¹ may be hydrogen.

[0125] R¹ may be substituted or unsubstituted alkyl. R¹ may be substituted alkyl. R¹ may be unsubstituted alkyl. R¹ may be substituted or unsubstituted Ci-C₂o alkyl. R¹ may be substituted Ci-C₂o alkyl. R¹ may be substituted or unsubstituted C1-C1₀ alkyl. R¹ may be substituted C1-C1₀ alkyl. R¹ may be substituted or unsubstituted C1-C5 alkyl. R¹ may be substituted C1-C5 alkyl. R¹ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. [0126] R¹ may be R^lc-substituted or unsubstituted alkyl. R¹ may be R^lc-substituted alkyl. R¹ may be R^lc-substituted or unsubstituted C1-C2₀ alkyl. R¹ may be R^lc-substituted C1-C2₀ alkyl. R¹ may be R^lc-substituted or unsubstituted C1-C1₀ alkyl. R¹ may be R^lc-substituted C1-C1₀ alkyl. R¹ may be R^lc-substituted or unsubstituted C1-C5 alkyl. R¹ may be R^lc-substituted C1-C5 alkyl. R¹ may be methyl, R^lc-substituted or unsubstituted ethyl, or R^lc-substituted or unsubstituted propyl.

[0127] R¹ may be substituted or unsubstituted heteroalkyl. R¹ may be substituted heteroalkyl. R¹ may be unsubstituted heteroalkyl. R¹ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R¹ may be substituted 2 to 20 membered heteroalkyl. R¹ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R¹ may be substituted 2 to 10 membered heteroalkyl. R¹ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R¹ may be substituted 2 to 6 membered heteroalkyl.

[0128] R¹ may be R^lc-substituted or unsubstituted heteroalkyl. R¹ may be R^lc-substituted heteroalkyl. R¹ may be R^lc-substituted or unsubstituted 2 to 20 membered heteroalkyl. R¹ may be R^lc-substituted 2 to 20 membered heteroalkyl. R¹ may be R^lc-substituted or unsubstituted 2 to 10 membered heteroalkyl. R¹ may be R^lc-substituted 2 to 10 membered heteroalkyl. R¹ may be R^lc-substituted or unsubstituted 2 to 6 membered heteroalkyl. R¹ may be R^lc-substituted 2 to 6 membered heteroalkyl.

[0129] R¹ may be substituted or unsubstituted cycloalkyl. R¹ may be substituted cycloalkyl. R¹ may be unsubstituted cycloalkyl. R¹ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R¹ may be substituted 3 to 20 membered cycloalkyl. R¹ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R¹ may be substituted 3 to 10 membered cycloalkyl. R¹ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R¹ may be substituted 3 to 6 membered cycloalkyl.

[0130] R¹ may be R^lc-substituted or unsubstituted cycloalkyl. R¹ may be R^lc-substituted cycloalkyl. R¹ may be R^lc-substituted or unsubstituted 3 to 20 membered cycloalkyl. R¹ may be R^lc-substituted 3 to 20 membered cycloalkyl. R¹ may be R^lc-substituted or unsubstituted 3 to 10 membered cycloalkyl. R¹ may be R^lc-substituted 3 to 10 membered cycloalkyl. R¹ may be R^1C- substituted or unsubstituted 3 to 6 membered cycloalkyl. R¹ may be R^lc-substituted 3 to 6 membered cycloalkyl. [0131] R¹ may be substituted or unsubstituted heterocycloalkyl. R¹ may be substituted heterocycloalkyl. R¹ may be unsubstituted heterocycloalkyl. R¹ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R¹ may be substituted 3 to 20 membered heterocycloalkyl. R¹ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R¹ may be substituted 3 to 10 membered heterocycloalkyl. R¹ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R¹ may be substituted 3 to 6 membered heterocycloalkyl. [0132] R¹ may be R^lc-substituted or unsubstituted heterocycloalkyl. R¹ may be R^lc-substituted heterocycloalkyl. R¹ may be R^lc-substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R¹ may be R^lc-substituted 3 to 20 membered heterocycloalkyl. R¹ may be R^1C- substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R¹ may be R^lc-substituted 3 to 10 membered heterocycloalkyl. R¹ may be R^lc-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R¹ may be R^lc-substituted 3 to 6 membered heterocycloalkyl.

[0133] R¹ may be substituted or unsubstituted aryl. R¹ may be substituted aryl. R¹ may be unsubstituted aryl. R¹ may be substituted or unsubstituted 5 to 20 membered aryl. R¹ may be substituted 5 to 20 membered aryl. R¹ may be substituted or unsubstituted 5 to 8 membered aryl. R¹ may be substituted 5 to 8 membered aryl. R¹ may be substituted or unsubstituted 5 or 6 membered aryl. R¹ may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0134] R¹ may be R^lc-substituted or unsubstituted aryl. R¹ may be R^lc-substituted aryl. R¹ may be R^lc-substituted or unsubstituted 5 to 20 membered aryl. R¹ may be R^lc-substituted 5 to 20 membered aryl. R¹ may be R^lc-substituted or unsubstituted 5 to 8 membered aryl. R¹ may be R^lc-substituted 5 to 8 membered aryl. R¹ may be R^lc-substituted or unsubstituted 5 or 6 membered aryl. R¹ may be R^lc-substituted 5 or 6 membered aryl (e.g. phenyl).

[0135] R¹ may be substituted or unsubstituted heteroaryl. R¹ may be substituted heteroaryl. R¹ may be unsubstituted heteroaryl. R¹ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R¹ may be substituted 5 to 20 membered heteroaryl. R¹ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R¹ may be substituted 5 to 8 membered heteroaryl. R¹ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R¹ may be substituted 5 or 6 membered heteroaryl.

[0136] R¹ may be R^lc-substituted or unsubstituted heteroaryl. R¹ may be R^lc-substituted heteroaryl. R¹ may be R^lc-substituted or unsubstituted 5 to 20 membered heteroaryl. R¹ may be R^lc-substituted 5 to 20 membered heteroaryl. R¹ may be R^lc-substituted or unsubstituted 5 to 8 membered heteroaryl. R¹ may be R^lc-substituted 5 to 8 membered heteroaryl. R¹ may be R^1C- substituted or unsubstituted 5 or 6 membered heteroaryl. R¹ may be R^lc-substituted 5 or 6 membered heteroaryl.

[0137] R¹ may be hydrogen, halogen, -C(0)R^1A, -C(0)OR^1A, -NR^1AR^1B, -OR^1A, 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 where R^1B is as described herein. R¹ may be hydrogen, halogen, -C(0)R^1A, -C(0)OR^1A, -NR^1AR^1B, -OR^1A, 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 where R^1B is hydrogen.

[0138] R¹ may be hydrogen, -C(0)R^1A, -C(0)OR^1A, R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^1C- substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^1C- substituted or unsubstituted heteroaryl, where R^1A and R^1C are as described herein. [0139] R¹ may be hydrogen, -C(0)R^1A, -C(0)OR^1A, R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^1C- substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^1C- substituted or unsubstituted heteroaryl, where R^1A is R^lc-substituted or unsubstituted alkyl, R^1C- substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^1C- substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^1C- substituted or unsubstituted heteroaryl and R^1C is as described herein.

[0140] R¹ may be hydrogen, halogen, -C(0)R^1A, -C(0)OR^1A, 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 where R^1A is as described herein.

[0141] R¹ may be hydrogen or R^lc-substituted or unsubstituted C1-C5 alkyl, where R^1C is as described herein. R¹ may be hydrogen or R^lc-substituted or unsubstituted C1-C5 alkyl, where R^1C is hydroxyl, R^1D-substituted or unsubstituted aryl, R^1D-substituted or unsubstituted heteroaryl, R^1D-substituted or unsubstituted cycloalkyl, or R^1D-substituted or unsubstituted heterocycloalkyl and R^1D is as described herein. R¹ may be hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, where R^1C is hydroxyl, R^1D-substituted or unsubstituted aryl, R^1D-substituted or unsubstituted heteroaryl, R -substituted or unsubstituted cycloalkyl, or R -substituted or unsubstituted heterocycloalkyl and R^1D is halogen or unsubstituted alkyl.

[0142] R¹ may be hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, where R^1C is as described herein. R¹ may be hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, where R^1C is hydroxyl.

[0143] R¹ may be hydrogen, methyl, ethyl, propyl,

or allyl. R¹ may be

OH

methyl, ethyl, propyl, OH or allyl. R¹ may be methyl. R¹ may be ethyl. R¹ may be propyl. R¹ may be OH . R¹ may be allyl.

[0144] R^1A may be substituted or unsubstituted alkyl. R^1A may be substituted alkyl. R^1A may be unsubstituted alkyl. R^1A may be substituted or unsubstituted C1-C20 alkyl. R^1A may be substituted C1-C2₀ alkyl. R^1A may be substituted or unsubstituted C1-C1₀ alkyl. R^1A may be substituted C1-C1₀ alkyl. R^1A may be substituted or unsubstituted C1-C5 alkyl. R^1A may be substituted C1-C5 alkyl. R^1A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. [0145] R^1A may be R^lc-substituted or unsubstituted alkyl. R^1A may be R^lc-substituted alkyl. R^1A may be R^lc-substituted or unsubstituted C1-C2₀ alkyl. R^1A may be R^lc-substituted C1-C2₀ alkyl. R^1A may be R^lc-substituted or unsubstituted C1-C1₀ alkyl. R^1A may be R^lc-substituted Ci- C1₀ alkyl. R^1A may be R^lc-substituted or unsubstituted C1-C5 alkyl. R^1A may be R^lc-substituted C1-C5 alkyl. R^1A may be methyl, R^lc-substituted or unsubstituted ethyl, or R^lc-substituted or unsubstituted propyl.

[0146] R^1A may be substituted or unsubstituted heteroalkyl. R^1A may be substituted heteroalkyl. R^1A may be unsubstituted heteroalkyl. R^1A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^1A may be substituted 2 to 20 membered heteroalkyl. R^1A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^1A may be substituted 2 to 10 membered heteroalkyl. R^1A may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R^1A may be substituted 2 to 6 membered heteroalkyl.

[0147] R^1A may be R^lc-substituted or unsubstituted heteroalkyl. R^1A may be R^lc-substituted heteroalkyl. R^1A may be R^lc-substituted or unsubstituted 2 to 20 membered heteroalkyl. R^1A may be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R^1A may be R^lc-substituted 2 to 10 membered heteroalkyl. R^1A may be R^lc-substituted or unsubstituted 2 to 6 membered heteroalkyl. R^1A may be R^lc-substituted 2 to 6 membered heteroalkyl. [0148] R^1A may be substituted or unsubstituted cycloalkyl. R^1A may be substituted cycloalkyl. R^1A may be unsubstituted cycloalkyl. R^1A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^1A may be substituted 3 to 20 membered cycloalkyl. R^1A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^1A may be substituted 3 to 10 membered cycloalkyl. R^1A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^1A may be substituted 3 to 6 membered cycloalkyl.

[0149] R^1A may be R^lc-substituted or unsubstituted cycloalkyl. R^1A may be R^lc-substituted cycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 20 membered cycloalkyl. R^1A may be R^lc-substituted 3 to 20 membered cycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 10 membered cycloalkyl. R^1A may be R^lc-substituted 3 to 10 membered cycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 6 membered cycloalkyl. R^1A may be R^lc-substituted 3 to 6 membered cycloalkyl.

[0150] R^1A may be substituted or unsubstituted heterocycloalkyl. R^1A may be substituted heterocycloalkyl. R^1A may be unsubstituted heterocycloalkyl. R^1A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^1A may be substituted 3 to 20 membered heterocycloalkyl. R^1A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^1A may be substituted 3 to 10 membered heterocycloalkyl. R^1A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^1A may be substituted 3 to 6 membered heterocycloalkyl.

[0151] R^1A may be R^lc-substituted or unsubstituted heterocycloalkyl. R^1A may be R^1C- substituted heterocycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^1A may be R^lc-substituted 3 to 20 membered heterocycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^1A may be R^lc-substituted 3 to 10 membered heterocycloalkyl. R^1A may be R^lc-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^1A may be R^lc-substituted 3 to 6 membered heterocycloalkyl. [0152] R^1A may be substituted or unsubstituted aryl. R^1A may be substituted aryl. R^1A may be unsubstituted aryl. R^1A may be substituted or unsubstituted 5 to 20 membered aryl. R^1A may be substituted 5 to 20 membered aryl. R may be substituted or unsubstituted 5 to 8 membered aryl. R^1A may be substituted 5 to 8 membered aryl. R^1A may be substituted or unsubstituted 5 or 6 membered aryl. R^1A may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0153] R^1A may be R^lc-substituted or unsubstituted aryl. R^1A may be R^lc-substituted aryl. R^1A may be R^lc-substituted or unsubstituted 5 to 20 membered aryl. R^1A may be R^lc-substituted 5 to 20 membered aryl. R^1A may be R^lc-substituted or unsubstituted 5 to 8 membered aryl. R^1A may be R^lc-substituted 5 to 8 membered aryl. R^1A may be R^lc-substituted or unsubstituted 5 or 6 membered aryl. R^1A may be R^lc-substituted 5 or 6 membered aryl (e.g. phenyl).

[0154] R^1A may be substituted or unsubstituted heteroaryl. R^1A may be substituted heteroaryl. R^1A may be unsubstituted heteroaryl. R^1A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^1A may be substituted 5 to 20 membered heteroaryl. R^1A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^1A may be substituted 5 to 8 membered heteroaryl. R^1A may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^1A may be substituted 5 or 6 membered heteroaryl. [0155] R^1A may be R^lc-substituted or unsubstituted heteroaryl. R^1A may be R^lc-substituted heteroaryl. R^1A may be R^lc-substituted or unsubstituted 5 to 20 membered heteroaryl. R^1A may be R^lc-substituted 5 to 20 membered heteroaryl. R^1A may be R^lc-substituted or unsubstituted 5 to 8 membered heteroaryl. R^1A may be R^lc-substituted 5 to 8 membered heteroaryl. R^1A may be R^lc-substituted or unsubstituted 5 or 6 membered heteroaryl. R^1A may be R^lc-substituted 5 or 6 membered heteroaryl.

[0156] R^1A may be R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^lc-substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl. [0157] R^1A may be hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted 3 to 10 membered aryl or substituted or unsubstituted 5 or 6 membered heteroaryl.

[0158] R^1A may be R^lc-substituted or unsubstituted alkyl, or R^lc-substituted or unsubstituted heteroalkyl where R^1D is as described herein. R^1A may be R^lc-substituted or unsubstituted alkyl, or R -substituted or unsubstituted heteroalkyl where R is halogen, unsubstituted alkyl or unsubstituted cycloalkyl.

[0159] R^1B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -NO2, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂,

-NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^1B may independently be 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^1B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^1B may independently be hydrogen. R^1B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl.

[0160] R^1C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^1D-substituted or unsubstituted alkyl, R^1D-substituted or unsubstituted heteroalkyl, R^1D-substituted or unsubstituted cycloalkyl, R^1D-substituted or unsubstituted heterocycloalkyl, R^1D-substituted or unsubstituted aryl, or R^1D-substituted or unsubstituted heteroaryl.

[0161] R^1D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0162] R² may be substituted or unsubstituted alkyl. R² may be substituted alkyl. R² may be unsubstituted alkyl. R² may be substituted or unsubstituted Ci-C₂o alkyl. R² may be substituted Ci-C₂o alkyl. R² may be substituted or unsubstituted C1-C1₀ alkyl. R² may be substituted C1-C1₀ alkyl. R² may be substituted or unsubstituted C1-C5 alkyl. R² may be substituted C1-C5 alkyl. R² may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R² may be hydrogen. R² may be methyl.

2 2C 2 2C 2

[0163] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

2C 2 2C 2 may be R -substituted or unsubstituted Ci-C₂o alkyl. R may be R -substituted Ci-C₂o alkyl. R 2C 2 2C 2 may be R -substituted or unsubstituted Ci-Cio alkyl. R may be R -substituted Ci-Cio alkyl. R

2C 2 2C 2 may be R -substituted or unsubstituted C1-C5 alkyl. R may be R -substituted C1-C5 alkyl. R may be methyl, R^2C-substituted or unsubstituted ethyl, or R^2C-substituted or unsubstituted propyl.

[0164] R² may be substituted or unsubstituted heteroalkyl. R² may be substituted heteroalkyl. R² may be unsubstituted heteroalkyl. R² may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R² may be substituted 2 to 20 membered heteroalkyl. R² may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R² may be substituted 2 to 10 membered heteroalkyl. R² may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R² may be substituted 2 to 6 membered heteroalkyl.

2 2C 2 2C

[0165] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted heteroalkyl. R² may be R^2C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R² may

2C 2 2C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R² may be R^2C-substituted 2 to 10 membered heteroalkyl. R² may

2C 2 2C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0166] R² may be substituted or unsubstituted cycloalkyl. R² may be substituted cycloalkyl. R² may be unsubstituted cycloalkyl. R² may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R² may be substituted 3 to 20 membered cycloalkyl. R² may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R² may be substituted 3 to 10 membered cycloalkyl. R² may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R² may be substituted 3 to 6 membered cycloalkyl.

2 2C 2 2C

[0167] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted cycloalkyl. R² may be R^2C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R² may be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10

2 2C 2 2C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R - substituted or unsubstituted 3 to 6 membered cycloalkyl. R² may be R^2C-substituted 3 to 6 membered cycloalkyl.

[0168] R² may be substituted or unsubstituted heterocycloalkyl. R² may be substituted heterocycloalkyl. R² may be unsubstituted heterocycloalkyl. R² may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R² may be substituted 3 to 20 membered heterocycloalkyl. R² may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R² may be substituted 3 to 10 membered heterocycloalkyl. R² may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R² may be substituted 3 to 6 membered heterocycloalkyl.

[0169] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted heterocycloalkyl. R² may be R^2C-substituted or unsubstituted 3 to 20 membered

2 2C 2 2C heterocycloalkyl. R may be R -substituted 3 to 20 membered heterocycloalkyl. R may be R - substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R² may be R^2C-substituted 3 to 10 membered heterocycloalkyl. R² may be R^2C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R² may be R^2C-substituted 3 to 6 membered heterocycloalkyl.

[0170] R² may be substituted or unsubstituted aryl. R² may be substituted aryl. R² may be unsubstituted aryl. R² may be substituted or unsubstituted 5 to 20 membered aryl. R² may be substituted 5 to 20 membered aryl. R² may be substituted or unsubstituted 5 to 8 membered aryl. R² may be substituted 5 to 8 membered aryl. R² may be substituted or unsubstituted 5 or 6 membered aryl. R² may be substituted 5 or 6 membered aryl (e.g. phenyl).

2 2C 2 2C 2

[0171] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R

2C 2 2C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R² may be R^2C-substituted or unsubstituted 5 to 8 membered aryl. R² may be

2C 2 2C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R² may be R^2C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0172] R² may be substituted or unsubstituted heteroaryl. R² may be substituted heteroaryl. R² may be unsubstituted heteroaryl. R² may be substituted or unsubstituted 5 to 20 membered heteroaryl. R² may be substituted 5 to 20 membered heteroaryl. R² may be substituted or unsubstituted 5 to 8 membered heteroaryl. R² may be substituted 5 to 8 membered heteroaryl. R² may be substituted or unsubstituted 5 or 6 membered heteroaryl. R² may be substituted 5 or 6 membered heteroaryl.

2 2C 2 2C

[0173] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted heteroaryl. R² may be R^2C-substituted or unsubstituted 5 to 20 membered heteroaryl. R² may be

2C 2 2C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R - substituted or unsubstituted 5 or 6 membered heteroaryl. R² may be R^2C-substituted 5 or 6 membered heteroaryl. [0174] R may be substituted or unsubstituted alkyl. R may be substituted alkyl. R may be unsubstituted alkyl. R^2A may be substituted or unsubstituted C1-C2₀ alkyl. R^2A may be substituted C1-C2₀ alkyl. R^2A may be substituted or unsubstituted C1-C1₀ alkyl. R^2A may be substituted C1-C1₀ alkyl. R^2A may be substituted or unsubstituted C1-C5 alkyl. R^2A may be substituted C1-C5 alkyl. R^2A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0175] R^2A may be R^2C-substituted or unsubstituted alkyl. R^2A may be R^2C-substituted alkyl.

2 .C 2A 2C

R may be R -substituted or unsubstituted C1-C2₀ alkyl. R may be R -substituted C1-C2₀

2 ^r∑ 2A 2C

alkyl. R may be R -substituted or unsubstituted C1-C1₀ alkyl. R may be R -substituted Ci- Cio alkyl. R^2A may be R^2C-substituted or unsubstituted C1-C5 alkyl. R^2A may be R^2C-substituted C1-C5 alkyl. R may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl.

[0176] R^2A may be substituted or unsubstituted heteroalkyl. R^2A may be substituted heteroalkyl. R^2A may be unsubstituted heteroalkyl. R^2A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^2A may be substituted 2 to 20 membered heteroalkyl. R^2A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^2A may be substituted 2 to 10 membered heteroalkyl. R^2A may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R^2A may be substituted 2 to 6 membered heteroalkyl.

[0177] R^2A may be R^2C-substituted or unsubstituted heteroalkyl. R^2A may be R^2C-substituted

2 ^r∑ 2A heteroalkyl. R may be R -substituted or unsubstituted 2 to 20 membered heteroalkyl. R may

2C 2A 2C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2

2A 2C 2A to 10 membered heteroalkyl. R may be R -substituted 2 to 10 membered heteroalkyl. R may

2C 2A 2C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl. [0178] R^2A may be substituted or unsubstituted cycloalkyl. R^2A may be substituted cycloalkyl. R^2A may be unsubstituted cycloalkyl. R^2A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^2A may be substituted 3 to 20 membered cycloalkyl. R^2A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^2A may be substituted 3 to 10 membered cycloalkyl. R^2A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^2A may be substituted 3 to 6 membered cycloalkyl. [0179] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted

2 ^r∑ 2A cycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered cycloalkyl. R may

2C 2A 2C

be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3

2 2( 2A to 10 membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0180] R^2A may be substituted or unsubstituted heterocycloalkyl. R^2A may be substituted heterocycloalkyl. R^2A may be unsubstituted heterocycloalkyl. R^2A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^2A may be substituted 3 to 20 membered heterocycloalkyl. R^2A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^2A may be substituted 3 to 10 membered heterocycloalkyl. R^2A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^2A may be substituted 3 to 6 membered heterocycloalkyl.

2 2(3 2A 2C

[0181] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R - substituted heterocycloalkyl. R^2A may be R^2C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R may be R -substituted 3 to 20 membered heterocycloalkyl. R may be

2C 2A 2C

R -substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to 10 membered heterocycloalkyl. R^2A may be R^2C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^2A may be R^2C-substituted 3 to 6 membered heterocycloalkyl. [0182] R^2A may be substituted or unsubstituted aryl. R^2A may be substituted aryl. R^2A may be unsubstituted aryl. R^2A may be substituted or unsubstituted 5 to 20 membered aryl. R^2A may be substituted 5 to 20 membered aryl. R^2A may be substituted or unsubstituted 5 to 8 membered aryl. R^2A may be substituted 5 to 8 membered aryl. R^2A may be substituted or unsubstituted 5 or 6 membered aryl. R^2A may be substituted 5 or 6 membered aryl (e.g. phenyl). [0183] R^2A may be R^2C-substituted or unsubstituted aryl. R^2A may be R^2C-substituted aryl. R^2A

2C 2A 2C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to

2 2(3 2A

20 membered aryl. R may be R -substituted or unsubstituted 5 to 8 membered aryl. R may

2C 2A 2C

be R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R^2A may be R^2C-substituted 5 or 6 membered aryl (e.g. phenyl). [0184] R^2A may be substituted or unsubstituted heteroaryl. R^2A may be substituted heteroaryl. R^2A may be unsubstituted heteroaryl. R^2A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R may be substituted 5 to 20 membered heteroaryl. R may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^2A may be substituted 5 to 8 membered heteroaryl.

_R2A

may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^2A may be substituted 5 or 6 membered heteroaryl.

2 ^r∑ 2A 2C

[0185] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted

2 2( 2A heteroaryl. R may be R -substituted or unsubstituted 5 to 20 membered heteroaryl. R may

2C 2A 2C

be R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5

2 2(3 2A to 8 membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be

2C 2A 2C

R -substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

2 2(3 2C

[0186] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^2C-substituted or unsubstituted cycloalkyl, R^2C-substituted or unsubstituted heterocycloalkyl, R^2C-substituted or unsubstituted aryl, or R^2C-substituted or unsubstituted heteroaryl. [0187] R^2B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂,

-NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^2B may independently be 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^2B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^2B may independently be hydrogen. R^2B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl. [0188] R^2C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^2D-substituted or unsubstituted alkyl, R^2D-substituted or unsubstituted heteroalkyl, R^2D-substituted or unsubstituted cycloalkyl, R^2D-substituted or unsubstituted heterocycloalkyl, R^2D-substituted or unsubstituted aryl, or R^2D-substituted or unsubstituted heteroaryl. [0189] R^zu is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0190] R³ may be substituted or unsubstituted alkyl. R³ may be substituted alkyl. R³ may be unsubstituted alkyl. R³ may be substituted or unsubstituted Ci-C₂o alkyl. R³ may be substituted Ci-C₂o alkyl. R³ may be substituted or unsubstituted Ci-Cio alkyl. R³ may be substituted Ci-Cio alkyl. R³ may be substituted or unsubstituted C1-C5 alkyl. R³ may be substituted C1-C5 alkyl. R³ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

3 3C 3 3C 3

[0191] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R may be R -substituted or unsubstituted Ci-C₂o alkyl. R may be R -substituted Ci-C₂o alkyl. R may be R -substituted or unsubstituted C1-C1₀ alkyl. R may be R -substituted C1-C1₀ alkyl. R

3C 3 3C 3 may be R -substituted or unsubstituted C1-C5 alkyl. R may be R -substituted C1-C5 alkyl. R may be methyl, R^3C-substituted or unsubstituted ethyl, or R^3C-substituted or unsubstituted propyl.

[0192] R³ may be substituted or unsubstituted heteroalkyl. R³ may be substituted heteroalkyl. R³ may be unsubstituted heteroalkyl. R³ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R³ may be substituted 2 to 20 membered heteroalkyl. R³ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R³ may be substituted 2 to 10 membered heteroalkyl. R³ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R³ may be substituted 2 to 6 membered heteroalkyl.

[0193] R³ may be R^3C-substituted or unsubstituted heteroalkyl. R³ may be R^3C-substituted heteroalkyl. R³ may be R^3C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R³ may

3C 3 3C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R³ may be R^3C-substituted 2 to 10 membered heteroalkyl. R³ may

3C 3 3C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0194] R³ may be substituted or unsubstituted cycloalkyl. R³ may be substituted cycloalkyl. R³ may be unsubstituted cycloalkyl. R³ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R³ may be substituted 3 to 20 membered cycloalkyl. R³ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R³ may be substituted 3 to 10 membered cycloalkyl. R³ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R³ may be substituted 3 to 6 membered cycloalkyl.

[0195] R³ may be R^3C-substituted or unsubstituted cycloalkyl. R³ may be R^3C-substituted cycloalkyl. R³ may be R^3C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R³ may be

3C 3 3C

R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10

3 3C 3 3C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R - substituted or unsubstituted 3 to 6 membered cycloalkyl. R³ may be R^3C-substituted 3 to 6 membered cycloalkyl.

[0196] R³ may be substituted or unsubstituted heterocycloalkyl. R³ may be substituted heterocycloalkyl. R³ may be unsubstituted heterocycloalkyl. R³ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R³ may be substituted 3 to 20 membered heterocycloalkyl. R³ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R³ may be substituted 3 to 10 membered heterocycloalkyl. R³ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R³ may be substituted 3 to 6 membered heterocycloalkyl.

3 3C 3 3C

[0197] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted heterocycloalkyl. R³ may be R^3C-substituted or unsubstituted 3 to 20 membered

3 3C 3 3C heterocycloalkyl. R may be R -substituted 3 to 20 membered heterocycloalkyl. R may be R - substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R³ may be R^3C-substituted 3 to 10 membered heterocycloalkyl. R³ may be R^3C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R³ may be R^3C-substituted 3 to 6 membered heterocycloalkyl.

[0198] R³ may be substituted or unsubstituted aryl. R³ may be substituted aryl. R³ may be unsubstituted aryl. R³ may be substituted or unsubstituted 5 to 20 membered aryl. R³ may be substituted 5 to 20 membered aryl. R³ may be substituted or unsubstituted 5 to 8 membered aryl (e.g. phenyl). R³ may be substituted 5 to 8 membered aryl. R³ may be substituted or

unsubstituted 5 or 6 membered aryl. R³ may be substituted 5 or 6 membered aryl.

3 3C 3 3C 3

[0199] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R

3C 3 3C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R³ may be R^3C-substituted or unsubstituted 5 to 8 membered aryl. R³ may be R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R³ may be R^3C-substituted 5 or 6 membered aryl (e.g. phenyl). [0200] R³ may be substituted or unsubstituted heteroaryl. R³ may be substituted heteroaryl. R³ may be unsubstituted heteroaryl. R³ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R³ may be substituted 5 to 20 membered heteroaryl. R³ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R³ may be substituted 5 to 8 membered heteroaryl. R³ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R³ may be substituted 5 or 6 membered heteroaryl.

3 3C 3 3C

[0201] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted heteroaryl. R³ may be R^3C-substituted or unsubstituted 5 to 20 membered heteroaryl. R³ may be

3C 3 3C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R - substituted or unsubstituted 5 or 6 membered heteroaryl. R³ may be R^3C-substituted 5 or 6 membered heteroaryl.

[0202] R³ may be halogen, -OR^3A, 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. R³ may be -OR^3A.

[0203] R^3A may be substituted or unsubstituted alkyl. R^3A may be substituted alkyl. R^3A may be unsubstituted alkyl. R^3A may be substituted or unsubstituted C1-C2₀ alkyl. R^3A may be substituted C1-C2₀ alkyl. R^3A may be substituted or unsubstituted C1-C1₀ alkyl. R^3A may be substituted C1-C10 alkyl. R^3A may be substituted or unsubstituted C1-C5 alkyl. R^3A may be substituted C1-C5 alkyl. R^3A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0204] R^3A may be R^3C-substituted or unsubstituted alkyl. R^3A may be R^3C-substituted alkyl.

_R3A

may be R^3C-substituted or unsubstituted C1-C2₀ alkyl. R^3A may be R^3C-substituted C1-C2₀ alkyl. R^3A may be R^3C-substituted or unsubstituted C1-C10 alkyl. R^3A may be R^3C-substituted Ci- C1₀ alkyl. R^3A may be R^3C-substituted or unsubstituted C1-C5 alkyl. R^3A may be R^3C-substituted

3A. 3C 3C

C1-C5 alkyl. R may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl.

[0205] R^3A may be substituted or unsubstituted heteroalkyl. R^3A may be substituted heteroalkyl. R^3A may be unsubstituted heteroalkyl. R^3A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^3A may be substituted 2 to 20 membered heteroalkyl. R^3A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R may be substituted 2 to 10 membered heteroalkyl. R^3A may be substituted or unsubstituted 2 to 6 membered heteroalkyl.

_R3A

may be substituted 2 to 6 membered heteroalkyl.

[0206] R^3A may be R^3C-substituted or unsubstituted heteroalkyl. R^3A may be R^3C-substituted heteroalkyl. R^3A may be R^3C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R^3A may

3C 3 A 3C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R^3A may be R^3C-substituted 2 to 10 membered heteroalkyl. R^3A may

3C 3A 3C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl. [0207] R^3A may be substituted or unsubstituted cycloalkyl. R^3A may be substituted cycloalkyl.

_R3A

may be unsubstituted cycloalkyl. R^3A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^3A may be substituted 3 to 20 membered cycloalkyl. R^3A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^3A may be substituted 3 to 10 membered cycloalkyl. R^3A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^3A may be substituted 3 to 6 membered cycloalkyl.

[0208] R^3A may be R^3C-substituted or unsubstituted cycloalkyl. R^3A may be R^3C-substituted cycloalkyl. R^3A may be R^3C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R^3A may be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10 membered cycloalkyl. R^3A may be R^3C-substituted 3 to 10 membered cycloalkyl. R^3A may

3C 3A 3C

be R -substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0209] R^3A may be substituted or unsubstituted heterocycloalkyl. R^3A may be substituted heterocycloalkyl. R^3A may be unsubstituted heterocycloalkyl. R^3A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^3A may be substituted 3 to 20 membered heterocycloalkyl. R^3A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl.

_R3A

may be substituted 3 to 10 membered heterocycloalkyl. R^3A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^3A may be substituted 3 to 6 membered heterocycloalkyl.

[0210] R^3A may be R^3C-substituted or unsubstituted heterocycloalkyl. R^3A may be R^3C- substituted heterocycloalkyl. R^3A may be R^3C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^3A may be R^3C-substituted 3 to 20 membered heterocycloalkyl. R^3A may be R -substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to 10 membered heterocycloalkyl. R^3A may be R^3C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^3A may be R^3C-substituted 3 to 6 membered heterocycloalkyl.

[0211] R^3A may be substituted or unsubstituted aryl. R^3A may be substituted aryl. R^3A may be unsubstituted aryl. R^3A may be substituted or unsubstituted 5 to 20 membered aryl. R^3A may be substituted 5 to 20 membered aryl. R^3A may be substituted or unsubstituted 5 to 8 membered aryl. R^3A may be substituted 5 to 8 membered aryl. R^3A may be substituted or unsubstituted 5 or 6 membered aryl. R^3A may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0212] R^3A may be R^3C-substituted or unsubstituted aryl. R^3A may be R^3C-substituted aryl. R^3A

3C 3A 3C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R^3A may be R^3C-substituted or unsubstituted 5 to 8 membered aryl. R^3A may

3C 3A 3C

be R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R^3A may be R^3C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0213] R^3A may be substituted or unsubstituted heteroaryl. R^3A may be substituted heteroaryl. R^3A may be unsubstituted heteroaryl. R^3A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^3A may be substituted 5 to 20 membered heteroaryl. R^3A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^3A may be substituted 5 to 8 membered heteroaryl.

_R3A

may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^3A may be substituted 5 or 6 membered heteroaryl. [0214] R^3A may be R^3C-substituted or unsubstituted heteroaryl. R^3A may be R^3C-substituted heteroaryl. R^3A may be R^3C-substituted or unsubstituted 5 to 20 membered heteroaryl. R^3A may

3C 3A 3C

be R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 membered heteroaryl. R^3A may be R^3C-substituted 5 to 8 membered heteroaryl. R^3A may be R -substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl. R^3A may be hydrogen or unsubstituted alkyl. R^3A is hydrogen or methyl.

3A 3C 3C

[0215] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R^3C-substituted or unsubstituted aryl, or R^3C-substituted or unsubstituted heteroaryl.

3A 3C 3C

[0216] R may be hydrogen, -Si(CH₃)₃, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl where R^3C is as described herein. R^3A may be hydrogen or -Si(CH₃)₃. R^3A may be hydrogen. R^3A may be -Si(CH₃)₃.

[0217] R may be hydrogen, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R^3C-substituted or unsubstituted aryl, R^3C-substituted or unsubstituted heteroaryl where R^3C is as described herein.

[0218] R^3B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂,

-NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^3B may independently be 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^3B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^3B may independently be hydrogen. R^3B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl.

[0219] R^3C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^3D-substituted or unsubstituted alkyl, R^3D-substituted or unsubstituted heteroalkyl, R^3D-substituted or unsubstituted cycloalkyl, R^3D-substituted or unsubstituted heterocycloalkyl, R^3D-substituted or unsubstituted aryl, or R^3D-substituted or unsubstituted heteroaryl.

[0220] R^3D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0221] R⁴ may be substituted or unsubstituted alkyl. R⁴ may be substituted alkyl. R⁴ may be unsubstituted alkyl. R⁴ may be substituted or unsubstituted Ci-C₂o alkyl. R⁴ may be substituted Ci-C₂o alkyl. R⁴ may be substituted or unsubstituted C1-C1₀ alkyl. R⁴ may be substituted C1-C1₀ alkyl. R⁴ may be substituted or unsubstituted C1-C5 alkyl. R⁴ may be substituted C1-C5 alkyl. R⁴ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0222] R⁴ may be R^4C-substituted or unsubstituted alkyl. R⁴ may be R^4C-substituted alkyl. R⁴ may be R^4C-substituted or unsubstituted C1-C2₀ alkyl. R⁴ may be R^4C-substituted C1-C2₀ alkyl. R⁴ may be R^4C-substituted or unsubstituted C1-C10 alkyl. R⁴ may be R^4C-substituted C1-C10 alkyl. R⁴ may be R^4C-substituted or unsubstituted C1-C5 alkyl. R⁴ may be R^4C-substituted C1-C5 alkyl. R⁴ may be methyl, R^4C-substituted or unsubstituted ethyl, or R^4C-substituted or unsubstituted propyl.

[0223] R⁴ may be substituted or unsubstituted heteroalkyl. R⁴ may be substituted heteroalkyl. R⁴ may be unsubstituted heteroalkyl. R⁴ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁴ may be substituted 2 to 20 membered heteroalkyl. R⁴ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁴ may be substituted 2 to 10 membered heteroalkyl. R⁴ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁴ may be substituted 2 to 6 membered heteroalkyl.

[0224] R⁴ may be R^4C-substituted or unsubstituted heteroalkyl. R⁴ may be R^4C-substituted heteroalkyl. R⁴ may be R^4C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁴ may

4C 4 4C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁴ may be R^4C-substituted 2 to 10 membered heteroalkyl. R⁴ may be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl. [0225] R⁴ may be substituted or unsubstituted cycloalkyl. R⁴ may be substituted cycloalkyl. R⁴ may be unsubstituted cycloalkyl. R⁴ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁴ may be substituted 3 to 20 membered cycloalkyl. R⁴ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁴ may be substituted 3 to 10 membered cycloalkyl. R⁴ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁴ may be substituted 3 to 6 membered cycloalkyl.

[0226] R⁴ may be R^4C-substituted or unsubstituted cycloalkyl. R⁴ may be R^4C-substituted cycloalkyl. R⁴ may be R^4C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁴ may be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁴ may be R^4C-substituted 3 to 10 membered cycloalkyl. R⁴ may be R^4C- substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁴ may be R^4C-substituted 3 to 6 membered cycloalkyl. [0227] R⁴ may be substituted or unsubstituted heterocycloalkyl. R⁴ may be substituted heterocycloalkyl. R⁴ may be unsubstituted heterocycloalkyl. R⁴ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R⁴ may be substituted 3 to 20 membered heterocycloalkyl. R⁴ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁴ may be substituted 3 to 10 membered heterocycloalkyl. R⁴ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁴ may be substituted 3 to 6 membered heterocycloalkyl.

[0228] R⁴ may be R^4C-substituted or unsubstituted heterocycloalkyl. R⁴ may be R^4C-substituted heterocycloalkyl. R⁴ may be R^4C-substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R⁴ may be R^4C-substituted 3 to 20 membered heterocycloalkyl. R⁴ may be R^4C- substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁴ may be R^4C-substituted 3 to 10 membered heterocycloalkyl. R⁴ may be R^4C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁴ may be R^4C-substituted 3 to 6 membered heterocycloalkyl.

[0229] R⁴ may be substituted or unsubstituted aryl. R⁴ may be substituted aryl. R⁴ may be unsubstituted aryl. R⁴ may be substituted or unsubstituted 5 to 20 membered aryl. R⁴ may be substituted 5 to 20 membered aryl. R⁴ may be substituted or unsubstituted 5 to 8 membered aryl. R⁴ may be substituted 5 to 8 membered aryl. R⁴ may be substituted or unsubstituted 5 or 6 membered aryl. R⁴ may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0230] R⁴ may be R^4C-substituted or unsubstituted aryl. R⁴ may be R^4C-substituted aryl. R⁴ may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R⁴ may be R^4C-substituted or unsubstituted 5 to 8 membered aryl. R⁴ may be

4C 4 4C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R⁴ may be R^4C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0231] R⁴ may be substituted or unsubstituted heteroaryl. R⁴ may be substituted heteroaryl. R⁴ may be unsubstituted heteroaryl. R⁴ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R⁴ may be substituted 5 to 20 membered heteroaryl. R⁴ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R⁴ may be substituted 5 to 8 membered heteroaryl. R⁴ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R⁴ may be substituted 5 or 6 membered heteroaryl.

[0232] R⁴ may be R^4C-substituted or unsubstituted heteroaryl. R⁴ may be R^4C-substituted heteroaryl. R⁴ may be R^4C-substituted or unsubstituted 5 to 20 membered heteroaryl. R⁴ may be

4C 4 4C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 membered heteroaryl. R⁴ may be R^4C-substituted 5 to 8 membered heteroaryl. R⁴ may be R^4C- substituted or unsubstituted 5 or 6 membered heteroaryl. R⁴ may be R^4C-substituted 5 or 6 membered heteroaryl.

[0233] R⁴ may be hydrogen, -OR^4A, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. R⁴ may be hydrogen, -OR^4A, R^4C-substituted or unsubstituted aryl, R^4C- substituted or unsubstituted heteroaryl, R^4C-substituted or unsubstituted cycloalkyl or R^4C- substituted or unsubstituted heterocycloalkyl. R⁴ may be hydrogen, -OR^4A, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl, R^4C-substituted or unsubstituted cycloalkyl or R^4C-substituted or unsubstituted heterocycloalkyl.

[0234] R^4A may be substituted or unsubstituted alkyl. R^4A may be substituted alkyl. R^4A may be unsubstituted alkyl. R^4A may be substituted or unsubstituted C1-C2₀ alkyl. R^4A may be substituted C1-C2₀ alkyl. R^4A may be substituted or unsubstituted C1-C1₀ alkyl. R^4A may be substituted C1-C1₀ alkyl. R^4A may be substituted or unsubstituted C1-C5 alkyl. R^4A may be substituted C1-C5 alkyl. R^4A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R^4A may be methyl. R^4A may be hydrogen.

[0235] R^4A may be R^4C-substituted or unsubstituted alkyl. R^4A may be R^4C-substituted alkyl. R^4A may be R^4C-substituted or unsubstituted C1-C2₀ alkyl. R^4A may be R^4C-substituted C1-C2₀ alkyl. R^4A may be R^4C-substituted or unsubstituted C1-C1₀ alkyl. R^4A may be R^4C-substituted Ci- Cio alkyl. R^4A may be R^4C-substituted or unsubstituted C1-C5 alkyl. R^4A may be R^4C-substituted C1-C5 alkyl. R^4A may be methyl, R^4C-substituted or unsubstituted ethyl, or R^4C-substituted or unsubstituted propyl.

[0236] R^4A may be substituted or unsubstituted heteroalkyl. R^4A may be substituted heteroalkyl. R^4A may be unsubstituted heteroalkyl. R^4A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^4A may be substituted 2 to 20 membered heteroalkyl. R^4A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^4A may be substituted 2 to 10 membered heteroalkyl. R^4A may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R^4A may be substituted 2 to 6 membered heteroalkyl.

[0237] R^4A may be R^4C-substituted or unsubstituted heteroalkyl. R^4A may be R^4C-substituted heteroalkyl. R^4A may be R^4C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R^4A may be R^4C-substituted 2 to 20 membered heteroalkyl. R^4A may be R^4C-substituted or unsubstituted 2 to 10 membered heteroalkyl. R may be R -substituted 2 to 10 membered heteroalkyl. R may be R^4C-substituted or unsubstituted 2 to 6 membered heteroalkyl. R^4A may be R^4C-substituted 2 to 6 membered heteroalkyl.

[0238] R^4A may be substituted or unsubstituted cycloalkyl. R^4A may be substituted cycloalkyl. R^4A may be unsubstituted cycloalkyl. R^4A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^4A may be substituted 3 to 20 membered cycloalkyl. R^4A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^4A may be substituted 3 to 10 membered cycloalkyl. R^4A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^4A may be substituted 3 to 6 membered cycloalkyl. [0239] R^4A may be R^4C-substituted or unsubstituted cycloalkyl. R^4A may be R^4C-substituted cycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R^4A may be R^4C-substituted 3 to 20 membered cycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 10 membered cycloalkyl. R^4A may be R^4C-substituted 3 to 10 membered cycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 6 membered cycloalkyl. R^4A may be R^4C-substituted 3 to 6 membered cycloalkyl.

[0240] R^4A may be substituted or unsubstituted heterocycloalkyl. R^4A may be substituted heterocycloalkyl. R^4A may be unsubstituted heterocycloalkyl. R^4A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^4A may be substituted 3 to 20 membered heterocycloalkyl. R^4A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^4A may be substituted 3 to 10 membered heterocycloalkyl. R^4A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^4A may be substituted 3 to 6 membered heterocycloalkyl.

[0241] R^4A may be R^4C-substituted or unsubstituted heterocycloalkyl. R^4A may be R^4C- substituted heterocycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^4A may be R^4C-substituted 3 to 20 membered heterocycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^4A may be R^4C-substituted 3 to 10 membered heterocycloalkyl. R^4A may be R^4C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^4A may be R^4C-substituted 3 to 6 membered heterocycloalkyl.

[0242] R^4A may be substituted or unsubstituted aryl. R^4A may be substituted aryl. R^4A may be unsubstituted aryl. R^4A may be substituted or unsubstituted 5 to 20 membered aryl. R^4A may be substituted 5 to 20 membered aryl. R^4A may be substituted or unsubstituted 5 to 8 membered aryl. R may be substituted 5 to 8 membered aryl. R may be substituted or unsubstituted 5 or 6 membered aryl. R^4A may be substituted 5 or 6 membered aryl.

[0243] R^4A may be R^4C-substituted or unsubstituted aryl. R^4A may be R^4C-substituted aryl. R^4A may be R^4C-substituted or unsubstituted 5 to 20 membered aryl. R^4A may be R^4C-substituted 5 to 20 membered aryl. R^4A may be R^4C-substituted or unsubstituted 5 to 8 membered aryl. R^4A may be R^4C-substituted 5 to 8 membered aryl. R^4A may be R^4C-substituted or unsubstituted 5 or 6 membered aryl. R^4A may be R^4C-substituted 5 or 6 membered aryl.

[0244] R^4A may be substituted or unsubstituted heteroaryl. R^4A may be substituted heteroaryl. R^4A may be unsubstituted heteroaryl. R^4A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^4A may be substituted 5 to 20 membered heteroaryl. R^4A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^4A may be substituted 5 to 8 membered heteroaryl. R^4A may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^4A may be substituted 5 or 6 membered heteroaryl.

[0245] R^4A may be R^4C-substituted or unsubstituted heteroaryl. R^4A may be R^4C-substituted heteroaryl. R^4A may be R^4C-substituted or unsubstituted 5 to 20 membered heteroaryl. R^4A may be R^4C-substituted 5 to 20 membered heteroaryl. R^4A may be R^4C-substituted or unsubstituted 5 to 8 membered heteroaryl. R^4A may be R^4C-substituted 5 to 8 membered heteroaryl. R^4A may be R^4C-substituted or unsubstituted 5 or 6 membered heteroaryl. R^4A may be R^4C-substituted 5 or 6 membered heteroaryl. [0246] R^4A may be R^4C-substituted or unsubstituted alkyl, R^4C-substituted or unsubstituted heteroalkyl, R^4C-substituted or unsubstituted cycloalkyl, R^4C-substituted or unsubstituted heterocycloalkyl, R^4C-substituted or unsubstituted aryl, or R^4C-substituted or unsubstituted heteroaryl.

[0247] R^4A may be hydrogen, R^4C-substituted or unsubstituted alkyl, R^4C-substituted or unsubstituted heteroalkyl, R^4C-substituted or unsubstituted cycloalkyl, R^4C-substituted or unsubstituted heterocycloalkyl, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl where R^4C is as described herein.

[0248] R^4A may be R^4C-substituted or unsubstituted alkyl where R^4C is as described herein. R^4A may be R^4C-substituted or unsubstituted alkyl where R^4C is R^4D-substituted or unsubstituted aryl and where R^4D is as described herein. [0249] R^4A may be

, wherein z4 is an integer from 1 to 5. The symbol z4 may be

1 or 2. The symbol z4 may be 0.

[0250] R^4B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂,

-NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^4B may independently be 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^4B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^4B may independently be hydrogen. R^4B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl.

[0251] R^4C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D-substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl.

[0252] R^4D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0253] R⁵ may be substituted or unsubstituted alkyl. R⁵ may be substituted alkyl. R⁵ may be unsubstituted alkyl. R⁵ may be substituted or unsubstituted Ci-C₂o alkyl. R⁵ may be substituted Ci-C₂o alkyl. R⁵ may be substituted or unsubstituted C1-C1₀ alkyl. R⁵ may be substituted C1-C1₀ alkyl. R⁵ may be substituted or unsubstituted C1-C5 alkyl. R⁵ may be substituted C1-C5 alkyl. R⁵ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. [0254] R⁵ may be R^5C-substituted or unsubstituted alkyl. R⁵ may be R^5C-substituted alkyl. R⁵ may be R^5C-substituted or unsubstituted C1-C2₀ alkyl. R⁵ may be R^5C-substituted C1-C2₀ alkyl. R⁵ may be R^5C-substituted or unsubstituted C1-C1₀ alkyl. R⁵ may be R^5C-substituted C1-C1₀ alkyl. R⁵ may be R^5C-substituted or unsubstituted C1-C5 alkyl. R⁵ may be R^5C-substituted C1-C5 alkyl. R⁵ may be methyl, R^5C-substituted or unsubstituted ethyl, or R^5C-substituted or unsubstituted propyl.

[0255] R⁵ may be substituted or unsubstituted heteroalkyl. R⁵ may be substituted heteroalkyl. R⁵ may be unsubstituted heteroalkyl. R⁵ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁵ may be substituted 2 to 20 membered heteroalkyl. R⁵ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁵ may be substituted 2 to 10 membered heteroalkyl. R⁵ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁵ may be substituted 2 to 6 membered heteroalkyl.

[0256] R⁵ may be R^5C-substituted or unsubstituted heteroalkyl. R⁵ may be R^5C-substituted heteroalkyl. R⁵ may be R^5C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁵ may be R^5C-substituted 2 to 20 membered heteroalkyl. R⁵ may be R^5C-substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁵ may be R^5C-substituted 2 to 10 membered heteroalkyl. R⁵ may be R^5C-substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁵ may be R^5C-substituted 2 to 6 membered heteroalkyl.

[0257] R⁵ may be substituted or unsubstituted cycloalkyl. R⁵ may be substituted cycloalkyl. R⁵ may be unsubstituted cycloalkyl. R⁵ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁵ may be substituted 3 to 20 membered cycloalkyl. R⁵ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁵ may be substituted 3 to 10 membered cycloalkyl. R⁵ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁵ may be substituted 3 to 6 membered cycloalkyl.

[0258] R⁵ may be R^5C-substituted or unsubstituted cycloalkyl. R⁵ may be R^5C-substituted cycloalkyl. R⁵ may be R^5C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁵ may be R^5C-substituted 3 to 20 membered cycloalkyl. R⁵ may be R^5C-substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁵ may be R^5C-substituted 3 to 10 membered cycloalkyl. R⁵ may be R^5C- substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁵ may be R^5C-substituted 3 to 6 membered cycloalkyl. [0259] R⁵ may be substituted or unsubstituted heterocycloalkyl. R⁵ may be substituted heterocycloalkyl. R⁵ may be unsubstituted heterocycloalkyl. R⁵ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R⁵ may be substituted 3 to 20 membered heterocycloalkyl. R⁵ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁵ may be substituted 3 to 10 membered heterocycloalkyl. R⁵ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁵ may be substituted 3 to 6 membered heterocycloalkyl. [0260] R⁵ may be R^5C-substituted or unsubstituted heterocycloalkyl. R⁵ may be R^5C-substituted heterocycloalkyl. R⁵ may be R^5C-substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R⁵ may be R^5C-substituted 3 to 20 membered heterocycloalkyl. R⁵ may be R^5C- substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁵ may be R^5C-substituted 3 to 10 membered heterocycloalkyl. R⁵ may be R^5C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁵ may be R^5C-substituted 3 to 6 membered heterocycloalkyl.

[0261] R⁵ may be substituted or unsubstituted aryl. R⁵ may be substituted aryl. R⁵ may be unsubstituted aryl. R⁵ may be substituted or unsubstituted 5 to 20 membered aryl. R⁵ may be substituted 5 to 20 membered aryl. R⁵ may be substituted or unsubstituted 5 to 8 membered aryl. R⁵ may be substituted 5 to 8 membered aryl. R⁵ may be substituted or unsubstituted 5 or 6 membered aryl. R⁵ may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0262] R⁵ may be R^5C-substituted or unsubstituted aryl. R⁵ may be R^5C-substituted aryl. R⁵ may be R^5C-substituted or unsubstituted 5 to 20 membered aryl. R⁵ may be R^5C-substituted 5 to 20 membered aryl. R⁵ may be R^5C-substituted or unsubstituted 5 to 8 membered aryl. R⁵ may be R^5C-substituted 5 to 8 membered aryl. R⁵ may be R^5C-substituted or unsubstituted 5 or 6 membered aryl. R⁵ may be R^5C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0263] R⁵ may be substituted or unsubstituted heteroaryl. R⁵ may be substituted heteroaryl. R⁵ may be unsubstituted heteroaryl. R⁵ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R⁵ may be substituted 5 to 20 membered heteroaryl. R⁵ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R⁵ may be substituted 5 to 8 membered heteroaryl. R⁵ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R⁵ may be substituted 5 or 6 membered heteroaryl.

[0264] R⁵ may be R^5C-substituted or unsubstituted heteroaryl. R⁵ may be R^5C-substituted heteroaryl. R⁵ may be R^5C-substituted or unsubstituted 5 to 20 membered heteroaryl. R⁵ may be R^5C-substituted 5 to 20 membered heteroaryl. R⁵ may be R^5C-substituted or unsubstituted 5 to 8 membered heteroaryl. R⁵ may be R^5C-substituted 5 to 8 membered heteroaryl. R⁵ may be R^5C- substituted or unsubstituted 5 or 6 membered heteroaryl. R⁵ may be R^5C-substituted 5 or 6 membered heteroaryl.

[0265] R^5A may be substituted or unsubstituted alkyl. R^5A may be substituted alkyl. R^5A may be unsubstituted alkyl. R^5A may be substituted or unsubstituted C1-C2₀ alkyl. R^5A may be substituted C1-C20 alkyl. R^5A may be substituted or unsubstituted C1-C10 alkyl. R^5A may be substituted C1-C1₀ alkyl. R^5A may be substituted or unsubstituted C1-C5 alkyl. R^5A may be substituted C1-C5 alkyl. R^5A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0266] R^5A may be R^5C-substituted or unsubstituted alkyl. R^5A may be R^5C-substituted alkyl. R^5A may be R^5C-substituted or unsubstituted C1-C2₀ alkyl. R^5A may be R^5C-substituted C1-C2₀ alkyl. R^5A may be R^5C-substituted or unsubstituted C1-C1₀ alkyl. R^5A may be R^5C-substituted Ci- C1₀ alkyl. R^5A may be R^5C-substituted or unsubstituted C1-C5 alkyl. R^5A may be R^5C-substituted C1-C5 alkyl. R^5A may be methyl, R^5C-substituted or unsubstituted ethyl, or R^5C-substituted or unsubstituted propyl. [0267] R^5A may be substituted or unsubstituted heteroalkyl. R^5A may be substituted heteroalkyl. R^5A may be unsubstituted heteroalkyl. R^5A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^5A may be substituted 2 to 20 membered heteroalkyl. R^5A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^5A may be substituted 2 to 10 membered heteroalkyl. R^5A may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R^5A may be substituted 2 to 6 membered heteroalkyl.

[0268] R^5A may be R^5C-substituted or unsubstituted heteroalkyl. R^5A may be R^5C-substituted heteroalkyl. R^5A may be R^5C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R^5A may be R^5C-substituted 2 to 20 membered heteroalkyl. R^5A may be R^5C-substituted or unsubstituted 2 to 10 membered heteroalkyl. R^5A may be R^5C-substituted 2 to 10 membered heteroalkyl. R^5A may be R^5C-substituted or unsubstituted 2 to 6 membered heteroalkyl. R^5A may be R^5C-substituted 2 to 6 membered heteroalkyl.

[0269] R^5A may be substituted or unsubstituted cycloalkyl. R^5A may be substituted cycloalkyl. R^5A may be unsubstituted cycloalkyl. R^5A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^5A may be substituted 3 to 20 membered cycloalkyl. R^5A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^5A may be substituted 3 to 10 membered cycloalkyl. R may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be substituted 3 to 6 membered cycloalkyl.

[0270] R^5A may be R^5C-substituted or unsubstituted cycloalkyl. R^5A may be R^5C-substituted cycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R^5A may be R^5C-substituted 3 to 20 membered cycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 10 membered cycloalkyl. R^5A may be R^5C-substituted 3 to 10 membered cycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 6 membered cycloalkyl. R^5A may be R^5C-substituted 3 to 6 membered cycloalkyl.

[0271] R^5A may be substituted or unsubstituted heterocycloalkyl. R^5A may be substituted heterocycloalkyl. R^5A may be unsubstituted heterocycloalkyl. R^5A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^5A may be substituted 3 to 20 membered heterocycloalkyl. R^5A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^5A may be substituted 3 to 10 membered heterocycloalkyl. R^5A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^5A may be substituted 3 to 6 membered heterocycloalkyl.

[0272] R^5A may be R^5C-substituted or unsubstituted heterocycloalkyl. R^5A may be R^5C- substituted heterocycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^5A may be R^5C-substituted 3 to 20 membered heterocycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^5A may be R^5C-substituted 3 to 10 membered heterocycloalkyl. R^5A may be R^5C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^5A may be R^5C-substituted 3 to 6 membered heterocycloalkyl.

[0273] R^5A may be substituted or unsubstituted aryl. R^5A may be substituted aryl. R^5A may be unsubstituted aryl. R^5A may be substituted or unsubstituted 5 to 20 membered aryl. R^5A may be substituted 5 to 20 membered aryl. R^5A may be substituted or unsubstituted 5 to 8 membered aryl. R^5A may be substituted 5 to 8 membered aryl. R^5A may be substituted or unsubstituted 5 or 6 membered aryl. R^5A may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0274] R^5A may be R^5C-substituted or unsubstituted aryl. R^5A may be R^5C-substituted aryl. R^5A may be R^5C-substituted or unsubstituted 5 to 20 membered aryl. R^5A may be R^5C-substituted 5 to 20 membered aryl. R^5A may be R^5C-substituted or unsubstituted 5 to 8 membered aryl. R^5A may be R^5C-substituted 5 to 8 membered aryl. R^5A may be R^5C-substituted or unsubstituted 5 or 6 membered aryl. R^5A may be R^5C-substituted 5 or 6 membered aryl (e.g. phenyl). [0275] R may be substituted or unsubstituted heteroaryl. R may be substituted heteroaryl. R^5A may be unsubstituted heteroaryl. R^5A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^5A may be substituted 5 to 20 membered heteroaryl. R^5A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^5A may be substituted 5 to 8 membered heteroaryl. R^5A may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^5A may be substituted 5 or 6 membered heteroaryl.

[0276] R^5A may be R^5C-substituted or unsubstituted heteroaryl. R^5A may be R^5C-substituted heteroaryl. R^5A may be R^5C-substituted or unsubstituted 5 to 20 membered heteroaryl. R^5A may be R^5C-substituted 5 to 20 membered heteroaryl. R^5A may be R^5C-substituted or unsubstituted 5 to 8 membered heteroaryl. R^5A may be R^5C-substituted 5 to 8 membered heteroaryl. R^5A may be R^5C-substituted or unsubstituted 5 or 6 membered heteroaryl. R^5A may be R^5C-substituted 5 or 6 membered heteroaryl.

[0277] R^5A may be R^5C-substituted or unsubstituted alkyl, R^5C-substituted or unsubstituted heteroalkyl, R^5C-substituted or unsubstituted cycloalkyl, R^5C-substituted or unsubstituted heterocycloalkyl, R^5C-substituted or unsubstituted aryl, or R^5C-substituted or unsubstituted heteroaryl.

[0278] R^5A may be hydrogen, R^5C-substituted or unsubstituted alkyl, R^5C-substituted or unsubstituted heteroalkyl, R^5C-substituted or unsubstituted cycloalkyl, R^5C-substituted or unsubstituted heterocycloalkyl, R^5C-substituted or unsubstituted aryl, R^5C-substituted or unsubstituted heteroaryl where R^5C is as described herein.

[0279] R^4A may be hydrogen, R^4C-substituted or unsubstituted alkyl, R^4C-substituted or unsubstituted heteroalkyl, R^4C-substituted or unsubstituted cycloalkyl, R^4C-substituted or unsubstituted heterocycloalkyl, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl where R is as described herein and R may be hydrogen, R - substituted or unsubstituted alkyl, R^5C-substituted or unsubstituted heteroalkyl, R^5C-substituted or unsubstituted cycloalkyl, R^5C-substituted or unsubstituted heterocycloalkyl, R^5C-substituted or unsubstituted aryl, R^5C-substituted or unsubstituted heteroaryl where R^5C is as described herein.

[0280] R^5A may be R^5C-substituted or unsubstituted alkyl where R^5C is as described herein. R^5A may be R^5C-substituted or unsubstituted alkyl where R^5C is R^5D-substituted or unsubstituted aryl and where R^5D is as described herein. [0281] R may be R -substituted or unsubstituted alkyl where R is as described herein. R may be R^4C-substituted or unsubstituted alkyl where R^4C is R^4D-substituted or unsubstituted aryl and where R^4D is as described herein and R^5A may be R^5C-substituted or unsubstituted alkyl

5C 5A. 5C 5C where R is as described herein. R may be R -substituted or unsubstituted alkyl where R is R^5D-substituted or unsubstituted aryl and where R^5D is as described herein.

[0282]

, where z5 is an integer from 1 to 5. The symbol z5 may be 1 or 2. The symbol z5 may be 0. 4^A may be

, where z4 is an integer from 1 to 5 and R^SA may be

, where z5 is an integer from 1 to 5. The symbol z4 may be 1 or 2 and z5 may be 1 or 2. The symbols z4 and z5 may be 0.

[0284] R^5B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂,

-NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^5B may independently be 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^5B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^5B may independently be hydrogen. R^5B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl.

[0285] R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D-substituted or unsubstituted alkyl, R^5D-substituted or unsubstituted heteroalkyl, R^5D-substituted or unsubstituted cycloalkyl, R^5D-substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted

> 5D

aryl, or R -substituted or unsubstituted heteroaryl. [0286] R^3U is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0287] R⁶ may be substituted or unsubstituted alkyl. R⁶ may be substituted alkyl. R⁶ may be unsubstituted alkyl. R⁶ may be substituted or unsubstituted Ci-C₂o alkyl. R⁶ may be substituted Ci-C₂o alkyl. R⁶ may be substituted or unsubstituted Ci-Cio alkyl. R⁶ may be substituted Ci-Cio alkyl. R⁶ may be substituted or unsubstituted C1-C5 alkyl. R⁶ may be substituted C1-C5 alkyl. R⁶ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R⁶ may be hydrogen, methyl, ethyl or propyl. R⁶ may be hydrogen. R⁶ may be methyl.

[0288] R⁶ may be R^6C-substituted or unsubstituted alkyl. R⁶ may be R^6C-substituted alkyl. R⁶ may be R^6C-substituted or unsubstituted Ci-C₂o alkyl. R⁶ may be R^6C-substituted Ci-C₂o alkyl. R⁶ may be R^6C-substituted or unsubstituted C1-C10 alkyl. R⁶ may be R^6C-substituted C1-C10 alkyl. R⁶ may be R^6C-substituted or unsubstituted C1-C5 alkyl. R⁶ may be R^6C-substituted C1-C5 alkyl. R⁶ may be methyl, R^6C-substituted or unsubstituted ethyl, or R^6C-substituted or unsubstituted propyl.

[0289] R⁶ may be substituted or unsubstituted heteroalkyl. R⁶ may be substituted heteroalkyl. R⁶ may be unsubstituted heteroalkyl. R⁶ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁶ may be substituted 2 to 20 membered heteroalkyl. R⁶ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁶ may be substituted 2 to 10 membered heteroalkyl. R⁶ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁶ may be substituted 2 to 6 membered heteroalkyl.

[0290] R⁶ may be R^6C-substituted or unsubstituted heteroalkyl. R⁶ may be R^6C-substituted heteroalkyl. R⁶ may be R^6C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁶ may be R^6C-substituted 2 to 20 membered heteroalkyl. R⁶ may be R^6C-substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁶ may be R^6C-substituted 2 to 10 membered heteroalkyl. R⁶ may be R^6C-substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁶ may be R^6C-substituted 2 to 6 membered heteroalkyl.

[0291] R⁶ may be substituted or unsubstituted cycloalkyl. R⁶ may be substituted cycloalkyl. R⁶ may be unsubstituted cycloalkyl. R⁶ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁶ may be substituted 3 to 20 membered cycloalkyl. R⁶ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁶ may be substituted 3 to 10 membered cycloalkyl. R⁶ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁶ may be substituted 3 to 6 membered cycloalkyl.

[0292] R⁶ may be R^6C-substituted or unsubstituted cycloalkyl. R⁶ may be R^6C-substituted cycloalkyl. R⁶ may be R^6C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁶ may be R^6C-substituted 3 to 20 membered cycloalkyl. R⁶ may be R^6C-substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁶ may be R^6C-substituted 3 to 10 membered cycloalkyl. R⁶ may be R^6C- substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁶ may be R^6C-substituted 3 to 6 membered cycloalkyl. [0293] R⁶ may be substituted or unsubstituted heterocycloalkyl. R⁶ may be substituted heterocycloalkyl. R⁶ may be unsubstituted heterocycloalkyl. R⁶ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R⁶ may be substituted 3 to 20 membered heterocycloalkyl. R⁶ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁶ may be substituted 3 to 10 membered heterocycloalkyl. R⁶ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁶ may be substituted 3 to 6 membered heterocycloalkyl.

[0294] R⁶ may be R^6C-substituted or unsubstituted heterocycloalkyl. R⁶ may be R^6C-substituted heterocycloalkyl. R⁶ may be R^6C-substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R⁶ may be R^6C-substituted 3 to 20 membered heterocycloalkyl. R⁶ may be R^6C- substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁶ may be R^6C-substituted 3 to 10 membered heterocycloalkyl. R⁶ may be R^6C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁶ may be R^6C-substituted 3 to 6 membered heterocycloalkyl.

[0295] R⁶ may be substituted or unsubstituted aryl. R⁶ may be substituted aryl. R⁶ may be unsubstituted aryl. R⁶ may be substituted or unsubstituted 5 to 20 membered aryl. R⁶ may be substituted 5 to 20 membered aryl. R⁶ may be substituted or unsubstituted 5 to 8 membered aryl. R⁶ may be substituted 5 to 8 membered aryl. R⁶ may be substituted or unsubstituted 5 or 6 membered aryl. R⁶ may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0296] R⁶ may be R^6C-substituted or unsubstituted aryl. R⁶ may be R^6C-substituted aryl. R⁶ may be R^6C-substituted or unsubstituted 5 to 20 membered aryl. R⁶ may be R^6C-substituted 5 to 20 membered aryl. R⁶ may be R^6C-substituted or unsubstituted 5 to 8 membered aryl. R⁶ may be R^6C-substituted 5 to 8 membered aryl. R⁶ may be R^6C-substituted or unsubstituted 5 or 6 membered aryl. R⁶ may be R^6C-substituted 5 or 6 membered aryl (e.g. phenyl). [0297] R⁶ may be substituted or unsubstituted heteroaryl. R⁶ may be substituted heteroaryl. R⁶ may be unsubstituted heteroaryl. R⁶ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R⁶ may be substituted 5 to 20 membered heteroaryl. R⁶ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R⁶ may be substituted 5 to 8 membered heteroaryl. R⁶ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R⁶ may be substituted 5 or 6 membered heteroaryl.

[0298] R⁶ may be R^6C-substituted or unsubstituted heteroaryl. R⁶ may be R^6C-substituted heteroaryl. R⁶ may be R^6C-substituted or unsubstituted 5 to 20 membered heteroaryl. R⁶ may be R^6C-substituted 5 to 20 membered heteroaryl. R⁶ may be R^6C-substituted or unsubstituted 5 to 8 membered heteroaryl. R⁶ may be R^6C-substituted 5 to 8 membered heteroaryl. R⁶ may be R^6C- substituted or unsubstituted 5 or 6 membered heteroaryl. R⁶ may be R^6C-substituted 5 or 6 membered heteroaryl.

[0299] R⁶ may be hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, -NR^6AR^6B, -OR^6A, 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, where R^6A and R^6B are as described herein. R⁶ may be hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, -NR^6AR^6B, -OR^6A, 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, where R^6A is as described herein and R^6B is hydrogen.

[0300] R⁶ may be hydrogen, -C(0)R^6A, -C(0)OR^6A, R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C- substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^6C- substituted or unsubstituted heteroaryl, where R^6A and R^6C are as described herein. R⁶ may be hydrogen, -C(0)R^6A, -C(0)OR^6A, R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroaryl, where R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl and R^6C is as described herein. [0301] R⁶ may be R^6C-substituted or unsubstituted alkyl, where R^6C is as described herein. R⁶ may be R^6C-substituted or unsubstituted alkyl, where R^6C is R^6D-substituted or unsubstituted aryl and R^6D is as described herein.

[0302] R⁶ may be -C(0)OR^6A where R^6A is R^6C-substituted or unsubstituted aryl and R^6C is as described herein. R⁶ may be -C(0)OR^6A where R^6A is as described herein. R⁶ may be -C(0)OR^6A where R^6A is unsubstituted alkyl. R⁶ may be -C(0)OR^6A where R^6A is R^6C-substituted or unsubstituted alkyl and R^6C is unsubstituted alkyl or halogen.

[0303] R⁶ may be hydrogen, unsubstituted C1-C5 alkyl, -C(0)OR^6A or

, where z6 is an integer from 1 to 5 and R^6A and R^6C are as described herein. R⁶ may be hydrogen,

unsubstituted C1-C5 alkyl, -C(0)OR^6A or

, where z6 is an integer from 1 to 5 and

R^6A is R^6C-substituted or unsubstituted alkyl and R^6C is as described herein. The symbol z6 may be 1 or 2.

[0304] R⁶ may be hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, 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 where R^6A is as described herein. R⁶ may be hydrogen, halogen, - C(0)R^6A, -C(0)OR^6A, 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 where R^6A is hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3 to Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C₁₀ aryl or substituted or unsubstituted 5 or 6 membered heteroaryl.

[0305] R⁶ may be hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, 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 where R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroalkyl and R^6C is as described herein. R⁶ may be hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, 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 where R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroalkyl and R^6C is halogen, unsubstituted alkyl or unsubstituted cycloalkyl.

[0306] R⁶ may be hydrogen or R^6C-substituted or unsubstituted Ci to C5 alkyl, where R^6C is hydroxyl, R^6D-substituted or unsubstituted aryl, R^6D-substituted or unsubstituted heteroaryl, R^6D- substituted or unsubstituted cycloalkyl, or R^6D-substituted or unsubstituted heterocycloalkyl and R^6D is as described herein. R⁶ may be hydrogen or R^6C-substituted or unsubstituted Ci to C5 alkyl, where R^6C is hydroxyl, R^6D-substituted or unsubstituted aryl, R^6D-substituted or unsubstituted heteroaryl, R^6D-substituted or unsubstituted cycloalkyl, or R^6D-substituted or unsubstituted heterocycloalkyl and R^6D is halogen or unsubstituted alkyl.

[0307] R^6A may be substituted or unsubstituted alkyl. R^6A may be substituted alkyl. R^6A may be unsubstituted alkyl. R^6A may be substituted or unsubstituted C1-C2₀ alkyl. R^6A may be substituted C1-C2₀ alkyl. R^6A may be substituted or unsubstituted C1-C1₀ alkyl. R^6A may be substituted C1-C10 alkyl. R^6A may be substituted or unsubstituted C1-C5 alkyl. R^6A may be substituted C1-C5 alkyl. R^6A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. [0308] R^6A may be R^6C-substituted or unsubstituted alkyl. R^6A may be R^6C-substituted alkyl.

_R6A

may be R^6C-substituted or unsubstituted C1-C2₀ alkyl. R^6A may be R^6C-substituted C1-C2₀ alkyl. R^6A may be R^6C-substituted or unsubstituted C1-C1₀ alkyl. R^6A may be R^6C-substituted Ci- C1₀ alkyl. R^6A may be R^6C-substituted or unsubstituted C1-C5 alkyl. R^6A may be R^6C-substituted C1-C5 alkyl. R^6A may be methyl, R^6C-substituted or unsubstituted ethyl, or R^6C-substituted or unsubstituted propyl.

[0309] R^6A may be substituted or unsubstituted heteroalkyl. R^6A may be substituted heteroalkyl. R^6A may be unsubstituted heteroalkyl. R^6A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R^6A may be substituted 2 to 20 membered heteroalkyl. R^6A may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^6A may be substituted 2 to 10 membered heteroalkyl. R^6A may be substituted or unsubstituted 2 to 6 membered heteroalkyl.

_R6A

may be substituted 2 to 6 membered heteroalkyl. [0310] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted heteroalkyl. R^6A may be R^6C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R^6A may be R^6C-substituted 2 to 20 membered heteroalkyl. R^6A may be R^6C-substituted or unsubstituted 2 to 10 membered heteroalkyl. R^6A may be R^6C-substituted 2 to 10 membered heteroalkyl. R^6A may be R^6C-substituted or unsubstituted 2 to 6 membered heteroalkyl. R^6A may be R^6C-substituted 2 to 6 membered heteroalkyl.

[0311] R^6A may be substituted or unsubstituted cycloalkyl. R^6A may be substituted cycloalkyl.

_R6A

may be unsubstituted cycloalkyl. R^6A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^6A may be substituted 3 to 20 membered cycloalkyl. R^6A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^6A may be substituted 3 to 10 membered cycloalkyl. R^6A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^6A may be substituted 3 to 6 membered cycloalkyl.

[0312] R^6A may be R^6C-substituted or unsubstituted cycloalkyl. R^6A may be R^6C-substituted cycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R^6A may be R^6C-substituted 3 to 20 membered cycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 10 membered cycloalkyl. R^6A may be R^6C-substituted 3 to 10 membered cycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 6 membered cycloalkyl. R^6A may be R^6C-substituted 3 to 6 membered cycloalkyl.

[0313] R^6A may be substituted or unsubstituted heterocycloalkyl. R^6A may be substituted heterocycloalkyl. R^6A may be unsubstituted heterocycloalkyl. R^6A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^6A may be substituted 3 to 20 membered heterocycloalkyl. R^6A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl.

_R6A

may be substituted 3 to 10 membered heterocycloalkyl. R^6A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^6A may be substituted 3 to 6 membered heterocycloalkyl.

[0314] R^6A may be R^6C-substituted or unsubstituted heterocycloalkyl. R^6A may be R^6C- substituted heterocycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^6A may be R^6C-substituted 3 to 20 membered heterocycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^6A may be R^6C-substituted 3 to 10 membered heterocycloalkyl. R^6A may be R^6C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^6A may be R^6C-substituted 3 to 6 membered heterocycloalkyl. [0315] R may be substituted or unsubstituted aryl. R may be substituted aryl. R may be unsubstituted aryl. R^6A may be substituted or unsubstituted 5 to 20 membered aryl. R^6A may be substituted 5 to 20 membered aryl. R^6A may be substituted or unsubstituted 5 to 8 membered aryl. R^6A may be substituted 5 to 8 membered aryl. R^6A may be substituted or unsubstituted 5 or 6 membered aryl. R^6A may be substituted 5 or 6 membered aryl (e.g. phenyl).

[0316] R^6A may be R^6C-substituted or unsubstituted aryl. R^6A may be R^6C-substituted aryl. R^6A may be R^6C-substituted or unsubstituted 5 to 20 membered aryl. R^6A may be R^6C-substituted 5 to 20 membered aryl. R^6A may be R^6C-substituted or unsubstituted 5 to 8 membered aryl. R^6A may be R^6C-substituted 5 to 8 membered aryl. R^6A may be R^6C-substituted or unsubstituted 5 or 6 membered aryl. R^6A may be R^6C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0317] R^6A may be substituted or unsubstituted heteroaryl. R^6A may be substituted heteroaryl.

_R6A

may be unsubstituted heteroaryl. R^6A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^6A may be substituted 5 to 20 membered heteroaryl. R^6A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^6A may be substituted 5 to 8 membered heteroaryl. R^6A may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^6A may be substituted 5 or 6 membered heteroaryl.

[0318] R^6A may be R^6C-substituted or unsubstituted heteroaryl. R^6A may be R^6C-substituted heteroaryl. R^6A may be R^6C-substituted or unsubstituted 5 to 20 membered heteroaryl. R^6A may be R^6C-substituted 5 to 20 membered heteroaryl. R^6A may be R^6C-substituted or unsubstituted 5 to 8 membered heteroaryl. R^6A may be R^6C-substituted 5 to 8 membered heteroaryl. R^6A may be R^6C-substituted or unsubstituted 5 or 6 membered heteroaryl. R^6A may be R^6C-substituted 5 or 6 membered heteroaryl.

[0319] R^6A may be R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroaryl.

[0320] R^6A may be hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted 3 to 10 membered aryl or substituted or unsubstituted 5 or 6 membered heteroaryl. [0321] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroalkyl where R^6C is as described herein. R^6A may be R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted aryl, or R^6C- substituted or unsubstituted heteroalkyl where R^6C is halogen, unsubstituted alkyl or

unsubstituted cycloalkyl.

[0322] R^6B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂,

-NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)₃. R^6B may independently be 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^6B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R^6B may independently be hydrogen. R^6B may independently be hydrogen, unsubstituted C1-C5 alkyl, or unsubstituted aryl.

[0323] R^6C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D-substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl.

[0324] R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0325] R^6A may be R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl, where R^6C is as described herein. [0326] R⁷ may be substituted or unsubstituted alkyl. R⁷ may be substituted alkyl. R⁷ may be unsubstituted alkyl. R⁷ may be substituted or unsubstituted C1-C2₀ alkyl. R⁷ may be substituted C1-C2₀ alkyl. R⁷ may be substituted or unsubstituted C1-C1₀ alkyl. R⁷ may be substituted C1-C1₀ alkyl. R⁷ may be substituted or unsubstituted C1-C5 alkyl. R⁷ may be substituted C1-C5 alkyl. R⁷ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R⁷ may be hydrogen.

7 7C 7 7C 7

[0327] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

7C 7 7C 7 may be R -substituted or unsubstituted C1-C2₀ alkyl. R may be R -substituted C1-C2₀ alkyl. R

7C 7 7C 7 may be R -substituted or unsubstituted C1-C1₀ alkyl. R may be R -substituted C1-C1₀ alkyl. R may be R -substituted or unsubstituted C1-C5 alkyl. R may be R -substituted C1-C5 alkyl. R may be methyl, R^7C-substituted or unsubstituted ethyl, or R^7C-substituted or unsubstituted propyl.

[0328] R⁷ may be substituted or unsubstituted heteroalkyl. R⁷ may be substituted heteroalkyl. R⁷ may be unsubstituted heteroalkyl. R⁷ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁷ may be substituted 2 to 20 membered heteroalkyl. R⁷ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁷ may be substituted 2 to 10 membered heteroalkyl. R⁷ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R⁷ may be substituted 2 to 6 membered heteroalkyl.

[0329] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted heteroalkyl. R⁷ may be R^7C-substituted or unsubstituted 2 to 20 membered heteroalkyl. R⁷ may

7C 7 7C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R⁷ may be R^7C-substituted 2 to 10 membered heteroalkyl. R⁷ may

7C 7 7C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0330] R⁷ may be substituted or unsubstituted cycloalkyl. R⁷ may be substituted cycloalkyl. R⁷ may be unsubstituted cycloalkyl. R⁷ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁷ may be substituted 3 to 20 membered cycloalkyl. R⁷ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R⁷ may be substituted 3 to 10 membered cycloalkyl. R⁷ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁷ may be substituted 3 to 6 membered cycloalkyl.

7 7C 7 7C

[0331] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted cycloalkyl. R⁷ may be R^7C-substituted or unsubstituted 3 to 20 membered cycloalkyl. R⁷ may be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10

7 7C 7 7C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R - substituted or unsubstituted 3 to 6 membered cycloalkyl. R⁷ may be R^7C-substituted 3 to 6 membered cycloalkyl. [0332] R⁷ may be substituted or unsubstituted heterocycloalkyl. R⁷ may be substituted heterocycloalkyl. R⁷ may be unsubstituted heterocycloalkyl. R⁷ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R⁷ may be substituted 3 to 20 membered heterocycloalkyl. R⁷ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁷ may be substituted 3 to 10 membered heterocycloalkyl. R⁷ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁷ may be substituted 3 to 6 membered heterocycloalkyl.

7 7C 7 7C

[0333] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted heterocycloalkyl. R⁷ may be R^7C-substituted or unsubstituted 3 to 20 membered

7 7C 7 7C heterocycloalkyl. R may be R -substituted 3 to 20 membered heterocycloalkyl. R may be R - substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R⁷ may be R^7C-substituted 3 to 10 membered heterocycloalkyl. R⁷ may be R^7C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R⁷ may be R^7C-substituted 3 to 6 membered heterocycloalkyl.

[0334] R⁷ may be substituted or unsubstituted aryl. R⁷ may be substituted aryl. R⁷ may be unsubstituted aryl. R⁷ may be substituted or unsubstituted 5 to 20 membered aryl. R⁷ may be substituted 5 to 20 membered aryl. R⁷ may be substituted or unsubstituted 5 to 8 membered aryl. R⁷ may be substituted 5 to 8 membered aryl. R⁷ may be substituted or unsubstituted 5 or 6 membered aryl. R⁷ may be substituted 5 or 6 membered aryl (e.g. phenyl).

7 7C 7 7C 7

[0335] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R⁷ may be R^7C-substituted or unsubstituted 5 to 8 membered aryl. R⁷ may be

7C 7 7C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R⁷ may be R^7C-substituted 5 or 6 membered aryl (e.g. phenyl).

[0336] R⁷ may be substituted or unsubstituted heteroaryl. R⁷ may be substituted heteroaryl. R⁷ may be unsubstituted heteroaryl. R⁷ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R⁷ may be substituted 5 to 20 membered heteroaryl. R⁷ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R⁷ may be substituted 5 to 8 membered heteroaryl. R⁷ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R⁷ may be substituted 5 or 6 membered heteroaryl.

[0337] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted heteroaryl. R⁷ may be R^7C-substituted or unsubstituted 5 to 20 membered heteroaryl. R⁷ may be

7C 7 7C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8

7 7C 7 7C membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R - substituted or unsubstituted 5 or 6 membered heteroaryl. R⁷ may be R^7C-substituted 5 or 6 membered heteroaryl.

[0338] R⁷ may be hydrogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^7C-substituted or unsubstituted alkyl,

7C 7C 7C

R -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R - substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C- substituted or unsubstituted heteroaryl where is R^7C-substituted or unsubstituted alkyl, R^7C- substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C- substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C- substituted or unsubstituted heteroaryl and R^7C is as described herein.

[0339] R^7A may be substituted or unsubstituted alkyl. R^7A may be substituted alkyl. R^7A may be unsubstituted alkyl. R^7A may be substituted or unsubstituted Ci-C₂o alkyl. R^7A may be substituted Ci-C₂o alkyl. R^7A may be substituted or unsubstituted Ci-Cio alkyl. R^7A may be substituted Ci-Cio alkyl. R^7A may be substituted or unsubstituted C1-C5 alkyl. R^7A may be substituted C1-C5 alkyl. R^7A may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0340] R^7A may be R^7C-substituted or unsubstituted alkyl. R^7A may be R^7C-substituted alkyl.

7 A 7C 7 A 7C

R may be R -substituted or unsubstituted Ci-C₂o alkyl. R may be R -substituted Ci-C₂o

7 A 7C 7 A 7C

alkyl. R may be R -substituted or unsubstituted C1-C1₀ alkyl. R may be R -substituted Ci-

7 A 7C 7 A 7C

Cio alkyl. R may be R -substituted or unsubstituted C1-C5 alkyl. R may be R -substituted

7A 7C 7C

C1-C5 alkyl. R may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl. [0341] R^7A may be substituted or unsubstituted heteroalkyl. R^7A may be substituted heteroalkyl. R^7A may be unsubstituted heteroalkyl. R^7A may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R may be substituted 2 to 20 membered heteroalkyl. R may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R^7A may be substituted 2 to 10 membered heteroalkyl. R^7A may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R^7A may be substituted 2 to 6 membered heteroalkyl.

7 A 7C 7 A 7C

[0342] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted

7 A 7C 7 A heteroalkyl. R may be R -substituted or unsubstituted 2 to 20 membered heteroalkyl. R may

7C 7A 7C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2

7A 7C 7A to 10 membered heteroalkyl. R may be R -substituted 2 to 10 membered heteroalkyl. R may

7C 7A 7C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0343] R^7A may be substituted or unsubstituted cycloalkyl. R^7A may be substituted cycloalkyl. R^7A may be unsubstituted cycloalkyl. R^7A may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R^7A may be substituted 3 to 20 membered cycloalkyl. R^7A may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R^7A may be substituted 3 to 10 membered cycloalkyl. R^7A may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R^7A may be substituted 3 to 6 membered cycloalkyl.

7A 7C 7A 7C

[0344] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted cycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered cycloalkyl. R may be R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3

7A 7C 7A to 10 membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may

7C 7A 7C

be R -substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0345] R^7A may be substituted or unsubstituted heterocycloalkyl. R^7A may be substituted heterocycloalkyl. R^7A may be unsubstituted heterocycloalkyl. R^7A may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R^7A may be substituted 3 to 20 membered heterocycloalkyl. R^7A may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R^7A may be substituted 3 to 10 membered heterocycloalkyl. R^7A may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^7A may be substituted 3 to 6 membered heterocycloalkyl. [0346] R^7A may be R^7C-substituted or unsubstituted heterocycloalkyl. R^7A may be R^7C- substituted heterocycloalkyl. R^7A may be R^7C-substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R may be R -substituted 3 to 20 membered heterocycloalkyl. R may be

7C 7 A 7C

R -substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to 10 membered heterocycloalkyl. R^7A may be R^7C-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R^7A may be R^7C-substituted 3 to 6 membered heterocycloalkyl. [0347] R^7A may be substituted or unsubstituted aryl. R^7A may be substituted aryl. R^7A may be unsubstituted aryl. R^7A may be substituted or unsubstituted 5 to 20 membered aryl. R^7A may be substituted 5 to 20 membered aryl. R^7A may be substituted or unsubstituted 5 to 8 membered aryl. R^7A may be substituted 5 to 8 membered aryl. R^7A may be substituted or unsubstituted 5 or 6 membered aryl. R^7A may be substituted 5 or 6 membered aryl (e.g. phenyl). [0348] R^7A may be R^7C-substituted or unsubstituted aryl. R^7A may be R^7C-substituted aryl. R^7A

7C 7 A 7C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to

7 A 7C 7 A

20 membered aryl. R may be R -substituted or unsubstituted 5 to 8 membered aryl. R may

7C 7A 7C

be R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6 membered aryl. R^7A may be R^7C-substituted 5 or 6 membered aryl (e.g. phenyl). [0349] R^7A may be substituted or unsubstituted heteroaryl. R^7A may be substituted heteroaryl. R^7A may be unsubstituted heteroaryl. R^7A may be substituted or unsubstituted 5 to 20 membered heteroaryl. R^7A may be substituted 5 to 20 membered heteroaryl. R^7A may be substituted or unsubstituted 5 to 8 membered heteroaryl. R^7A may be substituted 5 to 8 membered heteroaryl. R^7A may be substituted or unsubstituted 5 or 6 membered heteroaryl. R^7A may be substituted 5 or 6 membered heteroaryl.

7A 7C 7A 7C

[0350] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted

7A 7C 7A heteroaryl. R may be R -substituted or unsubstituted 5 to 20 membered heteroaryl. R may be R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be

7C 7A 7C

R -substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

7A 7C 7C

[0351] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C-substituted or unsubstituted heteroaryl. [0352] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C-substituted or unsubstituted heteroaryl, where R^7C is as described herein. [0353] R^7B may independently be hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂,

-NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, or -Si(CH₃)3. R^7B may independently be 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^7B may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0354] R^7C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^7D-substituted or unsubstituted alkyl, R^7D-substituted or unsubstituted heteroalkyl, R^7D-substituted or unsubstituted cycloalkyl, R^7D-substituted or unsubstituted heterocycloalkyl, R^7D-substituted or unsubstituted aryl, or R^7D-substituted or unsubstituted heteroaryl.

[0355] R^7D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0356] L¹ and L² may independently be -0-, -C(0)0-, -C(0)NH-, -NH-, or -S-. L¹ and L² may be -0-. L¹ and L² may be -C(0)0-. L¹ and L² may be -C(0)NH-. L¹ and L² may be -NH-. L¹ and L may be -S-. L¹ and L² may independently be substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0357] L¹ and L² may independently be substituted or unsubstituted alkylene. L¹ and L² may independently be substituted alkyl. L¹ and L² may independently be unsubstituted alkylene. L¹ and L² may independently be substituted or unsubstituted Ci-C₂o alkylene. L¹ and L² may independently be substituted C1-C2₀ alkylene. . L¹ and L² may independently be unsubstituted C1-C2₀ alkylene. L¹ and L² may independently be substituted or unsubstituted C1-C1₀ alkylene. L¹ and L² may independently be substituted C1-C1₀ alkylene. L¹ and L² may independently be unsubstituted C1-C1₀ alkylene. L¹ and L² may independently be substituted or unsubstituted Ci- C5 alkylene. L¹ and L² may independently be substituted C1-C5 alkylene. L¹ and L² may independently be unsubstituted C1-C5 alkylene. L¹ and L² may be substituted -CH₂-.

[0358] L¹ and L² may independently be R⁸-substituted or unsubstituted alkylene. L¹ and L² may independently be R⁸-substituted alkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted C1-C2₀ alkylene. L¹ and L² may independently be R⁸-substituted C1-C2₀ alkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted C1-C1₀ alkylene. L¹ and L² may independently be R⁸-substituted C1-C1₀ alkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted C1-C5 alkylene. L¹ and L² may independently be R⁸-substituted C1-C5 alkylene.

[0359] L¹ and L² may independently be substituted or unsubstituted heteroalkylene. L¹ and L² may independently be substituted heteroalkylene. L¹ and L² may independently be unsubstituted heteroalkylene. L¹ and L² may independently be substituted or unsubstituted 2 to 20 membered heteroalkylene. L¹ and L² may independently be substituted 2 to 20 membered heteroalkylene. L¹ and L² may independently be substituted or unsubstituted 2 to 10 membered heteroalkylene. L¹ and L² may independently be substituted 2 to 10 membered heteroalkylene. L¹ and L² may independently be substituted or unsubstituted 2 to 6 membered heteroalkylene. L¹ and L² may independently be substituted 2 to 6 membered heteroalkylene.

[0360] L¹ and L² may independently be R⁸-substituted or unsubstituted heteroalkylene. L¹ and L² may independently be R⁸-substituted heteroalkylene. L¹ and L² may independently be R⁸- substituted or unsubstituted 2 to 20 membered heteroalkylene. L¹ and L² may independently be R⁸-substituted 2 to 20 membered heteroalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 2 to 10 membered heteroalkylene. L¹ and L² may independently be R⁸- substituted 2 to 10 membered heteroalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 2 to 6 membered heteroalkylene. L¹ and L² may independently be R⁸-substituted 2 to 6 membered heteroalkylene.

[0361] L¹ and L² may independently be substituted or unsubstituted cycloalkylene. L¹ and L² may independently be substituted cycloalkylene. L¹ and L² may independently be unsubstituted cycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 20 membered cycloalkylene. L¹ and L² may independently be substituted 3 to 20 membered cycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 10 membered cycloalkylene. L¹ and L² may independently be substituted 3 to 10 membered cycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 6 membered cycloalkylene. L¹ and L² may independently be substituted 3 to 6 membered cycloalkylene.

[0362] L¹ and L² may independently be R⁸-substituted or unsubstituted cycloalkylene. L¹ and L² may independently be R⁸-substituted cycloalkylene. L¹ and L² may independently be R⁸- substituted or unsubstituted 3 to 20 membered cycloalkylene. L¹ and L² may independently be R⁸-substituted 3 to 20 membered cycloalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 3 to 10 membered cycloalkylene. L¹ and L² may independently be R⁸- substituted 3 to 10 membered cycloalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 3 to 6 membered cycloalkylene. L¹ and L² may independently be R⁸-substituted 3 to 6 membered cycloalkylene.

[0363] L¹ and L² may independently be substituted or unsubstituted heterocycloalkylene. L¹ and L² may independently be substituted heterocycloalkylene. L¹ and L² may independently be unsubstituted heterocycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 20 membered heterocycloalkylene. L¹ and L² may independently be substituted 3 to 20 membered heterocycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 10 membered heterocycloalkylene. L¹ and L² may independently be substituted 3 to 10 membered heterocycloalkylene. L¹ and L² may independently be substituted or unsubstituted 3 to 6 membered heterocycloalkylene. L¹ and L² may independently be substituted 3 to 6 membered heterocycloalkylene.

[0364] L¹ and L² may independently be R⁸-substituted or unsubstituted heterocycloalkylene. L¹ and L² may independently be R⁸-substituted heterocycloalkylene. L¹ and L² may

independently be R⁸-substituted or unsubstituted 3 to 20 membered heterocycloalkylene. L¹ and L² may independently be R⁸-substituted 3 to 20 membered heterocycloalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 3 to 10 membered heterocycloalkylene. L¹ and L² may independently be R⁸-substituted 3 to 10 membered heterocycloalkylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 3 to 6 membered heterocycloalkylene. L¹ and L² may independently be R⁸-substituted 3 to 6 membered heterocycloalkylene. [0365] L¹ and L² may independently be substituted or unsubstituted arylene. L¹ and L² may independently be substituted arylene. L¹ and L² may independently be unsubstituted arylene. L¹ and L² may independently be substituted or unsubstituted 5 to 20 membered arylene. L¹ and L² may independently be substituted 5 to 20 membered arylene. L¹ and L² may independently be substituted or unsubstituted 5 to 8 membered arylene. L¹ and L² may independently be substituted 5 to 8 membered arylene. L¹ and L² may independently be substituted or

unsubstituted 5 or 6 membered aryl(e.g. phenylene). L¹ and L² may independently be substituted 5 or 6 membered arylene (e.g. phenylene).

[0366] L¹ and L² may independently be R⁸-substituted or unsubstituted arylene. L¹ and L² may independently be R⁸-substituted arylene. R⁷ may be R⁸-substituted or unsubstituted 5 to 20 membered arylene. L¹ and L² may independently be R⁸-substituted 5 to 20 membered arylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 5 to 8 membered arylene. L¹ and L² may independently be R⁸-substituted 5 to 8 membered arylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 5 or 6 membered arylene(e.g. phenylene). L¹ and L² may independently be R⁸-substituted 5 or 6 membered arylene (e.g. phenylene).

[0367] L¹ and L² may independently be substituted or unsubstituted heteroarylene. L¹ and L² may independently be substituted heteroaryl. L¹ and L² may independently be unsubstituted heteroarylene. L¹ and L² may independently be substituted or unsubstituted 5 to 20 membered heteroarylene. L¹ and L² may independently be substituted 5 to 20 membered heteroarylene. L¹ and L² may independently be substituted or unsubstituted 5 to 8 membered heteroarylene. L¹ and L² may independently be substituted 5 to 8 membered heteroarylene. L¹ and L² may

independently be substituted or unsubstituted 5 or 6 membered heteroarylene. L¹ and L² may independently be substituted 5 or 6 membered heteroarylene.

[0368] L¹ and L² may independently be R⁸-substituted or unsubstituted heteroarylene. L¹ and L² may independently be R⁸-substituted heteroarylene. L¹ and L² may independently be R⁸- substituted or unsubstituted 5 to 20 membered heteroarylene. L¹ and L² may independently be R⁸-substituted 5 to 20 membered heteroarylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 5 to 8 membered heteroarylene. L¹ and L² may independently be R⁸-substituted 5 to 8 membered heteroarylene. L¹ and L² may independently be R⁸-substituted or unsubstituted 5 or 6 membered heteroarylene. L¹ and L² may independently be R⁸-substituted 5 or 6 membered heteroarylene. [0369] The compound of formula (I) may have the formula:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^3A, R^4A, R^5A, L¹, L², and n are as described herein.

[0370] The compound of formula (I), may have formula:

where R¹, R^3A, R^4A, R^5A, R⁶, L¹, and L² are as described herein.

[0371] R of the compound of formula (Ic) may be

, where z4 is an integer from

1 to 5 and R^4C is as described herein. R^5A of the compound of formula (Ic) may be

where z5 is an integer from 1 to 5 and R^5C is as described herein. [0372] R of the compound of formula (Ic) may be where z4 is an integer from

1 to 5 and R^5A of the compound of formula (Ic) may be

, where z5 is an integer from 1 to 5, and where R^4C and R^5C are as described herein. The symbols z4 and z5 may be 1. R^4C and R^5C may be hydrogen.

[0373] R⁶ of the compound of formula (Ic) may be hydrogen, unsubstituted C1-C5 alkyl, -

C(0)OR^bA or

where z6 is an integer from 1 to 5 and R°^{^} is as described herein.

_R6C may be hydrogen. The symbol z6 may be 1. L¹ and L² of the compound of formula (Ic) may be unsubstituted C1-C5 alkylene. L¹ and L² of the compound of formula (Ic) may be methylene.

[0374] R^3A of the compound of formula (Ic) may be hydrogen or methyl. R^3A of the compound of formula (Ic) may be hydrogen.

[0375] R¹ of the compound of formula (Ic) may be substituted or unsubstituted alkyl. R¹ of the compound of formula (Ic) may be hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, where f the compound of formula (Ic) may be hydrogen, methyl, ethyl, propyl or allyl. R of the compound of formula (Ic) may be methyl, ethyl, propyl,

or allyl. R of the compound of formula (Ic) may be allyl.

[0376] The compound of formula (II) may have the formula:

where R¹, R², R^4A, R^5A, R⁶, R⁷, L¹, L², and n are as described herein. [0377] The compound of formula (III) may have the formula:

Where R^4A, R^5A, R⁶, R⁷, L¹, L² and m are as described herein. [0378] The compound of formula (IV) may have the formula:

where R^4A, R^5A, R⁶, L¹, and L² are as described herein.

[0379] The compound of formula (IV) may have the formula:

where R^4A, R^5A, R⁶, L¹, and L² are as described herein.

[0380] R^4A of the compound of formula (IVb) may be

, where z4 is an integi described herein. R^5A of the compound of formula (IVb) may be

is an integer from 1 to 5 and R is as described herein. [0381] R of the compound of formula (IVb) may be e z4 is an integer

from 1 to 5 and R of the compound of formula (IVb) m

ay be , where z5 is an integer from 1 to 5, and where R and R are as described herein. The symbols z4 and z5 may be 1. R^4C and R^5C may be hydrogen.

[0382] R⁶ of the compound of formula (IVb) may be hydrogen, unsubstituted C1-C5 alkyl, -

RC(0)OR^OA or

where z6 is an integer from 1 to 5, R is R -substituted or unsubstituted alkyl, and R^6C is as described herein. R⁶ of the compound of formula (IVb) may be hydrogen. The symbol z6 of the compound of formula (IVb) may be 1. R⁶ of the compound of

formula (IVb) may be

, where R^6C is as described herein. R⁶ of the compound of formula (IVb) may be -C(0)OR^&A where R^&A is unsubstituted alkyl. R^&A of the compound of formula (IVb) may be tertiary butyl.

[0383] The compound of formula (V) may have the formula:

where R^4A, R^5A, R⁶, R⁷, L¹, and L² are as described herein.

[0384] In any of the formula provided herein, R¹, R², R³, R^3A, R⁴, R^4A, R⁵, R^5A, R⁶, and R⁷ may independently be:

5] The compound may be one or more of the compounds set forth below in Table 1.

Table 1

[0386] The compound may have formula:

[0387] The compound may have formula:

[0388] The compound may have formula:

[0389] The compound may have formula:

[0390] The compound may have formula:

[0391] In embodiments, the compound is not actinophyllic acid (formula (1)).

[0392] In embodiments the compound is not actinophyllic methyl ester (formula (2)).

[0393] In embodiments, the compound is not:

where R' and R' ' are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted aryl. In embodiments, the compound does not have formula (3) where R' and R" are independently unsubstituted alkyl. In embodiments, the compound does not have formula (3) where R' and R" are independently substituted alkyl. In embodiments, the compound does not have formula (3) where R' and R" are independently unsubstituted aryl (e.g. benzyl). In embodiments, the compound does not have formula (3) where R' and R" are independently substituted alkyl. In embodiments, the compound does not have formula (3) where R' of the compound of formula (3), is Boc, and R" is hydrogen, methyl, or t-butyl.

[0394] In embodiments, the compound is not

[0395] In embodiments, the compound is not

where R' " is hydrogen, alloc, -(CH₂)₂OH or -(CH II. Pharmaceutical Compositions

[0396] Provided herein are pharmaceutical compositions of the compounds herein. In one aspect is a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a compound (e.g. formula (I), (II), (III), (IV), (V), or a compound of Table 1) as described herein. The compound may be a compound having the formula (I) as described herein. The compound may be a compound having the formula (II) as described herein. The compound may be a compound having the formula (III) as described herein. The compound may be a compound having the formula (IV) as described herein. The compound may be a compound having the formula (V) as described herein. The compound may be a compound having the formula (I), or (IV) as described herein. The compound may be a compound having the formula (Ic), or (IVb) as described herein. The compound may be a compound set forth in Table 1.

[0397] The pharmaceutical composition may include a second agent in a therapeutically effective amount. The pharmaceutical composition may include a second agent where the second agent treats cancer. The second agent may be an anti-cancer agent as described herein. 1. Formulations

[0398] The pharmaceutical composition may be prepared and administered in a wide variety of dosage formulations. Compounds described herein (e.g. formula (I), (II), (III), (IV), (V), or a compound of Table 1) may be administered orally, rectally, or by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). [0399] For preparing pharmaceutical compositions from compounds having formula (I), (II), (III), (IV), (V), or a compound of Table 1, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0400] In powders, the carrier may be a finely divided solid in a mixture with the finely divided active component. In tablets, the active component may be mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. [0401] The powders and tablets preferably contain from 5% to 70% of the active compound.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. 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.

[0402] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0403] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [0404] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. [0405] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0406] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. [0407] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0408] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include:

Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight. Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

[0409] The pharmaceutical compositions 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.

[0410] The pharmaceutical composition may be intended for intravenous use. The

pharmaceutically acceptable excipient can include buffers to adjust the pH to a desirable range for intravenous use. Many buffers including salts of inorganic acids such as phosphate, borate, and sulfate are known.

2. Effective Dosages

[0411] The pharmaceutical composition may include compositions wherein the active ingredient is 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. [0412] The dosage and frequency (single or multiple doses) of compounds administered can vary depending upon a variety of factors, including 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; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0413] For any compound described herein or combination thereof, the therapeutically effective amounts can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of increasing the extent of cancer cell death as measured, for example, using methods known in the art.

[0414] Therapeutically effective amounts for use in humans may 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 response of the cancer to the treatment and adjusting the dosage upwards or downwards, as described above.

[0415] Dosages may be varied depending upon the requirements of the subject and the compound being employed. The dose administered to a subject, in the context of the

pharmaceutical compositions presented herein, should be sufficient to effect a beneficial therapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. 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.

[0416] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds 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.

[0417] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely 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.

3. Toxicity

[0418] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and ED5₀ (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED5₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g. Fingl et al, In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. l, p.l, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.

[0419] When parenteral application is needed or desired, particularly suitable admixtures for the compounds included in the pharmaceutical composition may be injectable, sterile solutions, oily or aqueous solutions, as well as suspensions, emulsions, or implants, including

suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages.

Pharmaceutical admixtures suitable for use in the pharmaceutical compositions presented herein may include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.

III. Methods of Treatment

[0420] Also provided herein are methods of treating cancer in a subject in need thereof. In one aspect is a method of treating cancer in a subject in need thereof by administering a

therapeutically effective amount of a compound (e.g. formula (I), (II), (III), (IV), (V), or a compound of Table 1) as described herein. The compound may be a compound having the formula (I) as described herein. The compound may be a compound having the formula (II) as described herein. The compound may be a compound having the formula (III) as described herein. The compound may be a compound having the formula (IV) as described herein. The compound may be a compound having the formula (V) as described herein. The compound may be a compound having the formula (I), or (IV) as described herein. The compound may be a compound having the formula (Ic), or (IVb) as described herein. The compound may be a compound set forth in Table 1.

[0421] The cancer may be lung cancer, lymphoma, breast cancer, cervical cancer, or brain cancer. The cancer may be lung cancer. The lung cancer may be non-small cell lung cancer. The cancer may be lymphoma. The cancer may be brain cancer. Thus, in another aspect is a method of treating lung cancer by administering a compound as described herein. In yet another aspect is a method of treating lymphoma by administering a compound as described herein. In still another aspect is a method of treating brain cancer by administering a compound as described herein. In still another aspect is a method of treating breast cancer by administering a compound as described herein. In another aspect is a method of treating cervical cancer by administering a compound as described herein.

IV. Other Aspects

[0422] Provided herein, in another aspect, are compositions and methods of synthesizing the compositions. The following definitions and embodiments apply to only to the compounds of formula (pi), this section (i.e. section IV) and embodiments PI to P17 listed below. [0423] This section generally relates to novel compositions, process, and methods related to cancer treatments. More specifically, this section provides novel compounds that may be useful as antineoplastic agents derived from the total synthesis of actinophyllic acid and the related processes. One aspect provides a novel process to prepare actinophyllic acid. Another aspect provides compositions that comprise compounds that are derived from actinophyllic acid or its intermediates. The compounds in this section have shown biological activities against several types of human cancers.

[0424] In one aspect, this section is directed to a composition comprising a compound of Formula (pi):

[0425] wherein R¹ is H, alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, C0₂R⁹, S0₂R⁹, allyl, benzyl with optional substitutions, or alkyl with optional substitutions by at least one OR⁸, SR⁸ or

8 2 1 3 8 8

N(R )₂; R is H or together with R to form a five- or six-membered ring; R is OR , halo, SR , N(R⁸)₂ or together with the adjacent carbon to form a carbonyl group; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

[0426] In certain embodiments, the compound of Formula (pi) may be a diastereomer. For example, a compound of Formula (pi) may be represented as Formula (pIA):

[0427] In one embodiment, R³ is OR⁸, halo, SR⁸, or N(R⁸)₂. In another embodiment, R³ is OR⁸. In another embodiment, the compound of Formula (pi) is selected from the group consisting of:

[0428] In another embodiment, the compound of Formula (pi) is selected from the group consisting of:

[0429] In another embodiment, R³, together with the adjacent carbon, form a carbonyl group a compound of Formula (pll):

[0430] wherein R¹, R², R⁴, R⁵, R⁶, R⁷ and n are defined as above.

[0431] In another embodiment, R⁶ in Formula (pll) is alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹. another embodiment, R⁶ is Boc. In another embodiment, the compound of Formula (pi) is a compound of formula (pill):

[0432] wherein R³, R⁴, R⁵, R⁶, R⁷ and n are defined as above; and m is 1 or 2.

[0433] Another aspect of this section is directed to a composition comprising a compound of formula (pIV):

[0434] wherein each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, CO₂R⁹; R⁸ is H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; R¹⁰ is CO₂H, C0₂alkyl or CH₂OR⁸; n is 0, 1, 2, 3, or 4; and with a proviso that when R¹⁰ is C0₂H, R⁶, R⁷ and R⁸ cannot all be H; or a pharmaceutically acceptable salt thereof. [0435] Another aspect of the present disclosure is directed to a process comprising the protecting the nitrogen atom of the indole ring and removing R¹ group in a compound of Formula (pIIA):

with suitable agents to form a compound of Formula (pIIB):

wherein R¹ is alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, CO₂R⁹, SO₂R⁹, allyl, benzyl with optional substitutions, alkyl with optional substitutions by at least one OR⁸, SR⁸ or (R⁸)₂; R² is H or together with R¹ to form a five- or six-membered ring; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4.

[0436] Examples of suitable agents to protect the nitrogen atom of the indole ring include but are not limited to Boc-anhydride (B0C2O), acid chlorides (RⁿCOCl), anhydrides

(RⁿC0₂CORⁿ), chloroformates (RⁿC0₂Cl), sulfonyl chlorides (RⁿS0₂Cl), where R¹¹ is alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl.

[0437] Examples of suitable agents to remove R¹ group include but are not limited to a palladium catalyst with N,N-dimethyl barbituric acid (NDMBA), a palladium catalyst with phenyl silane (PhSiHs), preferably palladium catalyst in the presence of phosphine ligands and with NDMBA. [0438] A process comprising the step of alkylating, reductively alkylating, acylating, or sulfonylating a compound of Formula (pIIB):

[0439] with a suitable alkylating agent, a suitable aldehyde and reducing agent, a suitable acid chloride or anhydride, a suitable haloformate, or a suitable sulfonyl halide to form a compound of Formula (pIIC):

[0440] wherein R² is H; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; R¹² is alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, C0₂R⁹, S0₂R⁹, allyl, benzyl with optional substitutions, or alkyl with optional substitutions by at least one OR⁸, SR⁸ or N(R⁸)₂; and n is 0, 1, 2, 3, or 4. [0441] Examples of suitable alkylating agents include but are not limited to methyl iodide, ethyl iodide, benzyl bromide, and allyl bromide. Examples of suitable aldehyde and reducting agents include but are not limited to formaldehyde, acetaldehyde, chloroacetaldehyde, propionaldehyde, 3-chloropropionaldehyde, butanal, benzaldehyde and mono- and disubstituted benzaldehydes, heterocyclic aldehydes such as 2-, 3-, and 4-formylpyridine. For some applications, of this invention chloroacetaldehyde is may be preferred.

[0442] Examples of suitable acid chlorides include but are not limited to acetyl chloride, propionyl chloride, crotonyl chloride, benzoyl chloride, and mono- and disubstituted benzoyl chlorides. Examples of suitable acid anhydrides include but are not limited to acetic anhydride, succinic anhydride, and glutaric anhydride.

[0443] Examples of suitable haloformates include but are not limited to methyl chloroformate, ethyl chloroformate, allyl chloroformate, and benzyl chloroformate. Examples of suitable sulfonyl halide include but are not limited to methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride.

[0444] A process comprising the steps of (1) reductively alkylating a compound of Formula (pIIB):

[0445] with a suitable aldehyde and a suitable reducing agent; then (2) cyclizing under a suitable cyclization condition to form a compound of Formula (pIIIA):

(pIIIA);

[0446] wherein R² is H; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0447] [0448] Examples of suitable aldehydes include but are not limited to

chloroacetaldehyde or 3-chloropropionaldehyde, preferably chloroacetaldehyde. Examples of suitable reducing agents include but are not limited to NaBH(OAc)3 or aBHsC . Examples of suitable cyclization conditions include but are not limited to ?-BuONa with ?-BuOH/THF.

[0449] Another aspect of this section is directed to a process comprising the step of removing protecting groups in a compound of Formula (pIIIB):

[0450] with suitable agents to form a compound of Formula (pIVA):

[0451] wherein R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; PG is a suitable protecting group; and n is 0, 1, 2, 3, or 4.

[0452] Examples of suitable agents include but are not limited to Pd/C with H₂ in the presence of HC1 or Pd(OH)₂/C with H₂ in the presence of HC1.

[0453] Another aspect of this section is directed to a process comprising the step of oxidizing a compound of Formula (p VIA):

[0454] with a suitable oxidizing agent to form a compound of Formula (pVIB):

[0455] wherein R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4.

[0456] Examples of suitable oxidizing agents include but are not limited to IBX in DMSO at 50 °C followed by N-hydroxysuccinimide then basic hydrolysis e.g., NaOH. Other oxidants may include TPAP/NMO H₂0, CH₃CN, room temperature or PDC, DMF, 50 °C.

[0457] For purposes of this section, the term "alkyl" means a saturated aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain. "Branched" means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl, means 1 to 4 carbon atoms in the chain which may be straight or branched. The alkyl may be substituted with one or more alkyl group substituents, which may be the same or different, and include for instance halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy.

[0458] For purposes of this section, the term "aryl" means an aromatic monocyclic or multicyclic ring system radical of up to about 20 carbon atoms. Preferably aryl is phenyl, naphthyl or anthracenyl. The aryl moiety is optionally substituted with one or more groups, e.g., alkyl, alkenyl, hydroxyl, alkoxy, or halo. [0459] For purposes of this section, the term "heteroaryl" means a monocyclic or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all- carbon counter parts. Thus, for the purposes of this section, a heteroaryl group need only have some degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,

(1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted or substituted with one or two suitable substituents.

[0460] Where the processes for the preparation of the compounds according to this section give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

Alternatively, the compounds may be resolved using a chiral HPLC column.

EXAMPLES FOR SECTION IV

[0461] General Methods: Methanol (MeOH), acetonitrile (CH₃CN), and N,N- dimethylformamide (DMF) were dried by filtration through two columns of activated molecular sieves. Tetrahydrofuran (THF) and toluene were passed through two columns of activated neutral alumina prior to use. Triethylamine (Ε¾Ν), Ν,Ν-diisopropylamine, benzene,

dichloromethane (CH2CI2), 1,2-dimethoxy ethane (DME), morpholine, piperidine, trans-crotonyl chloride, 2-furoyl chloride, phenyl isocyanate, and boron trifluoride diethyl etherate (BF₃ ^»OEt2) were freshly distilled over CaH2. Trimethylsilyl trifluoro-methanesulfonate (TMSOTf) was distilled over P2O5. Zinc chloride (ZnC^) was fused by melting under vacuum prior to use. Thionyl chloride (SOCI2) was distilled from triphenylphosphite. All solvents used for palladium- catalyzed cross-coupling reactions were degassed by sparging with nitrogen for 20 min prior to use. All other reagents and solvents were reagent grade and were purchased and used as received unless otherwise noted. Reactions were performed under a nitrogen or argon atmosphere in round-bottom flasks sealed under rubber septa with magnetic stirring, unless otherwise noted. Water sensitive reactions were performed with flame- or oven-dried glassware, stir-bars and steel needles. Reaction temperatures are reported as the temperatures of the bath surrounding the vessel. Sensitive reagents and solvents were transferred using plastic or oven-dried glass syringes and steel needles using standard techniques.

[0462] Proton nuclear magnetic resonance (^lH NMR) and carbon nuclear magnetic resonance (¹³C NMR) spectra were acquired in CDCI₃ unless otherwise noted. Chemical shifts are reported in parts per million (ppm, δ), downfield from tetramethylsilane (TMS, δ = 0.00 ppm) and are referenced to residual solvent (CDCI₃, δ = 7.26 ppm (^XH) and 77.16 ppm (¹³C)). Coupling constants (J) are reported in hertz (Hz) and the resonance multiplicity abbreviations used are: s, singlet; d, doublet; t, triplet; dt, doublet of triplets; td, triplet of doublets; dd, doublet of doublets; ddd, doublet of doublet of doublets; m, multiplet; comp, overlapping multiplets of magnetically non-equivalent protons. The abbreviations br and app stand for broad and apparent, respectively. Infrared (IR) spectra were obtained with a Thermo Scientific Nicolet IR-IOO FT-IR series spectrometer as thin films on sodium chloride plates. Melting points were determined using a Thomas-Hoover Uni-melt capillary melting point apparatus. Thin-layer chromatography (TLC) was performed on EMD 60 F254 glass-backed pre-coated silica gel plates and were visualized using one or more of the following methods: UV light (254 nm) and staining with basic potassium permanganate (KMnCk) or acidic -anisaldehyde (PAA). Flash chromatography was performed using glass columns and with Silicycle SiliaFlash F60 (40-63 μιη) silica gel eluting with the solvents indicated according to the procedure of Still. (Still et al. J. Org. Chem.

43:2923, 1978.) Reverse phase chromatography was performed on a CombiFlash® Companion instrument utilizing a RediSep® R_f 43 g C18 Reverse Phase column.

[0463] Example 1 : Preparation of l,3-Bis(benzyloxy)-2-(lH-indol-2-yl)propan-2-yl acetate (4)

4

[0464] A solution of w-BuLi (6.8 mL of a 2.17 M solution in hexanes, 14.8 mmol) was added dropwise to a solution of indole (8) (1.6 g, 13.5 mmol) in dry THF (39 mL) at -78 °C. The reaction was stirred for 30 min, and dried CO₂ (gas) (passed through a short column anhydrous CaS0₄) was bubbled through the reaction for 15 min. The reaction was stirred for 15 min, the bath was removed, and the reaction was stirred for 1 h at room temperature. Excess CO₂ was removed via freeze-pump-thaw (3 cycles), and then the reaction was evacuated for 30 sec and sparged with Ar for 20 min. The reaction was cooled to -78 °C, whereupon ?-BuLi (10.0 mL of a 1.47 M solution in pentane, 14.8 mmol) was added dropwise. The reaction was stirred for 80 min and transferred via cannula to a solution of 1,3-dibenzyloxyacetone (9) (4.0 g, 14.8 mmol) in dry THF (39 mL) at -78 °C. (Compound 9 can be synthesized following the procedure discloses in Choi et al. Arch. Pharm. Res. 26:990, 2003.) The reaction was stirred for 2.5 h, acetic anhydride (9.70 mL, 103.47 mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 7 h. Saturated aHC03 (50 mL) was added, and the reaction was stirred for 30 min, whereupon saturated brine (80 mL) and Et₂0 (200 mL) were added. The layers were separated, and the aqueous layer was extracted with Et₂0 (2 x 100 mL). The combined organic layers were dried (MgS0₄), filtered and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (90 : 10→ 85 : 15→ 80 : 20→ 75 : 25→ 70 : 20) containing 1% Et₃N to give 5.0 g (85%) of 4 as a pale yellow solid: mp 78-79 °C; ^XH NMR (400 MHz, CD₃CN) δ 9.55 (br s, 1 H), 7.58 (d, J= 8.0 Hz, 1 H), 7.45 (d, J= 8.0 Hz, 1 H), 7.39-731 (comp, 10 H), 7.21-7.17 (m, 1 H), 7.1 1-7.07 (m, 1 H), 6.46 (dd, J= 2.4, 0.8 Hz, 1 H), 4.58 (s, 4 H), 4.21 (s, 4 H), 2.08 (s, 3 H); ¹³C NMR (100 MHz, CD₃CN) δ 169.8, 138.6, 137.3, 136.2, 128.6, 128.0, 127.9, 122.0, 120.5, 119.8, 1 11.4, 99.9, 80.7, 73.4, 70.7, 21.5; IR (neat) 3416, 2864, 1741, 1454, 1367, 1237, 1 103, 1018, 738, 698 cm^"1; mass spectrum (CI) m/z 430.2010 [C₂₇H₂₈N04 (M+l) requires 430.2018].

[0465] Example 2: Preparation of Allyl 5-oxo-2,3,4,5-tetrahydro-lH-azepine-l-carboxylate (2)

Alloc

[0466] A solution of w-BuLi (9.7 mL of a 2.8 M solution in hexanes, 27.2 mmol) was added dropwise to a solution of 10 (2.5 g, 22.7 mmol) in THF (200 mL) at -78 °C. (Compound 10 can be prepared following the procedure disclosed in DE 2013761.) After stirring for 0.5 h, allyl chloroformate (3.1 mL, 3.5 g, 29.5 mmol) was added dropwise, and the reaction was stirred for 1.5 h. The bath was removed, and the reaction was stirred for 1.5 h at room temperature. The reaction was concentrated, partitioned between a mixture of saturated aqueous NaHC(¾ (50 mL), saturated brine (50 mL) and CH2CI2 (100 mL). The layers were separated, and the aqueous layer was extracted with CH₂CI₂ (2 x 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant crude material was purified by flash column chromatography eluting with

hexanes/EtOAc (7 : 3→ 8 : 4→ 1 : 1) to give 3.7 g (84%) of compound 2 as a pale yellow oil: 'H NMR (400 MHz) δ 7.46 (d, J= 10.6 Hz, 1 H), 5.99-5.89 (m, 1 H), 5.37-5.23 (comp, 3 H), 4.70 (app dt, J= 1.4, 5.8 Hz, 2 H), 3.96-3.93 (comp, 2 H), 2.65 (app t, J= 6.5 Hz, 2 H), 2.07- 2.01 (comp, 2 H); "C NMR (100 MHz) δ 200.9, 166.0, 137.2, 131.4, 119.3, 109.9, 68.0, 48.1, 42.7, 22.7; IR (neat) 3492, 3088, 2945, 1730, 1614, 1434, 1114, 943, 766 cm^"1; mass spectrum (CI) m/z 196.0974 [Ci₀H₁₃NO₃ (M+l) requires 196.0974].

Example 3: Preparation of Allyl 5-((triisopropylsilyl)oxy)-2,3-dihydro-lH-azepine-l-carboxylate (11)

TIP

11

[0467] Triisopropylsilyl chloride (7.2 g, 8.0 mL, 37.4 mmol) was added to a solution of compound 2 (6.0 g, 30.9 mmol) in THF (330 mL) at -78 °C and stirred for 12 min. Sodium hexamethyldisilazide (20.0 mL of a 2.04 M solution in THF, 40.1 mmol) was added to the reaction dropwise, and the reaction was stirred at -78 °C for 1.5 h. Saturated aHC03 (100 mL) was added, and the bath was removed and stirring continued for 15 min. Once at room temperature, the reaction was partitioned between a mixture of saturated aqueous aHC03 (100 mL), saturated brine (150 mL) and Et₂0 (200 mL). The layers were separated, and the aqueous layer was extracted with Et20 (2 x 200 mL). The combined organic layers were washed with saturated brine (300 mL), dried (Na₂S0₄), filtered and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (92 : 8→ 93 : 7) containing 1% Et₃N to give 11.3 g (92%) of 11 as a pale yellow oil: ^XH NMR (400 MHz, CD₃CN) δ 6.84 (d, J= 8.9 Hz, 1 H), 6.03-5.93 (m, 1 H), 5.36-5.19 (comp, 3 H), 5.06 (d, J= 9.9 Hz, 1 H), 4.64 (app dt, J= 1.4, 5.5 Hz, 2 H), 3.74 (app t, J= 4.1 Hz, 2 H), 2.35 (app q, J= 5.5 Hz, 2 H), 1.23-1.14 (comp, 3 H), 1.10-1.09 (comp, 18 H); ¹³C MR (125 MHz, CD₃CN) 153.9, 148.9, 133.7, 128.6, 118.2, 110.4, 109.6, 67.6, 46.2, 28.6, 18.5, 13.3; IR (neat) 3060, 3030, 2944, 2866, 1691, 1461, 1411, 1366, 1233, 1199, 1106, 885, 743.6, 697.9 cm^"1; mass spectrum (CI) m/z 351.2225 [d₉H₃₃N0₃Si (M+l) requires 351.2230].

[0468] Example 4: Preparation of Compound 12

[0469] A solution of TMSOTf (0.9 g, 0.7 mL, 3.7 mmol) in CH₂C1₂ (1.5 mL) was added dropwise to a solution of 11 (1.3 g, 3.6 mmol), 4 (1.5 g, 3.5 mmol) and 2,6-di(tert-butyl)pyridine (1.4 g, 1.3 mL, 7.0 mmol) in dry CH2CI2 (13.5 mL) at -78 °C. The reaction was stirred for 3 h at -78 °C, whereupon a solution of TBAF-3H₂0 (5.5 g, 17.5 mmol) in CH₂C1₂ (27.0 mL) was added via cannula. The bath was removed, and the reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCC (30 mL), and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried ( a₂S04), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (8 : 2→ 7 : 3→ 6 : 4) containing 1% Et₃N to give 1.8 g (92%) of compound 12 as an amorphous yellow solid: ^XH NMR (600 MHz, CD₃CN) δ 9.60 (s, 1 H), 7.45 (d, J= 7.81 Hz, 1 H), 7.36-7.23 (comp 9 H), 7.38 (d, J= 8.1 Hz, 1 H), 7.17-7.15 (m, 1 H), 7.16-7.12 (m, 1 H), 7.07 (app t, J= 7.9 Hz, 1 H), 6.10-5.89 (m, 1 H), 5.81-5.76 (m, 1 H), 5.40-5.15 (comp, 2 H), 4.66-4.54 (comp, 2 H), 4.62 (d, J= 11.0 Hz, 1 H), 4.57 (d, J= 1 1.0 Hz, 1 H), 4.38 (d, J= 11.9 Hz, 1 H), 4.31 (d, J= 1 1.9 Hz, 1 H), 3.98-3.80 (m, 1 H), 3.96 (d, J= 9.3 Hz, 1 H), 3.75 (d, J= 9.3 Hz, 1 H), 3.70 (d, J= 9.3 Hz, 1 H), 3.63 (d, J= 9.3 Hz, 1 H), 3.07 (dd, J= 2.6, 5.9 Hz, 1 H), 3.04 (app dd, J= 4.4, 18.8 Hz, 1 H), 3.03-2.87 (m, 1 H), 2.98-2.84 (m, 1 H), 2.13-2.01 (m, 1 H), 1.80-1.70 (m, 1 H); ¹³C MR (150 MHz) 211.9, 155.6, 139.1, 139.Γ, 136.4, 134.6, 129.4, 129.2, 128.9, 128.8, 128.7, 128.5, 127.4, 123.0, 120.5, 1 17.3, 1 12.0, 110.4, 75.9, 74.2, 74.0, 73.0, 66.6, 58.1, 50.4, 49.6, 46.1, 45.7, 40.5, 28.8, 28.4; IR (neat) 3031, 2863, 1694, 1414, 1344, 1305, 1228, 1 103, 1207, 983, 941, 861, 744, 699 cm^"1; mass spectrum (CI) m/z 564.2625 [C₃5H₃₆ 2O5 (M+l) requires 564.2725].

[0470] Example 5 : Preparation of Compound 3

[0471] 4-Dimethylaminopyridine (1.5 g, 12.3 mmol) was added to a solution of 12 (4.6 g, 8.2 mmol) in a mixture of di-tert-butyl dicarbonate (23 mL, 22 g, 102.5 mmol) and toluene (18 mL), and the reaction was stirred for 3 h at room temperature. The reaction was partitioned between H2O (100 mL) and Et20 (100 mL). The layers were separated, and the aqueous layer was extracted with Et₂0 (2 x 100 mL). The combined organic layers were dried (MgS0₄), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (8 : 2) to give 4.6 g (83%) of compound 3 as a yellow amorphous solid foam: ^XH NMR (400 MHz, as a mixture of rotamers) δ 7.80 (d, J= 8.0 Hz, 1 H), 7.58 (d, J= 7.6 Hz, 0.5 H), 7.43 (d, J= 8.4 Hz, 0.5 H), 7.34-7.15 (comp, 12 H), 6.09- 5.76 (comp, 2 H), 5.44-5.18 (comp, 2 H), 4.75-4.34 (comp, 7 H), 4.06-3.93 (comp, 1.5 H), 3.83- 3.71 (comp, 2.5 H), 3.33-3.28 (m, 1 H), 3.17-3.03 (comp, 2 H), 2.95-2.78 (m, 1 H), 2.07-1.95 (m, 1 H), 1.90-1.75 (m, 1 H), 1.64 (s, 9 H); ¹³C NMR (100 MHz, as a mixture of rotamers) δ 211.7, 211.5, 154.8, 154.5, 151.1, 137.7, 137.5, 137.3, 137.2, 136.3, 132.9, 132.8, 128.2, 128.0, 127.9, 127.6, 127.5, 127.4, 127.1, 127.0, 124.6, 122.3, 119.4, 1 19.2, 118.3, 1 17.7, 117.3, 1 14.1, 1 14.0, 84.4, 84.3, 75.5, 75.2, 73.2, 73.1, 73.0, 72.6, 66.3, 66.1, 63.3, 63.1, 48.8, 47.5, 46.7, 45.0, 39.7, 28.8, 28.3, 27.9; IR (neat) 2979, 2936, 2862, 1784, 1698, 1456, 1306, 1 145, 11 11, 767, 741, 700 cm^"1; mass spectrum (ESI) m/z 665.3215 [C₄oH_{45 2}07 (M+l) requires 665.3221].

[0472] Example 6: Preparation of Compound 13

[0473] A solution of Pd₂(dba)₃ (8.5 mg, 0.009 mmol) and l,4-bis(diphenylphosphino)butane (dppb) (3.9 mg, 0.009 mmol) in THF (3.1 mL) was stirred for 5 min at room temperature, and the resultant solution was transferred to a solution of compound 3 (614 mg, 0.92 mmol) and N,N- dimethylbarbituric acid (NMDBA) (1.44 g, 9.24 mmol) in THF (6.2 mL). The reaction was stirred for 1 h at room temperature, whereupon Et₂0 (20 mL) and saturated aqueous aHC03 (30 mL) were slowly added. The layers were separated, and the aqueous layer was extracted with Et₂0 (2 x 15 mL). The combined organic layers were dried (MgS0₄), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with EtOAc containing 1% Et₃N to provide 495 mg (92%) of compound 13 as a pale yellow amorphous solid foam: ^XH NMR (400 MHz) δ 7.82 (d, J= 8.8 Hz, 1 H), 7.49 (d, J= 7.6 Hz, 1 H), 7.35-7.20 (comp, 12 H), 4.67-4.65 (m, 1 H), 4.60 (d, J= 8.8 Hz, 1 H), 4.53 (d, J= 12.0 Hz, 1 H), 4.43 (d, J= 11.6 Hz, 1 H), 4.35 (d, J= 12.0 Hz, 1 H), 3.97 (d, J= 8.8 Hz, 1 H), 3.85- 3.81 (comp, 2 H), 3.37-3.34 (m, 1 H), 3.18 (dd, J= 2.4, 18.0 Hz, 1 H), 2.97 (dd, J= 4.4, 18.0 Hz, 1 H), 2.72-2.65 (comp, 2 H), 2.07-1.97 (comp, 2 H), 1.80-1.73 (m, 1 H), 1.64 (s, 9 H); ¹³C MR (100 MHz) δ 213.2, 151.7, 138.4, 138.0, 137.1, 136.9, 128.6, 128.4, 128.2, 128.1, 127.8, 127.6, 127.4, 124.6, 122.4, 120.6, 117.9, 114.5, 84.5, 75.9, 73.5, 73.4, 73.0, 62.9, 50.3, 49.2, 46.0, 41.4, 29.0, 28.3; IR (neat) 2920, 2857, 1737, 1698, 1456, 1311, 1143, 1098, 740, 699 cm^"1; mass spectrum (ESI) m/z 581.3012 [C₃6H₄i ₂0₅ (M+l) requires 581.3010].

[0474] Example 7: Preparation of Compound 14

[0475] Sodium triacetoxyborohydride (0.69 g, 3.27 mmol) was added to a mixture of compound 13 (0.95 g, 1.64 mmol) and chloroacetaldehyde (0.51 mL of a 50% by weight solution in H₂0, 3.27 mmol) in 1,2-DCE (18 mL) at 0 °C, and the reaction was stirred for 15 min at 0 °C. The reaction was partitioned between saturated aqueous aHC03 (20 mL) and CH₂C1₂ (10 mL), and the layers were separated. The aqueous layer was extracted with CH₂C1₂ (2 x 20 mL), and the combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure to give 1.16 g of yellow amorphous solid foam. The crude material was dissolved in a mixture of THF (38 mL) and ?-BuOH (11.7 mL) and cooled to 0 °C. Sodium tert-butoxide (0.79 g, 8.20 mmol) was added at 0 °C, the bath was removed, and the reaction was stirred for 1.5 h at room temperature. The reaction was partitioned between saturated aqueous NH₄C1 (30 mL) and Et20 (30 mL), and the layers were separated. The aqueous layer was extracted with Et₂0 (2 x 30 mL), and the combined organic layers were dried (MgSC^), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with CH₂Cl₂/MeOH (95 : 5) to provide 820 mg (83% over the two steps) of compound 14 as a pale yellow amorphous solid foam: ^XH NMR (400 MHz) δ 7.82 (d, J= 7.2 Hz, 1 H), 7.77 (dd, J= 7.6, 1.2 Hz, 1 H), 7.37-7.22 (comp, 10 H), 7.18-7.16 (comp, 2 H), 4.73 (d, J= 4.8 Hz, 1 H), 4.53 (d, J = 12.4 Hz, 1 H), 4.45-4.39 (comp, 2 H), 4.37-4.32 (comp, 2 H), 4.14 (d, J= 9.6 Hz, 1 H), 3.95 (d, J= 5.2 Hz, 1 H), 3.78 (d, J= 9.6 Hz, 1 H), 3.67-3.60 (m, 1 H), 3.29-3.28 (m, 1 H), 3.23 (dd, J = 7.2, 5.2 Hz, 1 H), 3.19-3.1 1 (comp, 2 H), 2.67 (dd, J= 14.4, 3.2 Hz, 1 H), 2.45-2.29 (comp, 2 H), 2.01-1.93 (m, 1 H), 1.88-1.80 (m, 1 H), 1.64 (s, 9 H); ¹³C NMR (100 MHz) δ 214.2, 151.0, 137.8, 137.7, 137.2, 136.2, 128.4, 128.1, 127.9, 127.6, 127.4, 127.1, 127.0, 124.4, 122.3, 118.6, 1 15.0, 1 13.7, 84.3, 74.4, 73.0, 72.6, 72.5, 61.6, 58.0, 54.3, 49.2, 49.1, 47.5, 32.3, 27.8, 23.8; IR (neat) 2929, 2873, 1740, 1695, 1314, 1 147, 742 cm^"1; mass spectrum (ESI) m/z 607.3169

[C38H43 2O5 (M+l) requires 607.3166].

[0476] Example 8: Preparation of Compound 15

[0477] A solution of 14 (1.0 g, 1.65 mmol) in a mixture of MeOH (23 mL) and 5 M HCl_(aq) (23 mL) was stirred at 65 °C for 1 h. The reaction was cooled to room temperature and palladium on carbon (250 mg of 10% loading) was added, and the reaction was stirred for 4 h under a balloon of H_2(g), filtered through cotton, and concentrated. The resultant yellow residue was purified by reverse phase chromatography eluting with MeOH/H20 (0 : 100→ 20 : 80 over 15 mins) containing 0.1% TFA to give 513 mg (86%) of 15 as a pale yellow amorphous solid foam: ^XH NMR (600 MHz, CD₃OD) δ 7.61 (d, J= 8.0 Hz, 1 H), 7.44 (d, J= 8.0 Hz, 1 H), 7.16 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.1 1 (ddd, J= 8.0, 7.0, 1.0 Hz, 1 H), 5.45 (d, J= 7.4 Hz, 1 H), 4.17 (d, J = 1 1.3 Hz, 1 H), 4.13 (d, J= 11.3 Hz, 1 H), 3.97 (d, J= 7.8 Hz, 1 H), 3.70 (ddd, J= 12.4, 12.4, 8.0 Hz, 1 H), 3.60-3.55 (m, 1 H), 3.56 (d, J= 7.8 Hz, 1 H), 3.21-3.14 (comp, 2 H), 2.95 (ddd, J = 13.7, 3.2, 3.2 Hz, 1 H), 2.74 (dddd, J= 12.8, 10.3, 8.0, 2.4 Hz, 1 H), 2.64-2.63 (m, 1 H), 2.53- 2.46 (m, 1 H), 2.40-2.33 (m, 1 H), 2.23 (dddd, J= 12.2, 9.0, 3.0, 3.0 Hz, 1 H); ¹³C NMR (150 MHz, CD₃OD) δ 143.1, 137.2, 128.4, 123.3, 121.1, 1 18.0, 112.5, 108.4, 102.5, 75.3, 64.3, 62.8, 55.3, 53.4, 53.1, 50.5, 47.3, 26.2, 19.7; IR (neat) 3395, 3285, 1441, 1233, 1086, 997, 738, 721 cm^"1; mass spectrum (ESI) m/z 327.1704

(M+l) requires 327.1703].

[0478] Example 9: Preparation of Compound 1

[0479] A solution of 2-iodoxybenzoic acid (115 mg, 0.41 mmol) and alcohol 15 (30 mg, 0.08 mmol) in DMSO (0.33 mL) was stirred at 50 °C for 2 h. N-hydroxysuccinimide (67 mg, 0.58 mmol) was added, and the reaction was stirred at 50 °C for 2 h. The reaction was cooled to room temperature, whereupon a solution of 1 M NaOH was added until the reaction was basic (~pH 10) according to pH paper. The reaction mixture was dry-loaded onto Si0₂ and purified by flash column chromatography eluting with CHCl₃/MeOH/NH₄OH (6 : 3 : 0.5), followed by reverse phase chromatography eluting with MeOH/H20 (0 : 100→ 20 : 80 over 15 mins) to give 9.8 mg (31%) of 1 as a colorless amorphous solid foam: ^XH NMR (600 MHz, D₂O, internal reference to MeOH at 3.34 ppm) δ 7.64 (d, J= 8.0 Hz, 1 H), 7.54 (d, J= 8.1 Hz, 1 H), 7.33-7.30 (m, 1 H), 7.25-7.22 (m, 1 H), 5.52 (d, J= 7.5 Hz, 1 H), 4.40 (d, J= 8.2 Hz, 1 H), 3.79 (d, J= 8.2 Hz, 1 H), 3.80-3.74 (m, 1 H), 3.64-3.60 (m, 1 H), 3.30-3.25 (comp, 2 H), 3.09-3.05 (comp, 2 H), 2.70-2.63 (m, 1 H), 2.61-2.54 (m, 1 H), 2.45-2.40 (m, 1 H), 2.37-2.33 (m, 1 H); ¹³C NMR (150 MHz, D₂0, internal reference to MeOH at 49.5 ppm) δ 173.8, 138.5, 136.1, 127.2, 123.7, 121.2, 117.8, 1 12.4, 107.7, 102.3, 74.6, 61.2, 58.3, 54.4, 51.8, 50.2, 46.2, 25.3, 18.7; IR (neat) 3321, 1589, 1460, 1372, 1 108, 1035, 738 cm^"1; mass spectrum (ESI) m/z 341.1497 [Ci₉H₂₁N₂0₄ (M+l) requires 341.1496]. [0480] Example 10: Preparation of Compound 16 (Allyl-6-6-bis((benzyloxy)methyl)-12- hydroxy-3,4,5,6-tetrahydro-lH-l,5-ethano-azocino[4,3-/?]indole-2(7H)-carboxylate)

[0481] Lithium borohydride (4 mg, 0.18 mmol) was added to ketone 12 (20 mg, 0.04 mmol) in anhydrous methanol (0.4 mL) at 0 °C, and the reaction was stirred for 18 h at 0 °C. The reaction was partitioned between brine (2 mL) and CH₂CI₂ (2 mL) and the layers were separated. The aqueous layer was extracted with CH₂CI₂ (2 x 2 mL) and the combined organic layers were washed once more with brine (5 mL). The organic layer was dried ( a₂S04), filtered, and concentrated under reduced pressure. The resultant yellow solid was purified by flash column chromatography eluting with hexanes/EtOAc (1 : 1 with 1% Et₃N) to give 16.3 mg (82%) of compound 16 as a white solid: mp 167-169 °C (colorless needles from EtOAc : hex); ^XH NMR (500 MHz, DMSO-i/₆, 120 °C) δ 10.23 (br s, 1 H), 7.40 (d, J= 8.0 Hz, 1 H), 7.36-7.31 (comp, 5 H), 7.29-7.21 (comp, 6 H), 7.07-7.04 (m, 1 H), 7.00-6.97 (m, 1 H), 6.05-5.97 (m, 1 H), 5.56 (d, J = 6.5 Hz, 1 H), 5.34 (d, J= 17.5 Hz, 1 H), 5.22 (d, J= 10.0 Hz, 1 H), 4.68-4.59 (comp, 4 H), 4.48 (dd, J= 14.5, 13.0 Hz, 2 H), 4.41 (br s, 1 H), 4.29 (d, J= 9.0 Hz, 1 H), 4.26-4.23 (m, 1 H), 4.08 (d, J= 10.0 Hz, 1 H), 4.02 (d, J= 10.0 Hz, 1 H), 3.76-3.73 (comp, 2 H), 2.97-2.91 (m, 1 H), 2.68-2.63 (comp, 2 H), 1.93 (app dt, J= 14.5, 3.5 Hz, 1 H), 1.85 (dd, J= 13.5, 9.5 Hz, 1 H), 1.76-1.68 (m, 1 H); ¹³C NMR (125 MHz, DMSO-i/₆, 120 °C) δ 154.0, 138.9, 138.2, 138.0, 134.9, 133.3, 127.5, 127.4, 126.74, 126.7, 126.6, 126.4, 125.5, 120.2, 118.2, 1 16.0, 115.97, 110.8, 1 10.5, 73.3, 73.2, 72.4, 72.2, 71.8, 64.4, 46.7, 46.4, 45.4, 39.9, 39.8, 29.4; IR (neat) 3408, 2943, 1680, 1454, 1413, 1104, 739 cm^"1; mass spectrum (ESI) m/z 566.2789 [C₃₅H₃₈N₂05 (M+l) requires 566.2781].

[0482] Example 11 : Preparation of Compound 17 (l l,l l-Bis[(benzyloxy)methyl]-15-(prop-2-en- 1-yl)- 9, 15- diazatetracyclo[10.3.2.0²'¹⁰ .0³'⁸]hep-tadeca-2(10),3(8),4,6-tetraen-17-ol)

[0483] A mixture of compound 16 (100 mg, 0.18 mmol) and Pd(PPh₃)₄ (20 mg, 0.02mmol) in CH2CI2 (2 mL) was stirred at room temperature for 1 h. The reaction was concentrated and purified by flash column chromatography eluting with CH^CVMeOH (99: 1) with 1% EtsN to provide 89 mg (92%) of compound 17 as a yellow solid: mp 50 °C (dec); ¾ NMR (600 MHz) δ 9.31 (br s, 1 H), 7.50 (d, J= 7.8 Hz, 1 H), 7.41-7.34 (comp, 5 H), 7.29-7.23 (comp, 4 H), 7.19- 7.18 (comp, 2 H), 7.14-7.12 (m, 1 H), 7.09-7.07 (m, 1 H), 6.01 (dddd, J= 16.8, 10.2, 6.6, 5.4 Hz, 1 H), 5.28 (dd, J= 16.8, 1.2 Hz, 1 H), 5.19 (dd, J= 10.2, 1.2 Hz, 1 H), 4.66 (d, J= 1 1.4 Hz, 1 H), 4.61 (d, J= 11.4 Hz, 1 H), 4.50-4.44 (comp, 3 H), 4.38 (d, J= 5.4 Hz, 1 H), 4.03 (d, J= 1.2 Hz, 2 H), 3.94 (d, J= 8.4 Hz, 1 H), 3.70 (d, J= 8.4 Hz, 1 H), 3.39 (d, J= 5.4 Hz, 1 H), 3.23 (dd, J = 13.8, 6.6 Hz, 1 H), 3.02-2.99 (m, 1 H), 2.86 (ddd, J= 13.8, 9.6, 6.6 Hz, 1 H), 2.47-2.43 (comp, 2 H), 2.21 (ddd, J= 13.2, 13.2, 3.6 Hz, 1 H), 1.93 (ddd, J= 13.8, 8.4, 1.8 Hz, 1 H), 1.89-1.83 (m, 1 H), 1.77-1.74 (m, 1 H); ¹³C NMR (150 MHz) δ 138.4, 137.7, 137.6, 137.5, 134.8, 128.7, 128.4, 128.2, 128.1, 127.8, 127.7, 121.4, 119.2, 1 18.3, 116.7, 11 1.3, 1 10.5, 75.6, 75.3, 73.9, 73.4, 72.5, 61.8, 52.4, 49.0, 46.8, 46.0, 42.9, 30.4; IR (neat) 3414, 3060, 3029, 2925, 2867, 1459, 1 101, 1074, 743, 689; mass spectrum m/z (ESI) 523.2957 [C34H39N2O3 ( +l) requires 523.2961].

[0484] Example 12: Preparation of Compound 18

[0485] A solution of Pd(PPh₃)₄ (10 mg, 0.009 mmol) in CH₂C1₂ (0.5 mL) was added dropwise to a solution of compound 16 (100 mg, 0.18 mmol) in CH2CI2 (0.5 mL) and PhSiH₃ (76 mg, 87 μί, 0.70 mmol) in CH2CI2 (0.5 mL), and the reaction was stirred for 0.5 h. Saturated aqueous aHC03 (5 mL) was added and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 5 mL). The combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant brown gum was purified by flash column chromatography eluting with CH₂Cl₂/MeOH (7 : 3 with 1% Et₃N) to give 51 mg (60%) of 18 as a brown amorphous solid foam: ^XH NMR (600 MHz, CD₂C1₂) δ 9.40 (br s, 1 H), 7.65 (d, J= 7.8 Hz, 1 H), 7.42-7.22 (comp, 11 H), 7.13 (ddd, J= 7.2, 7.2, 1.2 Hz, 1 H), 7.09 (ddd, J= 8.4, 8.4, 1.2 Hz, 1 H), 4.96 (d, J= 6.0 Hz, 1 H), 4.71-4.60 (comp, 4 H), 4.52-4.48 (comp, 3 H), 4.09-4.00 (comp, 4 H), 3.93 (d, J= 9.0 Hz, 1 H), 3.71 (d, J= 9.0 Hz, 1 H), 3.05 (ddd, J= 14.4, 8.4, 6.6 Hz, 1 H), 2.87 (dd, J= 13.8, 4.8 Hz, 1 H), 2.66-2.55 (comp, 3 H), 2.07 (dd, J= 13.8, 9.0 Hz, 1 H), 2.01- 1.85 (comp, 4 H); ¹³C NMR (150 Hz, CD₂C1₂) δ 140.0, 139.1, 138.5, 138.4, 138.4, 138.3, 138.2, 135.5, 135.3, 128.97, 128.94, 128.73, 128.72, 128.3, 128.20, 128.19, 128.2, 128.1, 126.5, 122.2, 121.4, 1 19.9, 119.4, 1 18.5, 1 11.0, 110.3, 76.4, 75.5, 74.8, 74.7, 74.2, 74.0, 73.7, 72.8, 64.5, 47.8, 47.0, 46.5, 41.8, 40.6, 31.0, 29.0; mass spectrum m/z (ESI) 483.2642 [C₃1H₃5N2O₃ (M+l) requires 483.2648].

[0486] Example 13 : Preparation of Compound 19

[0487] A 0.08 M solution of Os0₄ in s-BuOH (0.36 mL, 0.03 mmol) was added dropwise to a solution of compound 17 (150 mg, 0.29 mmol) and NMO (100 mg, 0.86 mmol) in a mixture of THF/?-BuOH/H20 (4:4: 1, 17 mL) and the reaction was stirred for 24 h at room temperature. The reaction was partitioned between H2O (20 mL) and CH2CI2 (20 mL) and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 20 mL) and the combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with EtOAc/MeOH (85 : 15 with 1% Et₃N) to give 106 mg (66%) of 19 as a yellow solid: ^XH NMR (600 MHz, CD₂C1₂) δ 9.39 (br s, 1.0 H), 7.46 (dd, J= 27.6, 8.4 Hz, 1 H), 7.40-7.39 (comp, 4 H), 7.36-7.34 (m, 1 H), 7.31-7.26 (comp, 4 H), 7.23-7.21 (comp, 2 H), 7.11 (dddd, J= 7.2, 7.2, 1.2, 1.2 Hz, 1 H), 7.06 (dddd, J= 9.0, 8.4, 3.0, 1.2 Hz, 1 H), 4.69 (d, J= 12.0 Hz, 1 H), 4.62 (d, J= 12.0 Hz, 1 H), 4.49 (d, J= 3.6 Hz, 1 H), 4.45-4.38 (comp, 2 H), 4.08-4.03 (comp, 2 H), 3.98-3.94 (m, 1 H), 3.77- 3.64 (comp, 3 H), 3.49 (dd, J= 1 1.4, 4.8 Hz, 1 H), 3.22 (br s, 1 H), 2.96-2.80 (comp, 3 H), 2.58- 2.26 (comp, 5 H), 1.97-1.77 (comp, 4 H); ¹³C NMR (150 MHz, CD₂C1₂) δ 139.3, 139.2, 138.2, 135.5, 135.4, 129.0, 128.7, 128.3, 128.20, 128.19, 128.1, 128.0, 127.7, 121.8, 1 19.8, 119.7, 1 18.3, 1 18.2, 11 1.6, 1 11.2, 1 11.0, 110.9, 75.8, 75.7, 75.24, 75.22, 74.2, 73.7, 72.9, 72.8, 68.4, 68.1, 67.2, 65.4, 65.3, 62.0, 60.4, 56.9, 55.9, 53.0, 50.4, 47.8, 47.1, 47.0, 46.5, 42.9, 42.6, 30.6, 30.3; mass spectrum m/z (ESI) 557.3011 [C₃4H41N2O5 (M+l) requires 557.3015]. [0488] Example 14: Preparation of Compound 20

[0489] 10% Pd/C (3 mg) was added to a solution of amine 16 (25 mg, 0.048 mmol) in anhydrous MeOH (0.8 mL), and the reaction was evacuated and backfilled with ¾ three times. The reaction was heated at 50 °C for 6 h, filtered through cotton, and concentrated. The resultant clear gum was purified by flash column chromatography eluting with EtOAc/MeOH (90 : 10 with 1%

Et₃N) to give 21 mg (83%) of 20 as a white amorphous solid foam: ¾ NMR (600 MHz, CDC1₃) δ 9.33 (br s, 1 H), 7.48 (d, J= 7.7 Hz, 1 H), 7.42-7.35 (comp, 5 H), 7.32-7.28 (comp, 3 H), 7.25 (d, J= 8.5 Hz, 1 H), 7.23-7.19 (comp, 2 H), 7.12 (ddd, J= 8.1, 7.2, 1.2 Hz, 1 H), 7.11 (ddd, J = 8.1, 7.2, 1.2 Hz, 1 H), 4.67 (d, J= 11.8 Hz, 1 H), 4.62 (d, J= 1 1.8 Hz, 1 H), 4.53-4.49 (comp, 3 H), 4.43 (d, J= 5.3 Hz, 1 H), 4.07 (d, J= 9.5 Hz, 1 H), 4.05 (d, J= 9.5 Hz, 1 H), 3.95 (d, J= 8.7 Hz, 1 H), 3.71 (d, J= 8.7 Hz, 1 H), 2.92 (ddd, J= 13.9, 8.9, 6.4 Hz, 1 H), 2.62 (ddd, J= 12.3, 9.8, 5.3 Hz, 1 H), 2.51-2.48 (comp, 2 H), 2.35-2.26 (comp, 2 H), 1.98-1.89 (comp, 2 H), 1.78- 1.63 (comp, 3 H); ¹³C NMR (150 MHz, CDC1₃) δ 138.6, 137.6, 137.5, 134.8, 128.6, 128.4, 128.0, 127.9, 127.8, 127.7, 121.4, 119.3, 1 18.0, 110.5, 11 1.2, 1 10.5, 75.4, 75.1, 73.8, 73.3, 72.4, 60.5, 52.8, 49.0, 46.6, 46.0, 42.6, 30.0, 21.9, 1 1.9; IR (neat) 3414, 3060, 3030, 2930, 2870, 1459, 1 101, 909, 736, 699 cm^"1; mass spectrum m/z (ESI) 547.2932 [C₃₄H₄o ₂0₃ a (M+Na) requires 547.2931].

[0490] Example 15: Preparation of Compound 21

[0491] Bis(ethylthio)acetaldehyde (31 mg, 28 μί, 0.19 mmol) was added to a solution of compound 18 (45 mg, 0.09 mmol) in anhydrous methanol (1.0 mL), and the solution was stirred for 20 h. Sodium cyanoborohydride (7.6 mg, 0.12 mmol) was added followed by bromocresol green (-0.5 mg). The pH of the resultant solution was adjusted with a 0.5 M solution of HC1 in methanol until the reaction changed color from green to bright orange. Methanolic HC1 was added dropwise as needed to maintain this bright orange color over 0.5 h, after which time the reaction was partitioned between saturated aqueous aHC03 (10 mL) and CH2CI2 (10 mL). The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 x 5 mL). The combined organic layers were dried (Na₂S0₄) and concentrated under reduced pressure. The resultant green gum was purified by flash column chromatography eluting with hexanes/EtOAc (3 : 1 with l%Et₃N) to give 14.7 mg (41%) of compound 21 as a pale yellow gum: ^XH NMR (400 MHz, CD2CI2) δ 9.38 (br s, 1 H), 7.52 (d, J= 8.0 Hz, 1 H), 7.41-7.22 (comp, 1 1 H), 7.13-7.05 (comp, 2 H), 4.70 (d, J= 12.0 Hz, 1 H), 4.62 (d, J= 12.0 Hz, 1 H), 4.50-4.39 (comp, 4 H), 4.05- 4.00 (comp, 3 H), 3.95 (d, J= 8.8 Hz, 1 H), 3.72 (d, J= 8.8 Hz, 1 H), 3.21-3.05 (comp, 2 H), 2.97-2.88 (m, 1 H), 2.82-2.64 (comp, 4 H), 2.50-2.37 (comp, 3 H), 1.90-1.69 (comp, 3 H), 1.33- 1.27 (comp, 6 H); mass spectrum m/z (ESI) 631.3024

(M+1) requires 631.3028].

[0492] Example 16: Preparation of Compound 22

[0493] Glacial acetic acid (2.8 mg, 3 [lL, 0.05 mmol) was added to a mixture of compound 18 (22 mg, 0.05 mmol) and benzaldehyde (24.4 mg, 23 μΐ,, 0.23 mmol) in 1 ,2-dichloroethane (0.8 mL). Sodium triacetoxyborohydride (19 mg, 0.09 mmol) was added, and the reaction was stirred for 3 h, after which time the reaction was partitioned between CH2CI2 (5 mL) and saturated aqueous NaHCC (5 mL). The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 x 5 mL). The combined organic layers were dried (Na₂S0₄) and concentrated under reduced pressure. The resultant pale yellow gum was purified by flash column chromatography eluting with hexanes/EtOAc (1 : 1) to give 21.4 mg (81%) of compound 22 as a colorless amorphous solid foam: ^XH NMR (600 MHz, CD₃CN) δ 9.49 (br s, 1 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.40-7.22 (comp, 15 H), 7.07 (ddd, J = 8.1 , 7.1 , 1.2 Hz, 1 H), 7.01 (ddd, J = 8.0, 7.1 , 1.1 Hz, 1 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.49-4.45 (m, 1 H), 4.45 (s, 2 H), 4.22 (d, J = 5.4 Hz, 1 H), 4.07 (d, J = 8.8 Hz, 1 H), 4.00 (d, J = 9.3 Hz, 1 H), 3.94 (d, J = 9.3 Hz, 1 H), 3.74 (d, J = 14.0 Hz, 1 H), 3.66 (d, J = 8.8 Hz, 1 H), 3.49 (d, J = 14.0 Hz, 1 H), 2.70-2.65 (m, 1 H), 2.50-2.48 (m, 1 H), 2.41 -2.37 (m, 1 H), 2.26-2.18 (comp, 2 H), 1.86- 1.81 (m, 1 H), 1.73- 1.69 (m, 1 H); 13C NMR (150 MHz, CD3CN) δ 142.0, 140.0, 139.6, 139.5, 136.3, 129.4, 129.3, 129.3 *, 129.2, 129.1, 128.8, 128.7, 128.6, 128.5, 127.8, 122.0, 1 19.9, 1 18.8, 1 12.1 , 1 1 1.7, 76.0, 74.4, 74.3, 74.2, 73.8, 63.4, 53.6, 50.1, 47.7, 47.3, 43.7, 31.1 ; IR (neat) 3412, 2927, 1455, 1 101 , 1071, 737, 698 cm- 1 ; mass spectrum m/z (ESI) 573.31 13 [C38H41N203 (M+l) requires 571.3 1 12].

[0494] Example 17: Preparation of Compound 23

[0495] Sodium triacetoxyborohydride (16.7 mg, 0.08 mmol) was added to a solution of compound 18 (19.0 mg, 0.04 mmol) and formaldehyde (6.4 μΐ, of a 37% by weight aqueous solution, 0.08 mmol) in 1,2-dichloroethane (0.4 mL) at 0 °C, and the reaction was stirred for 2 h at 0 °C. The reaction was partitioned between saturated aqueous NaHCC^ (5 mL) and (¾(¾ (5 mL) and the layers were separated. The aqueous layer was extracted with (¾(¾ (2 x 5 mL) and the combined organic layers were dried ( a₂S0₄), filtered, and concentrated under reduced pressure. The resultant brown was purified by flash column chromatography eluting with toluene/EtOAc/MeOH (30 : 30 : 40) to give 16.3 mg (83%) of compound 23 as a colorless gum: ^XH NMR (400 MHz, CDC1₃) δ 9.29 (br s, 1 H), 7.44 (d, J= 7.6 Hz, 1 H), 7.35-7.01 (comp, 15 H), 4.60 (d, J= 12.0 Hz, 1 H), 4.53 (d, J= 12.0 Hz, 1 H), 4.44-4.39 (comp, 3 H), 4.31 (d, J= 5.2 Hz, 1 H), 4.00-3.97 (comp, 2 H), 3.85 (d, J= 8.8 Hz, 1 H), 3.62 (d, J= 8.8 Hz, 1 H), 2.97 (ddd, J = 14.4, 9.2, 6.4 Hz, 1 H), 2.48-2.40 (comp, 5 H), 2.20 (ddd, J= 13.2, 13.2, 4.0 Hz, 1 H), 1.93- 1.86 (m, 1 H), 1.73-1.69 (m, 1 H); ¹³C NMR (100 MHz, CDC1₃) δ 138.8, 137.5, 137.4, 134.8, 128.7, 128.4, 128.1, 127.9, 127.8, 127.7, 121.6, 119.5, 118.1, 1 10.6, 109.5, 75.0, 74.8, 73.9,

73.4, 72.5, 55.7, 50.2, 47.1, 46.3, 46.0, 41.6, 29.4; IR (neat) 341 1, 2929, 2865, 1456, 1101, 1073, 735, 699 cm^"1; mass spectrum m/z (ESI) 497.2802 [C32H37N2O3 (M+l) requires 497.2799].

[0496] Examples 18: Preparation of Compound 5

5

[0497] TMSC1 (2.2 mL, 1.8 g, 17.4 mmol) was added to a solution of 16 (3.3 g, 5.8 mmol) and imidazole (2.0 g, 29.0 mmol) in anhydrous DMF (62 mL), and the reaction was stirred 2 h. The reaction was partitioned between saturated aqueous NaHCC^ (100 mL) and Et₂0 (150 mL), and the layers were separated. The aqueous layer was extracted with Et₂0 (2 x 100 mL), and the combined organic layers were washed with brine (1 x 100 mL). The organic layer was dried (MgS0₄), filtered, and concentrated under reduced pressure. The resultant clear oil was purified by flash column chromatography eluting with hexanes/EtOAc (9 : 1) containing 1% Ets to provide 3.6 g (97%) of 5 as a colorless amorphous solid foam: mp 1 15-116 °C (colorless crystals from i-PrOH/H₂0); 'H NMR (500 MHz, DMSO-i , 120 °C) δ 10.23 (br s, 1 H), 7.39 (d, J= 8.0 Hz, 1H), 7.32-7.29 (comp, 5 H), 7.27-7.22 (comp, 6 H), 7.05 (t, J= 8.0 Hz, 1 H), 6.97 (t, J= 8.0 Hz, 1 H), 6.04-5.97 (m, 1 H), 5.51 (d, J= 6.5 Hz, 1 H), 5.33 (d, J= 17.0 Hz, 1 H), 5.21 (d, J = 10.5 Hz, 1 H), 4.67-4.58 (comp, 4 H), 4.48 (d, J= 12.5 Hz, 1 H), 4.45 (d, J= 12.5 Hz, 1 H), 4.32-4.27 (comp, 2 H), 3.98 (d, J= 9.5 Hz, 1 H), 3.92 (d, J= 9.5 Hz, 1 H), 3.75-3.71 (comp, 2 H), 2.93-2.85 (m, 1 H), 2.67-2.61 (comp, 2 H), 1.92 (ddd, J= 14.5, 3.5, 3.5 Hz, 1 H), 1.86 (dd, J = 13.5, 9.0 Hz, 1 H), 1.75-1.67 (m, 1 H), 0.05 (s, 9 H); ¹³C MR (125 MHz, DMSO-i , 120 °C) δ 154.0, 138.8, 138.1, 138.0, 134.9, 133.2, 127.4, 127.3, 126.6, 126.6, 126.5, 126.4, 125.3, 120.2, 1 18.1, 1 16.0, 116.0 1 10.6, 110.5, 74.8, 72.5, 72.3, 72.1, 71.5, 64.4, 46.7, 46.2, 45.5, 40.5 39.7, 29.1, -0.8; IR (neat) 3030, 2951, 2871, 1693, 1454, 1412, 1251, 1072, 873, 842, 744, 698 cm^"1; mass spectrum (ESI) m/z 661.3066 [C₃8H₄₆N₂Na0₅Si (M+l) requires 661.3068].

[0498] Example 19: Preparation of Compound 6

6

[0499] DMAP (0.2 g, 1.64 mmol) was added to a solution of 5 (3.5 g, 5.5 mmol) in Boc₂0 (16 mL) at 100 °C, and the reaction was stirred for 30 min at 100 °C. The reaction was partitioned between H₂0 (100 mL) and Et₂0 (150 mL), and the layers were separated. The aqueous layer was extracted with Et₂0 (2 x 150 mL), and the combined organic layers were dried (MgS0₄), filtered, and concentrated under reduced pressure. The resultant brown oil was purified by flash column chromatography eluting with hexanes/EtOAc (1 : 0→ 95 : 5→ 9 : 1) to provide 3.8 g (93%) of 6 as a white amorphous solid foam: mp 139-140 °C (colorless crystals from i-

PrOH/H₂0); ^XH NMR (400 MHz, as a mixture of rotamers) δ 7.72 (dd, J= 8.4, 2.4 Hz, 1 H), 7.45 (d, J= 7.6 Hz, 0.5 H), 7.36-7.27 (comp, 4 H), 7.24-7.19 (comp, 2.5 H), 7.16-7.08 (comp, 4 H), 7.00-6.96 (comp, 2 H), 6.06-5.96 (m, 0.5 H), 5.93-5.84 (m, 0.5 H), 5.66 (d, J= 6.8 Hz, 0.5 H), 5.54 (d, J= 6.8 Hz, 0.5 H), 5.37 (dd, J= 17.2, 1.6 Hz, 0.5 H), 5.26-5.20 (comp, 1 H), 5.13 (dd, J= 10.4, 1.2, 0.5 H), 4.77-4.72 (comp, 1.5 H), 4.67-4.49 (comp, 3.5 H), 4.45-4.41 (comp, 2 H), 4.35-4.32 (comp, 1 H), 4.28-4.15 (comp, 2 H), 3.80 (dd, J= 14.4, 6.4 Hz, 0.5 H), 3.58 (dd, J = 14.4, 6.4 Hz, 0.5 H), 3.58 (d, J= 10.0 Hz, 1 H), 2.94-2.87 (comp, 1.5 H), 2.83-2.76 (m, 0.5 H), 2.69-2.57 (m, 1 H), 2.08-1.99 (m, 1 H), 1.91-1.65 (comp, 2 H), 1.50 (s, 9 H); 0.01 (s, 9 H); ¹³C NMR (100 MHz, as a mixture of rotamers) δ 155.4, 155.3, 151.0, 139.5, 138.9, 138.8, 138.2, 138.1, 136.3, 136.2, 133.31, 133.28, 127.2, 127.1, 126.9, 126.8, 126.7, 126.4, 126.3, 124.1, 121.74, 121.71, 121.3, 121.1, 1 18.0, 117.6, 1 17.4, 116.9, 114.1, 1 14.0, 83.7, 83.6, 78.0, 77.8, 77.2, 75.5, 75.4, 72.5, 72.4, 72.3, 72.0, 65.9, 65.8, 52.7, 52.6, 49.5, 47.0, 46.8, 41.1, 41.0, 39.8, 38.8, 31.5, 30.7, 28.0, 27.4, -0.08; IR (neat) 2952, 1739, 1696, 1456, 1316, 1250, 1 112, 845, 737 cm^"1; mass spectrum (ESI) m/z 739.3765 [C43H55N2O7S1 (M+l) requires 739.3773].

[0500] Example 20: Preparation of Compound 7

7 [0501] TBAF-3H₂0 (289 mg, 0.915 mmol) was added to a solution of 6 (135 mg, 0.183 mmol) in CH2CI2 (1.8 mL), and the reaction was stirred for 2 h. The reaction was partitioned between saturated aqueous aHC03 (10 mL) and CH2CI2 (10 mL), and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 10 mL), and the combined organic layers were dried (Na₂S04), filtered, and concentrated under reduced pressure. The resultant yellow gum was purified by flash column chromatography eluting with hexanes/EtOAc (70 : 30) containing 1% Et₃N to provide 1 18 mg (97%) of 7 as a colorless amorphous solid foam: mp 182-183 °C

(colorless crystals from -PrOH/H₂0); ^XH NMR (400 MHz, as a mixture of rotamers) δ 7.75 (dd, J= 8.4, 4.0 Hz, 1 H), 7.50 (d, J= 8.4 Hz, 0.5 H), 7.39 (d, J= 7.6 Hz, 0.5 H), 7.31-7.12 (comp, 12 H), 6.09-5.99 (m, 0.5 H), 5.95-5.87 (m, 0.5 H), 5.74 (d, J= 6.4 Hz, 0.5 H), 5.60 (d, J= 6.4 Hz, 0.5 H), 5.43-5.15 (comp, 2 H), 4.73-4.70 (m, 1 H), 4.63-4.25 (comp, 9 H), 4.12 (d, J= 9.2 Hz, 0.5 H), 4.05 (d, J= 9.2 Hz, 0.5 H), 3.88-3.66 (comp, 2 H), 3.09-2.95 (m, 1 H), 2.84 (br s, 1 H), 2.61-2.48 (m, 1 H), 2.14-2.05 (m, 1 H), 1.97-1.73 (comp, 2 H), 1.58 (s, 9 H); ¹³C NMR (100 MHz, as a mixture of rotamers) δ 155.2, 155.1, 151.4, 151.3, 137.8, 137.75, 137.66, 137.6, 137.4, 137.3, 136.4, 133.2, 133.1, 128.4, 128.2, 128.1, 128.0, 127.8, 127.5, 127.4, 127.3, 127.2, 126.8, 126.6, 124.5, 122.2, 122.1, 118.3, 1 17.9, 117.4, 117.1, 1 13.9, 84.2, 84.1, 77.2, 76.2, 75.4, 75.1, 74.8, 74.7, 73.54, 73.48, 72.9, 72.8, 66.1, 65.9, 53.7, 53.4, 49.5, 49.4, 47.1, 47.0, 40.7, 40.6, 39.2, 38.2, 31.4, 30.8, 28.0; IR (neat) 2941, 1739, 1693, 1456, 1316, 11 12, 738 cm^"1; mass spectrum (ESI) m/z 667.3374 [C4₀H47N2O7 (M+l) requires 667.3378].

[0502] Example 21 : Preparation of Compound 24 (1257)

24

[0503] A solution of tetrakis(triphenylphosphine)palladium(0) (10.4 mg, 0.009 mmol) in CH2CI2 (0.1 mL) was added to a solution of 7 (1 18 mg, 0.177 mmol) and PhSiH₃ (0.44 mL, 383 mg, 3.54 mmol) in CH2CI2 (1.7 mL), and the reaction was stirred for 0.5 h. The reaction was partitioned between saturated aqueous aHC0₃ (10 mL) and CH2CI2 (10 mL), and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 10 mL), and the combined organic layers were dried ( a₂S04), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with EtOAc/MeOH (85 : 15) containing 1% EtsN to provide 75 mg (73%) of 24 as a tan amorphous solid foam: ^XH NMR (400 MHz) δ 7.76 (d, J= 8.0 Hz, 1 H), 7.46 (d, J= 7.2 Hz, 1 H), 7.30-7.20 (comp, 10 H), 7.17-7.14 (comp, 2 H), 4.64-4.60 (comp, 2 H), 4.56 (s, 2 H), 4.51-4.46 (comp, 3 H), 4.42 (d, J= 12.4 Hz, 1 H), 4.05 (d, J= 9.2 Hz, 1 H), 3.74 (d, J= 9.2 Hz, 1 H), 2.86-2.78 (comp, 2 H), 2.58 (dd, J= 12.8, 5.2 Hz, 1 H), 2.36 (ddd, J= 12.8, 12.8, 3.6 Hz, 1 H), 2.13 (dd, J= 13.2, 9.2 Hz, 1 H), 1.97-1.90 (m, 1 H), 1.80-1.71 (m, 1 H), 1.58 (s, 9 H); ¹³C NMR (100 MHz) δ 151.6, 138.0, 137.5, 137.3, 136.8, 128.3, 128.2, 127.9, 127.7, 127.2, 126.8, 124.1, 122.8, 121.8, 117.7, 1 14.0, 83.8, 77.2, 76.3, 75.6, 75.0, 73.5, 72.9, 53.4, 49.5, 47.5, 42.3, 41.7, 31.8, 28.0; IR (neat) 2931, 1736, 1456, 1316, 1135, 738 cm^"1; mass spectrum (ESI) m/z 583.3170 [C36H43N2O5 (M+l) requires

583.3166].

[0504] Example 22: Biological Activity [0505] Activity of certain compounds of the present disclosure were tested against human breast (Hs578T, BT549,T47D, MCF7, BT20, HCC1954), human lymphoma (U937) and lung cancer cell lines (A549). The results are shown in Table pi . The compounds tested were:

Table pi: IC₅₀ Values (μΜ)

[0506] As shown above, the compounds tested are cytotoxic towards several human cancer cell lines, and appear to act by cell cycle arrest in Gl phase and apoptotic cell death indicated by caspase activation (data not shown).

V. Embodiments:

[0507] Embodiment 1 A compound having the formula:

wherein: R¹ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^1A, -OR^1A, - NR^1AR^1B, -C(0)OR^1A, -C(0)NR^1A R^1B, -N0₂, -SR^1A, -S(0)_niR^1A, -S(0)_niOR^1A, -S(0)_niNR^1AR^1B, -NHNR^1AR^1B, -ONR^1AR^1B, -NHC(0)NHNR^1AR^1B, 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; R² is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^2A, -OR^2A, -NR^2AR^2B, - C(0)OR^1A, -C(0)NR^2AR^2B, -N0₂, -SR^2A, -S(0)„₂R^2A, -S(0)„₂OR^2A, -S(0)„iNR^2AR^2B, - NHNR^2AR^2B, -ONR^2AR^2B, -NHC(0)NHNR^2AR^2B, 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; R³ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^3A, -OR^3A, -NR^3AR^3B, - C(0)OR^3A, -C(0)NR^3AR^3B, -N0₂, -SR^3A, -S(0)„₃R^3A, -S(0)„₃OR^3A, -S(0)„3NR^3AR^3B, - NHNR^3AR^3B, -ONR^3AR^3B, -NHC(0)NHNR^3AR^3B, 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; R⁴ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^4A, -OR^4A, -NR^4AR^4B, - C(0)OR^4A, -C(0)NR^4AR^4B, -N0₂, -SR^4A, -S(0)_n4R^4A, -S(0)_n4OR^4A, -S(0)_n4NR^4AR^4B, - NHNR^4AR^4B, -ONR^4AR^4B, -NHC(0)NHNR^4AR^4B, 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; R⁵ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^5A, -OR^5A, -NR^5AR^5B, - C(0)OR^5A, -C(0)NR^5AR^5B, -N0₂, -SR^5A, -S(0)„₅R^5A, -S(0)„₅OR^5A, -S(0)„₅NR^5AR^5B, - NHNR R , -ONR^R , -NHC(0)NHNR R , 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; R⁶ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^6A, -OR^6A, -NR^6AR^6B, - C(0)OR^6A, -C(0)NR^6AR^6B, -N0₂, -SR^6A, -S(0)„₆R^6A, -S(0)„₆OR^6A, -S(0)„₆NR^6AR^6B, -

NHNR^6AR^6B, -ONR^6AR^6B, -NHC(0)NHNR^6AR^6B, 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; R⁷ is independently hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^7A, -OR^7A, - NR^7AR^7B, -C(0)OR^7A, -C(0)NR^7AR^7B, -N0₂, -SR^7A, -S(0)„₇R^7A, -S(0)„₇OR^7A, -S(0)„₇NR^7AR^7B, -NHNR^7AR^7B, -ONR^7AR^7B, -NHC(0)NHNR^7AR^7B, 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; L¹ and L² are independently -0-, -C(0)0-. -C(0)NH-, -NH-. -S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; nl, n2, n3, n4, n5, n6 and n7 are independently 1 or 2; n is 1, 2, 3, 4 or 5; m is 1 or 2; and R^1A, R^1B, R^2A, R^2B, R^3A, R^3B, R^4A, R^4B, R^5A, R^5B, R^6A, R^6B, R^7A, R^7B are independently hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, -Si(CH₃)₃ 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, wherein the compound is not actinophyllic acid or its methyl ester. [0508] Embodiment 2 The compound of embodiment 1, wherein R⁴ is hydrogen, -OR^4A, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R⁵ is hydrogen, -OR^5A, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. [0509] Embodiment 3 The compound of embodiment 1 or 2, wherein R⁴ is hydrogen, -OR^4A,

4C 4C 4C

R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl, R -substituted or unsubstituted cycloalkyl or R^4C-substituted or unsubstituted heterocycloalkyl; R⁵ is hydrogen, -OR , R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl, R - substituted or unsubstituted cycloalkyl or R^5C-substituted or unsubstituted heterocycloalkyl; wherein R^4C and R^5C are independently halogen, hydroxyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl or

unsubstituted heterocycloalkyl.

[0510] Embodiment 4 The compound of any one of embodiments 1 to 3, wherein R⁴ is hydrogen, -OR^4A, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl, R^4C-substituted or unsubstituted cycloalkyl or R^4C-substituted or unsubstituted

5 5A. 5C 5C

heterocycloalkyl; R is hydrogen, -OR , R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl, R^5C-substituted or unsubstituted cycloalkyl or R^5C-substituted or unsubstituted heterocycloalkyl; wherein R^4C and R^5C are unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl or unsubstituted heterocycloalkyl.

[0511] Embodiment 5 The compound of any one of embodiments 1 to 4, wherein R⁴ is -OR^4A and R⁵ is -OR^5A. [0512] Embodiment 6 The compound of one embodiments 1 to 5 having the structure:

[0513] Embodiment 7 The compound of one embodiments 1 to 6, wherein R³ is halogen, - OR^3A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0514] Embodiment 8 The compound of one embodiments 1 to 6, wherein R³ is -OR^:

[0515] Embodiment 9 The compound of embodiment 1 having the structure:

[0516] Embodiment 10 The compound of any one of embodiments 1 to 9, wherein R¹ is hydrogen, halogen, -C(0)R^1A, -C(0)OR^1A, -NR^1AR^1B, -OR^1A, 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.

[0517] Embodiment 1 1 The compound of embodiment 10, wherein R^1B is hydrogen. [0518] Embodiment 12 The compound of embodiment 10, wherein R¹ is hydrogen, -C(0)R^1A, -C(0)OR^1A, R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^lc-substituted or unsubstituted heterocycloalkyl,

1 C 1C 1A. 1C

R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl; R is R - substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^lc-substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl; and R^1C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, - S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^1D-substituted or unsubstituted alkyl, R^1D-substituted or unsubstituted heteroalkyl, R^1D-substituted or unsubstituted cycloalkyl, R^1D-substituted or unsubstituted heterocycloalkyl, R^1D-substituted or unsubstituted aryl, or R^1D-substituted or unsubstituted heteroaryl; and R^1D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, - COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, - NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0519] Embodiment 13 The compound of embodiment 10, wherein R¹ is hydrogen, halogen, - C(0)R^1A, -C(0)OR^1A, 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. [0520] Embodiment 14 The compound of embodiment 10, wherein R^1A is hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3 to Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C₁₀ aryl or substituted or unsubstituted 5 or 6 membered heteroaryl. [0521] Embodiment 15 The compound of embodiment 10, wherein R^1A is R^lc-substituted or unsubstituted alkyl, or R^lc-substituted or unsubstituted heteroalkyl; and R^1D is halogen, unsubstituted alkyl or unsubstituted cycloalkyl.

[0522] Embodiment 16 The compound of embodiment 10, wherein R¹ is hydrogen or R^1C- substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl, R^1D-substituted or unsubstituted aryl, R^1D-substituted or unsubstituted heteroaryl, R^1D-substituted or unsubstituted cycloalkyl, or R^1D-substituted or unsubstituted heterocycloalkyl; and R^1D is halogen or unsubstituted alkyl.

[0523] Embodiment 17 The compound of embodiment 10, wherein R¹ is hydrogen or R^1C- substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl. [0524] Emb ound of embodiment 10, wherein R¹ is hydrogen, methyl, ethyl, propyl,

r allyl.

[0525] Embodiment 19 The compound of embodiment 10, wherein R is hydrogen.

[0526] Embodiment 20 The compound of embodiment 1 having the structure:

[0527] Embodiment 21 The compound of embodiment 20, wherein m is 1. [0528] Embodiment 22 The compound of embodiment 1 having the structure:

[0529] Embodiment 23 The compound of embodiment 1 having the structure:

[0530] Embodiment 24 The compound of any one of embodiments 1 to 23, wherein L¹ and L² are independently substituted or unsubstituted alkylene.

[0531] Embodiment 25 The compound of any one of embodiments 1 to 23, wherein L¹ and L² are independently unsubstituted alkylene. [0532] Embodiment 26 The compound of any one of embodiments 1 to 23, wherein L¹ and L² are independently unsubstituted Ci to C₁₀ alkylene.

[0533] Embodiment 27 The compound of any one of embodiments 1 to 23, wherein L¹ and L² are independently unsubstituted Ci to C5 alkylene.

[0534] Embodiment 28 The compound of any one of embodiments 1 to 23, wherein L¹ and L² are methylene.

[0535] Embodiment 29 The compound of any one of embodiments 1 to 28, wherein R^4A is hydrogen, R^4C-substituted or unsubstituted alkyl, R^4C-substituted or unsubstituted heteroalkyl, R^4C-substituted or unsubstituted cycloalkyl, R^4C-substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl; R is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D-substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R - substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D- substituted or unsubstituted heteroaryl; R^4D is independently oxo, halogen, -CF₃, -CN, -OH, - NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; R^5A is hydrogen, R^5C- substituted or unsubstituted alkyl, R^5C-substituted or unsubstituted heteroalkyl, R^5C-substituted or unsubstituted cycloalkyl, R^5C-substituted or unsubstituted heterocycloalkyl, R^5C-substituted or unsubstituted aryl, R^5C-substituted or unsubstituted heteroaryl; R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, - S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D-substituted or unsubstituted alkyl, R^5D-substituted or unsubstituted heteroalkyl, R^5D-substituted or unsubstituted cycloalkyl, R^5D-substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D-substituted or unsubstituted heteroaryl; and R^5D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, - COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, - NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0536] Embodiment 30 The compound of embodiment 29, wherein R^4A is R^4C-substituted or unsubstituted alkyl, wherein R^4C is R^4D-substituted or unsubstituted aryl; and R^5A is R^5C- substituted or unsubstituted alkyl, wherein R^5C is R^5D-substituted or unsubstituted aryl.

[0537] Embodiment 31 The compound of embodiment 29, wherein R^4A is

wherein z4 is an integer from 1 to 5; and R^5A is

, wherein z5 is an integer from 1 to

5.

[0538] Embodiment 32 The compound of embodiment 29, wherein z4 is 1 or 2 and z5 is 1 or 2. [0539] Embodiment 33 The compound of embodiment 29, wherein z4 and z5 are 0.

[0540] Embodiment 34 The compound of one of embodiments 1 to 29, wherein R⁶ is hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, -NR^6AR^6B, -OR^6A, 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.

[0541] Embodiment 35 The compound of embodiment 34, wherein R^6B is hydrogen.

[0542] Embodiment 36 The compound of embodiment 34, wherein R⁶ is hydrogen, -C(0)R^6A, -C(0)OR^6A, R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl; R is R - substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl; R^6C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, - S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D-substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, - COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, - NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0543] Embodiment 37 The compound of embodiment 36, wherein R⁶ is R^6C-substituted or unsubstituted alkyl, wherein R^6C is R^6D-substituted or unsubstituted aryl.

[0544] Embodiment 38 The compound of embodiment 36, wherein R⁶ is -C(0)OR^6A and R^6A is R^6C-substituted or unsubstituted aryl. [0545] Embodiment 39 The compound erein R⁶ is hydrogen,

unsubstituted C1-C5 alkyl, -C(0)OR or

z6 is an integer from 1 to 5 and

R^6A is R^6C-substituted or unsubstituted alkyl.

[0546] Embodiment 40 The compound of embodiment 36, wherein R⁶ is -C(0)OR^6A and R^6A is unsubstituted alkyl.

[0547] Embodiment 41 The compound of embodiment 36, wherein z6 is 1 or 2.

[0548] Embodiment 42 The compound of one of embodiments 1 to 18, wherein R⁶ is hydrogen, halogen, -C(0)R^6A, -C(0)OR^6A, 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.

[0549] Embodiment 43 The compound of embodiment 42, wherein R^6A is hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3 to Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C1₀ aryl or substituted or unsubstituted 5 or 6 membered heteroaryl.

[0550] Embodiment 44 The compound of embodiment 42, wherein R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroalkyl; and R^6C is halogen, unsubstituted alkyl or unsubstituted cycloalkyl.

[0551] Embodiment 45 The compound of embodiment 34, wherein R⁶ is hydrogen or R^6C- substituted or unsubstituted Ci to C5 alkyl, wherein R^6C is hydroxyl, R^6D-substituted or unsubstituted aryl, R^6D-substituted or unsubstituted heteroaryl, R^6D-substituted or unsubstituted cycloalkyl, or R^6D-substituted or unsubstituted heterocycloalkyl; and R^6D is halogen or unsubstituted alkyl.

[0552] Embodiment 46 The compound of embodiment 34, wherein R⁶ is -C(0)OR^6A; R^6A is R^6C-substituted or unsubstituted alkyl; and R^6C is unsubstituted alkyl or halogen.

[0553] Embodiment 47 The compound of embodiment 34, wherein R⁶ is hydrogen, methyl, ethyl or propyl.

[0554] Embodiment 48 The compound of embodiment 34, wherein R⁶ is hydrogen. [0555] Embodiment 49 The compound of embodiment 34, wherein R⁶ is methyl.

[0556] Embodiment 50 The compound of one of embodiments 1 to 49, wherein R⁷ is hydrogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, - S(0)₂NH₂, -NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^7C-substituted or unsubstituted alkyl, R^7C-substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C-substituted or

7 A. 7C 7C

unsubstituted heteroaryl; R is R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C-substituted or unsubstituted heteroaryl; R^7C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, - CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, - NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -

7D 7D 7D

OCHF₂, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R - substituted or unsubstituted cycloalkyl, R^7D-substituted or unsubstituted heterocycloalkyl, R^7D- substituted or unsubstituted aryl, or R^7D-substituted or unsubstituted heteroaryl; and R^7D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0557] Embodiment 51 The compound of one of embodiments 1 to 49, wherein R⁷ is hydrogen.

[0558] Embodiment 52 The compound of one of embodiments 1 to 51, wherein R^3A is hydrogen, -Si(CH₃)₃, R^3C-substituted or unsubstituted alkyl, R^3C-substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R^3C-substituted or unsubstituted aryl, R^3C-substituted or unsubstituted heteroaryl; R^3C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, - SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^3D-substituted or unsubstituted alkyl, R^3D-substituted or unsubstituted heteroalkyl, R^3D-substituted or unsubstituted cycloalkyl, R^3D-substituted or unsubstituted heterocycloalkyl, R^3D-substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl; and R is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0559] Embodiment 53 The compound of one of embodiments 1 to 51, wherein R^3A is hydrogen, R^3C-substituted or unsubstituted alkyl, R^3C-substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl,

3C 3C 3C

R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl; R is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF₂, R^3D-substituted or unsubstituted alkyl,

3D 3D 3D

R -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R - substituted or unsubstituted heterocycloalkyl, R^3D-substituted or unsubstituted aryl, or R^3D- substituted or unsubstituted heteroaryl; and R^3D is independently oxo, halogen, -CF₃, -CN, -OH, - NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0560] Embodiment 54 The compound of embodiment 52, wherein R^3A is hydrogen or unsubstituted alkyl.

[0561] Embodiment 55 The compound of embodiment 52, wherein R^3A is hydrogen or methyl.

[0562] Embodiment 56 The compound of one of embodiments 1, 24 to 49 or 52 to 55, having the structure:

[0563] Embodiment 57 The compound of embodiment 56, wherein R^' 4A

wherein z4 is an integer from 1 to 5; R^5A is

, wherein z5 is an integer from 1 to 5;

R^4C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, - S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, - NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D-substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl; R^4D is independently oxo, halogen, -CF₃, - CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D-substituted or unsubstituted alkyl, R^5D-substituted or unsubstituted heteroalkyl, R^5D-substituted or unsubstituted cycloalkyl, R^5D- substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D- substituted or unsubstituted heteroaryl; and R^5D is independently oxo, halogen, -CF₃, -CN, -OH, - NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0564] Embodiment 58 The compound of embodiment 57, wherein z4 and z5 are 1.

[0565] Embodiment 59 The compound of embodiment 57 or 58, wherein R^4C and R^4C are hydrogen.

[0566] Embodiment 60 The compound of one of embodiments 56 to 59, wherein R⁶ is

hydrogen, unsubstituted C1-C5 alkyl, -C(0)OR^6A or

, wherein z6 is an integer from 1 to 5; iC^L is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, - NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D-substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0567] Embodiment 61 The compound of embodiment 60, wherein R^6C is hydrogen.

[0568] Embodiment 62 The compound of embodiment 60 or 61 wherein z6 is 1.

[0569] Embodiment 63 The compound of one of embodiments 56 to 62, wherein L¹ and L² are unsubstituted Ci to C5 alkylene. [0570] Embodiment 64 The compound of embodiment 63, wherein L¹ and L² are methylene.

[0571] Embodiment 65 The compound of one of embodiments 56 to 67, wherein R^3A is hydrogen or methyl.

[0572] Embodiment 66 The compound of one of embodiments 56 to 67, wherein R^3A is hydrogen. [0573] Embodiment 67 The compound of one of embodiments 56 to 67, wherein R¹ is substituted or unsubstituted alkyl.

[0574] Embodiment 68 The compound of one of embodiments 56 to 67, wherein R¹ is hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl.

[0575] Embodiment 69 The co s 56 to 67, wherein R¹ is hydrogen, methyl, ethyl, propyl,

[0576] Emb ound of one of embodiments 56 to 67, wherein R¹ is methyl, ethyl, propyl,

r allyl. [0577] Embodiment 71 The compound of one of embodiments 56 to 67, wherein R¹ is allyl.

[0578] Embodiment 72 The compound of one of embodiments 1 or 24 to 49, said compound having the formula:

[0579] Embodiment 73 The comp

ound of embodiment 72, wherein R

wherein z4 is an integer from 1 to 5; R is

, wherein z5 is an integer from 1 to 5;

R^4C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, - S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, - NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D-substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl; R^4D is independently oxo, halogen, -CF₃, - CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D-substituted or unsubstituted alkyl,

5D > 5D

R -substituted or unsubstituted heteroalkyl, R^3LI-substituted or unsubstituted cycloalkyl, R substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D- substituted or unsubstituted heteroaryl; and R^5D is independently oxo, halogen, -CF₃, -CN, -OH, NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, - OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0580] Embodiment 74 The compound of embodiment 73, wherein z4 and z5 are 1.

[0581] Embodiment 75 The compound of embodiment 57 or 73, wherein R^4C and R^4C are hydrogen.

[0582] Embodiment 76 The compound of one of embodiment 72 to 75, wherein R⁶ is

hydrogen, unsubstituted C1-C5 alkyl, -RC(0)OR^6A or

, wherein z6 is an integer from 1 to 5; R^6A is R^6C-substituted or unsubstituted alkyl; R^6C is independently oxo, halogen, - CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, - NH H₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF₃, -OCHF₂, R^6D-substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -

NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0583] Embodiment 77 The compound of embodiment 76, wherein

[0584] Embodiment 78 The compound of embodiment 60, wherein R^6C is hydrogen.

[0585] Embodiment 79 The compound of embodiment 60 or 61 wherein z6 is 1.

[0586] Embodiment 80 The compound of embodiment 76, wherein R⁶ is -C(0)OR^6A and R^6A is unsubstituted alkyl.

[0587] Embodiment 81 The compound of embodiment 80, wherein R^6A is tertiary butyl. [0588] Embodiment 82: The compound of embodiment 1, having the formula:

[0589] Embodiment 83 A method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of any one of embodiments 1 to 82.

[0590] Embodiment 84 The method of embodiment 83, wherein said cancer is lung cancer, lymphoma, breast cancer, cervical cancer, or brain cancer.

[0591] Embodiment PI A composition comprising a compound of Formula (PI):

wherein R¹ is H, alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, C0₂R⁹, S0₂R⁹, allyl, benzyl with optional substitutions, or alkyl with optional substitutions by at least one OR⁸, SR⁸ or (R⁸)₂; R² is H or together with R¹ to form a five- or six-membered ring; R³ is OR⁸, halo, SR⁸, N(R⁸)₂ or together with the adjacent carbon to form a carbonyl group; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

[0592] Embodiment P2 The composition according to embodiment PI, wherein R³ is OR⁸, halo, SR⁸, or (R⁸)₂.

[0593] Embodiment P3 The composition according to embodiment PI, wherein R³ is OR⁸. [0594] Embodiment P4 The composition according to embodiment P I, wherein the compound of Formula (PI) is selected from the group consisting of:

[0596] Embodiment P6 The composition according to embodiment PI, wherein R³, together with the adjacent carbon, form a carbonyl group as a compound of Formula (PII):

[0597] Embodiment P7 The composition according to embodiment P6, wherein R⁶ is alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹.

[0598] Embodiment P8 The composition according to embodiment P7, wherein R⁶ is Boc.

[0599] Embodiment P9 The composition according to embodiment PI, wherein R¹ and R² form a five- or six-membered ring as a compound of Formula (PHI):

wherein m is 1 or 2.

[0600] Embodiment P 10 A composition comprising a compound of Formula (PIV):

wherein R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; R⁸ is H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; R¹⁰ is C0₂H, C0₂alkyl or CH₂OR⁸; n is 0, 1, 2, 3, or 4; and with a proviso that when R¹⁰ is C0₂H, R⁶, R⁷ and R⁸ cannot all be H; or a pharmaceutically acceptable salt thereof.

[0601] Embodiment PI 1 A process comprising the step of protecting the nitrogen atom of the indole ring and removing R¹ group in a compound of Formula (PIIA):

with suitable agents to form a compound of Formula (PUB):

wherein R¹ is alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, C0₂R⁹, S0₂R⁹, allyl, benzyl with optional substitutions, or alkyl with optional substitutions by at least one OR⁸, SR⁸ or (R⁸)₂; R² is H; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4. [0602] Embodiment P12 A process comprising the step of alkylating, reductively alkylating, acylating or sulfonylating a compound of Formula (PUB):

with a suitable alkylating agent, a suitable aldehyde and reducing agent, a suitable acid chloride or anhydride, a suitable haloformate, or a suitable sulfonyl halide to form a compound of Formula (PIIC):

wherein R² is H; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, NO₂, CN, CO₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; R¹² is alkyl, cycloalkyl, aryl, heteroaryl, COR⁹, C0₂R⁹, S0₂R⁹, allyl, benzyl with optional substitutions, or alkyl with optional substitutions by at least one OR⁸, SR⁸ or (R⁸)₂; and n is 0, 1, 2, 3, or 4.

[0603] Embodiment P13 A process comprising the steps of (1) reductively alkylating a compound of Formula (PUB):

with a suitable aldehyde and a suitable reducing agent; then (2) cyclizing under a suitable cyclization condition to form a compound of Formula (PIIIA):

wherein R² is H; R⁴ and R⁵ is each independently H, methyl, OH, or OR⁹; R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, O₂, CN, CO₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0604] Embodiment P 14 A process comprising the step of removing protecting groups in a compound of Formula (PIIIB):

with suitable agents to form a compound of Formula (PIVA):

wherein R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; PG is a suitable protecting group; and n is 0, 1, 2, 3, or 4. Embodiment P15 A process comprising the step of oxidizing a compound of Formula

with a suitable oxidizing agent to form a compound of Formula (PVIB):

wherein R⁶ is H, alkyl, Boc, COR⁹, C0₂R⁹, or S0₂R⁹; each R⁷ is independently H, halo, alkyl, fluoroalkyl, aryl, OR⁸, SR⁸, N(R⁸)₂, N0₂, CN, C0₂R⁹; each R⁸ is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or a protecting group; each R⁹ is independently H, alkyl, cycloalkyl, allyl, benzyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4. [0606] Embodiment P 16 A composition comprising a compound formed from the process of any of embodiments P11-P15.

[0607] Embodiment P 17 A method comprising introducing to a cancer cell a composition comprising a compound according to any of embodiments P1-P 10 or P I 6.

VI. Examples

[0608] Portions are reprinted with permission from Granger, B. A.; Jewett, I. T.; Butler, J. D.; Hua, B.; Knezevic, C. E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. Synthesis of (±)- actinophyllic acid and analogs: applications of cascade reactions and diverted total synthesis. J. Am. Chem. Soc. 2013, 135, 12984-12986. [0609] High-throughput screen and initial results

[0610] Screens of compound libraries have led to the discovery of a number of interesting and promising anticancer compounds, including the triphenylmethylamides¹ and

dexoynyboquinone.² Since the HTSF library is constantly expanding and incorporating new compounds from numerous synthetic labs, a screen of recently submitted HTSF library compounds for anticancer activity was conducted.

[0611] Screen protocol and results: Due to recent reports on the ability of cultured breast cancer cell lines to faithfully represent specific subtypes of actual patient tumors,³ a screen in three different breast cancer cell lines was conducted. Without being bound by any particular theory, by using cell lines representative of different types of breast cancer, anticancer agents that are selective for certain subtypes over others could be identified. Such compounds would be interesting because they could have predictable efficacy against tumors and the selective nature would suggest that the differences between subtypes is important for the compound's mechanism of action. Of course, compounds that are effective against a broad set of cancer cell lines would also be interesting, and would be identified by this type of screen. The three cell lines screened were Hs578t, a triple-negative cell line representative of the basal subtype, MCF-7, an ER- positive cell line representative of the luminal A subtype, and HCC1954, an ER-negative cell line representative of the basal subtype. Each of these cell lines falls within broad subtypes of basal, luminal or Erbb2, but they were also determined to each be representative of a different well-defined subtype of breast cancer through pathway analysis of their gene expression data.³

[0612] A brief protocol for the screen is as follows: the screen was conducted in 384-well plates, with a total volume of 50 in each well. First, 40 of media was distributed to all wells, 100 nL of screening compound was pin-transferred into the media, then 10 of a 200,000 cells/mL suspension of cells was added to each well (2,000 cells/well). Plates were sealed with a gas-permeable seal and incubated at 37 °C for 48 h. Next, alamar blue was added to each plate, which was resealed and incubated for 4-6 h, and the fluorescence of each well was read. Depending on the concentration of the compound plates, the final concentration of compound ranged from 2 - 20 μΜ. [0613] Initially, viability was assessed using sulforhodamine B (SRB) dye, using a protocol adapted from the commonly used protocol for 96-well plates.⁴ While good results could be obtained with SRB, significant over-dyeing of wells was often encountered, which could not be eliminated by optimization of the type of plate, washing steps, or plating methods. Thus, viability was assessed in the bulk of the screen by alamar blue. In this assay the dye resazurin is converted to a fluorescent compound resofurin within the reducing environment of a live cell.⁵ In addition to providing very consistent results, the alamar blue protocol is operationally simpler, in that dye is added at the desired timepoint and viability is assessed by reading the fluorescence after a few hours. No washing is required, whereas SRB has two washing steps. Additionally, alamar blue solutions can be made in-house, by simply dissolving the inexpensive dye resazurin in sterile PBS at 440 μΜ, at the cost of less than a penny per milliliter. Edge effects, where significantly more signal than expected was measured in the outer wells, were accounted for by preparing an untreated control plate in parallel with treatment plates, and applying a correction factor derived from the control plate to the final data.

[0614] Overall, more than 6,000 compounds were screened, with the majority originating from Prof. Kozmin's lab at the University of Chicago (-4,000 compounds screened at 2 μΜ). The remaining compounds were from plates 15-19 of the HTSF submitted library (-2,000 compounds screened at 20 μΜ) and early Complexity-to-Diversity compound collections (-200 compounds screened at 10 μΜ). From these efforts, 26 primary hits were identified. Upon testing the dose-response activity of these compounds in various cell lines, some primary hits were revealed to be false positives (no cell death up to 100 μΜ), while others had weak (IC₅₀ between 20 and 100 μΜ) or good (IC₅₀ below 20 μΜ) anticancer activity (Figure 1).

[0615] The primary hits with good anticancer activity were further assessed to determine their activity. One of the Complexity-to-Diversity (CtD) compounds, RH2_1_255C, had been reported previously in the literature, and has significant phototoxicity in mice.⁶ The compound GA4 was investigated for its anticancer activity.⁷ Compound 1202 contains a reactive α,β- unsaturated carbonyl whose electrophilic reactivity may be undesirable as it could result in nonspecific reactions with proteins. Further, compound 1223 is extremely flat, suggesting that it may act via DNA intercalation. The activity of 1227 was investigated as it has potent anticancer activity.

[0616] Activity of 1227 and analogs: The activity of 1227 was assessed in a small panel of cell lines to determine its overall activity (Table 1). Overall 1227 displayed potency, with IC5₀ values generally below 25 μΜ. Cell Line Cancer Type 1227 IC50 (μΜ)

Hs578t triple negative breast 63.1 ± 16.0

MCF7 ER+ breast 20.7 ± 1 .5

BT549 triple negative breast 14.0 ± 4.2

BT20 triple negative breast 18.8 ± 6.1

HCC1954 ER/PR -, Her2+ breast 13.0

T47D ER+ breast 13.1 ± 8.5

U937 lymphoma 17.9

[0617] Table 1. IC5₀ values for 1227 against a panel of cancer cell lines at 48 h. Where error is indicated n=3, s.e.m., where error is not indicated n=l .

[0618] Based the positive data from this class of molecules, the additional 1227 analogs were synthesized for testing (Figure 2). [0619] Each of these compounds is an intermediate or analog of an intermediate on a synthetic route to the natural product actinophyllic acid, a carboxypeptidase inhibitor.⁸ The ability of each analog, as well as that of actinophyllic acid, to induce cell death in Hs578t cells was determined (Table 2). Out of these 19 compounds, 1257 was identified as a potent compound and assessed further for activity in other breast cancer cell lines and other types of cancer.

[0620] Table 2. IC5₀ values of 1227-series compounds in Hs578t cells, n=3, s.e.m. 2.

[0621] Breadth of 1257 potency: Since no differential selectivity was observed for one cell line over another by 1227, the potency of 1257 against many diverse cancer cell lines was tested. [0622] Efficacy against various types of breast cancer: When tested against a panel of breast cancer cell lines representing many subtypes of breast cancer, 1257 was found to be equally potent in all subtypes, with IC5₀ values ranging from 4 - 10 μΜ (Table 3).

[0623] Table 3. IC5₀ values of 1257 against breast cancer cell lines. n=3, s.e.m. where error is indicated.

[0624] Efficacy against other types of cancer: When assessed against a diverse panel of cancer cell lines, 1257 consistently displayed potent activity, with IC₅₀ values ranging from 4 - 10 μΜ (Table 4). Due to 1257' s broad activity against a wide range of cancer cell lines, its mode of action and general properties were further investigated.

[0625] Table 4. IC5₀ valued of 1257 against non-breast cancer cell lines. n=3, s.e.m. where error is indicated.

3.

[0626] Assessing 1257-induced cell death: Initial assessments of 1257's mode of action focused on broadly characterizing how 1257 causes cell death in comparison to known cytotoxins. [0627] Speed of cell death compared to known cytotoxins and clinical anticancer agents: Cell death was observed to occur upon treatment with 1257, and increases in incubation time past 12 hours did not increase the overall amount of cell death. For this reason, the speed of cell death induced by 1257 was compared to that induced by other well-characterized cytotoxins and clinically-used therapeutics over a 48 h time period. As Figure 3 shows, 1257 induces cell death at approximately the same rate as 154 IB, velcade, thapsigargin, and staurosporine, while deoxynyboquinone (DNQ),² doxorubicin, paclitaxel, and mitomycin c cause cell death at a significantly slower rate. Comparison of the rate of induced cell death along with the known molecular mechanisms of action of these cytotoxins can shed some light on the possible mechanism of 1257.

[0628] Mitomycin c induces cell death by alkylating and crosslinking DNA, thereby rendering the cell unable to express genes or replicate DNA.⁹ Both doxorubicin and paclitaxel disrupt cell division, with doxorubicin intercalating DNA and inhibiting topoisomerase II during DNA replication¹⁰ and paclitaxel stabilizing microtubules during spindle disassembly.¹¹ All three of these slower-acting agents work by affecting the cell's ability to undergo mitosis. This mode of action is common to many chemotherapeutics, due to the ability of these agents to selectively kill dividing cells, such as tumor cells, over senescent cells, such as most healthy tissue. The somewhat delayed action of these compounds is due to the need for the cells to progress towards mitosis for cell death pathways to be activated. DNQ catalytically produces reactive oxygen species (ROS) that in turn damage DNA and render the cell unable to express genes and replicate, which also may also depend on the cell's ability to progress through the cell cycle.¹²

[0629] Staurosporine is a very potent pan-kinase inhibitor that is used widely in the literature due to its ability to consistently induce apoptosis.¹³ Thapsigargin is a SERCA

(sarco/endoplasmic reticulum Ca²⁺-ATPase) inhibitor that induces a build-up of cytosolic calcium,¹⁴ a signal that can activate apoptosis and other cell death pathways. Velcade (aka bortzeomib) is a recently-approved chemotherapeutic that works by inhibiting the proteasome.¹⁵ 1541B directly activates caspase-3, one of the key executioner caspases in the apoptotic pathway. ¹⁶ While DNA damage and inhibition of other mitotic processes can often activate cell death pathways, these four cytotoxins induce cell death without directly relying upon the cell cycle machinery or checkpoints. As such, they are each able to induce cell death within shorter time periods. Due to the rapid speed of cell death induced by 1257, its mode of action is likely independent of cell cycle machinery or checkpoints. [0630] Shape of 1257 cytotoxicity curve: Another aspect of 1257's effect on cancer cells is the shape of its dose-response curve. Compared to many other cytotoxins, 1257 has a very steep dose-response curve, which can be quantified by the Hill slope (HS). A number of factors have been proposed to influence dose-response curves of cytotoxins in various cell lines.¹⁷ One factor that influences the steepness of a cytotoxicity curve is the differences in cellular response within a given cancer cell population. If the sensitivity of cancer cells to a cytotoxin varies widely within a population, this will give rise to a shallow dose-response curve as higher concentrations are needed to affect the less sensitive cells. Conversely, a steep dose response curve indicates similar sensitivity to the cytotoxin throughout the cell population and can also indicate cooperativity of drug binding to the target. Thus, HS values greater than one have been proposed as a desirable property for anticancer compounds.¹⁷

[0631] Additionally, the value of E_max is an important aspect of 1257' s dose-response curve. E_max values near or equal to 100 (when plotting percent cell death) are beneficial because they indicate that a cytotoxin is capable of eliminating all or close-to-all of the cancer cells at high concentrations. Low E_max values indicate that a cytotoxin causes fractional killing of a cell population, leaving a portion of the cancer cells unaffected and able to regrow after the cytotoxin is cleared. As such, high E_max values are desirable as they indicate fewer cells will be left unaffected by the cytotoxin and hopefully reduce the frequency of resistance.

[0632] Theoretically, E_max values cannot exceed 100 (or be lower than zero when percent viability is plotted) since a cytotoxin can only kill 100% of the cells present and no more. In actuality, this value is influenced by a couple of factors that may lead to theoretically impossible values. The E_max value is derived from fitting a sigmoidal curve to the dose-response data points, which can give values above 100 even if most of the individual data points do no exceed 100. In these cases the E_max value is said to be equal to 100. Dose-response data also changes depending on the type of viability assay conducted (alamar blue, sulforhodamine B, Cell Titer-Glo, etc.) and the control conditions used to define 100% cell death. In this case, average values from wells containing 100 μΜ doxorubicin, velcade, and 4150 were used to define 100% cell death. Since each cytotoxin has its own E_max value, the set of compounds used to define 100% cell death will necessarily influence the resulting cell death values. Thus E_max can only be accurately compared when each compound is assessed with the same assay and the same controls. Secondary confirmation of E_max values can be accomplished through colony-forming assays, which assess whether any cells with replicative potential remain after cytotoxin treatment. [0633] An analysis of the HS and E_max values of 1257 and doxorubicin in a panel of cell lines reveals a clear difference between these two compounds (Figure 4). Compared to doxorubicin, 1257 consistently displays a HS value much greater than one (values range from 5-100), whereas the highest HS value for doxorubicin is 2.2 in U937 cells and in all other cell lines was near or below one (values range from 0.31-1.2). These values indicate that the cellular response to doxorubicin is much more varied within the cell population than it is to 1257. Additionally, at concentrations near the IC5₀ value, an increase in the amount of 1257 has a much larger effect than a similar increase in the amount of doxorubicin. The E_max value of 1257 is equal to 100 in five of the six cell lines tested and varies from 64-99 for doxorubicin. This demonstrates that 1257 effectively kills a larger fraction of the cell population than doxorubicin does.

[0634] The HS and E_max values of a panel of literature cytotoxins in U937 cells were also analyzed and the average values varied greatly (Figure 5). Mitomycin C, 154 IB, and velcade all have HS values equal to or less than one, whereas DNQ and thapsigargin each have values above one. The extremely high HS value determined for DNQ (HS = 49.0, Figure 5) is likely due to the catalytic production of ROS by this compound, leading to very large increases in toxicity from very small increases in compound concentration. Thapsigargin works by disrupting calcium homeostasis, and the tight regulation of intracellular calcium may be reflected in the steep does- response curve for this compound. The low HS values of 154 IB and velcade likely reflect high levels of variability within the U937 cell population in their response to the cytotoxin. Most of the compounds tested show high E_max values near 100, but DNQ has an E_max value of only 80. This could indicate the presence of a small portion of the cell population that is able to mitigate the effects of DNQ and survive.

[0635] Since both HS and E_max are known to correlate with drug type¹⁷ (and thus with mode of action) these values can provide clues as to the possible mechanism of action of 1257. Since 1257 consistently has a very steep cytotoxicity curve in a variety of cell lines, this suggests that it does not act through mechanisms known to yield shallow curves, such as mTOR inhibition or thymidylate synthase inhibition. Similarly, the consistent E_max values of 1257 suggest that it does not act through mechanisms known to result in fractional killing, such as EGFR inhibition or HSP90 inhibition. Based on this analysis, 1257 could induce HDAC inhibition or proteasome inhibition, as both of these drug classes display steep slopes and E_max values near 100, though these values alone cannot reveal the mode of action and 1257 could work through an entirely different mechanism than any known drug class. This analysis not only provides guidance for which modes of action may be induced by 1257, but also indicates that cells respond evenly to the effects and 1257 and are consistently sensitive to high concentrations of this cytotoxin.

4.

[0636] Cell cycle arrest by 1257: Another method for investigating the overall effect of a cytotoxin on cells is to assess cell cycle progression in the presence of a minimally toxic concentration of the compound. The phase of the cell cycle can be determined by dyeing the DNA of fixed cell with propidium iodide (PI), and assessing whether the amount of PI signal corresponds to one (Gl phase), two (G2/M phase), or an intermediate number of chromosome sets (S phase). Treatment of U937 cells with 6 μΜ 1257 results in a mild Gl arrest (Figure 6). [0637] The effect of 1257 was further tested in synchronized cells. First, U937 cells were treated for 16 h with nocodazole, which arrests cells in G2/M phase. After washing out the nocodazole, cells were treated with either DMSO or 4 μΜ 1257, and the distribution of the cell phases was assessed at intervals over 16 hours (Figure 7).

[0638] Here a clear and lasting arrest of cell cycle progression in Gl phase by 1257 is observed. This indicates that 1257 does not act through stabilization or destabilization of microtubules, as compounds that act through those mechanisms generally cause G2/M arrest.

[0639] Investigation of mechanism by flow cytometry and protective agents: Some types of cell death can be characterized by the use of appropriate fluorophores with flow cytometry. In addition, one straightforward method to probe the mechanism of a cytotoxic agent is to determine which other proteins are necessary for its function. The activity of various proteins in cell death or other pathways can be inhibited with small molecule tools, if inhibition of a protein with a small molecule leads to a decrease in cytotoxin-induced cell death, then that protein may play a key role in the function of the cytotoxin. Thus, the mechanism of action was investigated using flow cytometry and by assessing the combination of 1257 with a variety of small molecule tool compounds.

[0640] Annexin V-FITC and propidium iodide staining: Apoptosis is a specific type of programmed cell death with well-defined pathways and characteristics. To determine if 1257 induced cell death via apoptosis, cells were analyzed by flow cytometry using propidium iodide and the fluorophore-conjugated anti-phosphatidylserine antibody Annexin V-FITC. In this analysis, exposure of phosphatidylserine on the surface of the cell is used as a marker of the early stages of apoptosis and the fluorescence of the membrane-impermeable DNA dye propidium iodide, is used as a marker for overall cell death. Cells that undergo classical apoptosis experience these two events in strict succession, whereas cells undergoing other types of programmed or non-programmed cell death do not.

[0641] In U937 cells treated with 1257, a small population (-15%) was found to be present in the apoptotic quadrant (PI negative, Annexin V-FITC positive) at a given time (Figure 8). These results indicate that at least some of the 1257-treated cells undergo classical apoptosis.

[0642] Apoptosis inhibitors: A large number of well-characterized tool compounds are available to aid in the interrogation of apoptotic pathways (Figure 9). The general procedure used to assess whether a compound prevents the cytotoxicity of 1257 was to treat U937 cells for two hours with the tool compound, then add 1257 at a final concentration of 9 μΜ and incubate for another 3 h. Concentrations of protective agents were optimized, starting from concentrations used in the literature and increased such that they are utilized at their highest non-toxic concentration. A graph summarizing the amount of protection provided by a variety of apoptosis- inhibiting compounds is shown in Figure 10. [0643] To probe the caspase-dependence of 1257-induced cell death, QVD-OPh, a potent covalent pan-caspase inhibitor was utilized.¹⁸ No protection was observed with high

concentrations of QVD-OPh, indicating that cell death may not caspase-dependent. Apoptosis can occur in a caspase-independent manner, so other elements of apoptotic pathways were investigated. [0644] The compounds antimycin A, rotenone, and FCCP all use various mechanisms to uncouple oxidative phosphorylation and disrupt ATP synthesis in the mitochondria.¹⁹'²⁰

Apoptosis is an ATP-dependent process, thus blocking ATP synthesis should disrupt apoptosis. No protection with either rotenone or FCCP was observed, though some protection was observed with antimycin A (-40%, Figure 7). Without being bound by any particular theory, since only one of these three compounds provided protection, the protection from antimycin A may not be due to effects on ATP levels, but due to another function of antimycin A within the cell.

[0645] The organometallic compound Ru360, a specific inhibitor of calcium uptake by the mitochondrial permeability transition pore (MPTP),²¹ was also investigated. Increases in cytosolic calcium levels can activate the MPTP, causing the mitochondria to become permeable to cellular components less than 1500 Da in size. This increased permeability can then lead to the release of pro-apoptotic factors like cytochrome c. The lack of protection by Ru360 suggests that this mechanism is not important for 1257-induced cell death.

[0646] The pifithrins each block a different pro-apoptotic mechanism of p53, with pifithrin-^ blocking p53-induced transcription of pro-apoptotic genes and pifithrin-μ blocking p53 binding to the mitochondria, Bcl-xL and Bcl-3.²²'²³ The lack of protection by pifithrin-^ and pifithrin-μ suggests and 1257-induced cell death is not dependent upon p53 activity.

[0647] The compound BI-6C9 was developed to inhibit Bid-induced apoptosis.²⁴ This compound works by inhibiting the localization of cleaved Bid (tBid) to the mitochondria and thus preventing tBid-induced Bax and Bak oligomerization and subsequent cytochrome c release. No protection was observed with BI-6C9, indicating that tBid recruitment to the mitochondria is not necessary for 1257-induced cell death.

[0648] Compound iMAC-1 and peptide VPMLK both work to inhibit the Bax and Bak- induced release of cytochrome c from the mitochondria.²⁵'²⁶ No protection was provided by either compound, which is consistent with earlier results indicating the release of cytochrome c from the mitochondria may not be a critical step in 1257-induced cell death.

[0649] The compound NS3694 was reported to prevent caspase-dependent apoptosis by inducing the formation of an inactive apoptosome dimer.²⁷ Surprisingly, NS3694 provided significant protection against the cytotoxicity of 1257. This suggested that although

mitochondrial release of cytochrome c and caspase activation was not necessary for 1257 toxicity, formation of the apoptosome was necessary. Since the apoptosome consists of the proteins Apaf-1, caspase-9, and cytochrome c, and serves to activate executioner caspases 3 and 7, this protection was somewhat inconsistent with previous results.

[0650] Isogenic cell lines: Isogenic cell lines were utilized to further investigate the role of certain apoptotic proteins in 1257-induced cell death. To probe the role of the apoptosome, the sensitivity of an isogenic mouse embryo fibroblast (MEF) cell line pair in which the gene for Apaf-1 was knocked out in one cell line was tested. In addition to assessing viability after treatment with 1257, the ability of NS3694 to protect against 1257 in each cell line was also assessed (Figure 1 1). Both cell lines were sensitive to 1257, and the Apaf-1 knock-out cells were even slightly more sensitive to the cytotoxin. Interpretation of these results is complicated by the fact that NS3694 did not provide any significant protection from 1257 in either the WT or KO cell line. This difference may indicate that 1257 induces cell death in a different manner in MEF cells than it does in U937 cells, and the sensitivity of Apaf-1 knock-out cells to 1257 only reveals that the apoptosome is not required in MEF cells. Another explanation is that NS3694 protects against 1257-induced cell death in U937 cells by a mechanism other than inhibition of the apoptosome, and that this mechanism is not operative in MEF cells. Either way, further experiments to investigate the type of cell death induced by 1257 were warranted.

[0651] Another set of isogenic MEF cell lines that were either wild-type (WT) or were knockouts for either Bid or Bax and Bak genes were utilized. The sensitivity of each cell line to 1257 was assessed and all three cell lines were found to be equally sensitive (Figure 12). This result is consistent with the lack of protection observed with BI-6C9, iMAC-1, VPMLK, and Ru360. [0652] To explore the importance of the extrinsic apoptotic pathway in 1257-induced cell death, isogenic Jurkat cell lines in which the gene for either caspase-8 or FADD (Fas-associated death domain) was knocked-out were examined. The sensitivity of each cell line to 1257 alone or in the presence of necrostatin-1 (a RIPK inhibitor that prevents necrosis), SP600125 (a JNK inhibitor that also prevents necrosis), or QVD-OPh, was determined (Figure 13). Comparing their sensitivities to 1257 alone reveals that while the caspase-8 knock-out cells are slightly less sensitive than wild-type, there is no difference in sensitivity with the FADD knock-out cells.

[0653] As with U937 cells, none of the three tool compounds significantly increased viability after 1257 treatment. Interestingly, treatment with SP600125 consistently induced slightly higher amounts of cell death in each cell line. Overall these results suggest that the extrinsic apoptotic pathway is not a key pathway for 1257-induced cell death.

[0654] Necrosis and other inhibitors: A panel of tool compounds that inhibit various components of necrosis pathways and other cell death pathways was tested. For most of these compounds, little-to-no protection was observed (Figure 14). Necrostatin-1 and SP600125 each target a different kinase in a key necrosis pathway. Necrostatin-1 inhibits RIP kinase (RIPK)²⁸ and SP600125 inhibits JNK,²⁹ and the lack of protection provided by each of these compounds suggests that necrosis pathways are not critical for 1257-induced cell death. Calpains are a class of calcium-activated proteases that can play a role in both apoptosis and necrosis. The use of calpeptin, a specific calpain inhibitor,³⁰ did not affect cellular viability, indicating that calpains do not play a critical role here. [0655] The ability of the antioxidant N-acetyl cysteine (NAC)³¹ to prevent cell death was assessed, and it provided slight protection. This suggests that some ROS may be generated during 1257 treatment but that it is not the main cause of cell death. No change in the amount of cell death was observed when NMDA-receptor inhibitor MK-801³² was employed, indicating that the ion transport activity of NMD A receptors is not required for cell death. Modest protection with neomycin, a compound that is commonly used as an antibiotic, was also observed. Unfortunately, neomycin is a non-specific weak anion exchanger,³³ which hinders our ability to interpret this modest protection.

5.

[0656] Endoplasmic reticulum stress inhibitors

[0657] Next, the role endoplasmic reticulum (ER) stress in this context was explored. A number of different tool compounds have been published that affect various aspects of ER stress (Figure 15). One of the major sensors of ER stress is IREla, a transmembrane ER protein that has both kinase and endonuclease activity. The endonuclease activity has been shown to be part of the ER stress response that works to ensure cell survival and it is this activity that is inhibited by STF083010.³⁴ [0658] Co-treatment with STF083010 actually increased the amount of cell death induced by 1257 (Figure 16). This could suggest that ER stress plays a role in cell death in this context, since STF083010 blocks a pathway which counteracts ER stress. Another major sensor of ER stress is PERK, an transmembrane ER protein whose kinase activity serves to counteract the detrimental effects of ER stress, although high levels of activation can lead to pro-cell death signaling. When utilizing the PERK inhibitor GSK2606414,³⁵ no protection from 1257

cytotoxicity was observed.

[0659] Since ER stress can be caused by a build-up of unfolded proteins within the ER, the chemical chaperone TUDCA³⁶ was utilized to probe the role of such proteins. No protection was observed with TUDCA, indicating that an excess of unfolded proteins is unlikely to play a role in 1257-induced cell death. In a similar vein, use of the protein synthesis inhibitor cycloheximide also did not provide any protection. Use of the ryanodine receptor inhibitor dantrolene³⁷ did not provide any protection, suggesting that calcium release by the intracellular calcium channel ryanodine receptors does not play a critical role in 1257-induced cell death. As the ER is involved in cholesterol synthesis, the hypothesis that supplementing the cholesterol synthesis pathway with mevalonolactone would attenuate 1257 toxicity was tested.³⁸ High concentrations of mevalonolactone did not affect the amount of cell death, indicating that toxicity was likely not due to inhibition of cholesterol synthesis.

[0660] Incubation with PP1/GADD34 inhibitor salubrinal ³⁹ (Figures 16 and 17) resulted in very robust protection, with prevention of approximately 90% of the cell death caused by 1257. Salubrinal inhibits the dephosphorylation of eIF2a by the PP 1/GADD34 complex;

phosphorylated eIF2a causes global translation repression by preventing eIF2a from participating in translation.⁴⁰ Along with a global decrease in translation is a concurrent increase in translation of chaperone proteins, which help to counteract any build-up of unfolded proteins.⁴¹ Short-term phospho-eIF2a maintenance works to counteract ER stress, but suppression of translation by phosphorylation of eIF2a decreases ATF4 (activating transcription factor-4) levels, leading to increased CHOP (C/EBP homologous protein) levels, which then promotes apoptosis through the action of Bcl-2 family proteins.⁴² Salubrinal is sometimes referred to as a general ER stress inhibitor and has been shown to protect from the cytotoxic effects of tunicamycin,³⁹ rotenone,⁴³ and kainic acid⁴⁴ but not those of thapsigargin.⁴⁵ Investigations into the protective activity of salubrinal in the context of diseases such as osteoporosis are also under way ⁴⁶

[0661] The protection provided by salubrinal suggests that 1257 causes cell death by inducing ER stress in such a way that the cellular events induced by salubrinal can decrease the effects of this insult. Since no protection was observed when translation was inhibited with cycloheximide, the protective effect of salubrinal may be due to the increased translation of ER stress-reducing proteins.

[0662] Western blot analysis of apoptotic and ER stress markers: Specific biochemical markers of apoptosis and ER stress were monitored in U937 cells treated with 1257 with or without certain protective agents. Procaspase-3 cleavage and mitochondrial cytochrome c release were observed in 1257 treated cells (Figure 18). These events are completely prevented by salubrinal, but not by NS3694 or QVD-OPh, in agreement with previous results. The apoptosis- inducing compound staurosporine was also tested as a positive control, where it induces cleavage of procaspase-3 to the active apoptotic caspase-3 fragment.

[0663] The caspase-3 fragment produced in the presence of QVD-OPh is a larger non- apoptotic fragment, since all caspases are covalently inhibited.⁴⁷ Interestingly, the apoptotic cleavage of caspase-3 in the presence of NS3694 confirms the hypothesis that this compound is not working through the apoptosome, since no apoptotic caspase cleavage would be expected if the apoptosome was inhibited. Since previous experiments demonstrated that 1257-induced cell death is caspase-independent, this experiment demonstrates that apoptotic caspase fragments can be formed in response to 1257 but are not required for cell death. Unfortunately, the induction of biochemical apoptotic events by 1257 was not consistent, in that its timing varied between replicates and in some cases no biochemical apoptotic events could be observed. For example, in some replicates no PARP-1 cleavage, which is a robust signal of caspase activation, was observed at up to 2 h of treatment with 1257 (Figure 19).

[0664] A number of phosphorylation events can be monitored as biochemical markers of ER stress, including phosphorylation of PERK, IRE la, eIF2a and cleavage of ATF6.⁴⁸'⁴⁹ Treatment with 1257 rapidly induces an increase in eIF2a phosphorylation, but not in IRE la

phosphorylation (Figure 20).

[0665] Unlike the apoptotic biochemical events, the increase in eIF2a phosphorylation has consistently occurred in our all our attempts to monitor it by western blot, further demonstrating the importance of ER stress in 1257-induced cell death. A similar increase in phosphorylated eIF2a can be seen when U937 cells are treated with tunicamycin, an ER stress inducer, for long time periods (Figure 21).

[0666] TEM imaging: To further characterize the effects of 1257, transmission electron microscopy (TEM) was utilized to assess the morphology of U937 cells after treatment.

[0667] Utility of TEM imaging for cell death assessment: Although TEM imaging is not routinely used to characterize the type of cell death occurring upon different insults, our laboratory has found that it can, in conjunction with other assessments, provide useful information. For many years, cell death was classified by the morphology of dying cells, with rupture or permeabilization indicating necrosis and blebbing indicating apoptosis.⁵⁰ While biochemical markers allow us to quantify cell death routines as well as further characterize into subroutines, valuable information can still be gleaned from morphological characterization.

Certain limitations, such as the large number of cells needed per sample, the lengthy staining and slicing protocol as well as the requirement for specialized TEM instrumentation limit the generality of this procedure.

[0668] Images from treated U937 cells: Our first attempt to obtain images of U937 cells treated with 1257 was not successful, likely due to interactions between the compound and the dyes used to stain the fixed cells. Thus, the number of washes with PBS after harvesting the cells was increased, enabling the capture of very high quality images of intact cells (Figure 22).

[0669] DMSO-treated U937 cells have a very similar appearance to other TEM images of healthy vehicle-treated cells obtained by our group.⁷ Notable features of these healthy cells include the significant number of cellular membrane protrusions, indicating active endocytosis, a nucleus with well-distributed uncondensed DNA, mitochondria with intact parallel cristae, and thin unstressed ER throughout the cytosol (arrows, Figure 22). Upon treatment with 1257, a number of different morphological changes are observed. First, the outer membrane is much smoother, with fewer endocytosis protrusions. Next, there is a gap at the nuclear membrane, a change that generally indicates cellular stress. Additionally, the ER structures are much larger and rounded, with white interiors indicative of protein accumulation (Figures 22 and 23). No ER structures with normal morphology are present and all other visible organelles are readily identified, strongly indicated that the large white structures are in fact the ER. The morphology of the mitochondria is similar to that of the DMSO control initially, but as the incubation with 1257 continues, the cristae begin to reorganize and form vesicle-type structures.⁵¹

[0670] When cells are treated with salubrinal and 1257, the cells have a healthy morphology with the ER appearing as thin bodies, similar to the appearance of DMSO treated cells. No other indicators of cellular stress, such as the nuclear gap, changes in mitochondrial morphology, or smoothening of the outer membrane are observed in cells treated with salubrinal and 1257

(Figures 22 and 23). Conversely, when cells were treated with either NS3694 or QVD-OPh and 1257, their morphology was distinctly unhealthy, with many unusual features occurring. For example, large membrane-bound structures were observed in NS3694 treated cells, which may be expanded ER or may arise from unregulated endocytosis. QVD-OPh treatment did not prevent expansion of ER membranes. [0671] For comparison, images of cells treated with staurosporine and thapsigargin were also obtained (Figures 22 and 23). Staurosporine is known to induce apoptosis as determined by both morphological and biochemical measures. These TEM images very clearly showed blebbing of the outer membrane, with most cells in this population visualized as completely permeabilized and dead or as undergoing large-scale blebbing and nuclear condensation. Images of

thapsigargin-treated cells revealed expanded ER structures very similar to those in 1257-treated cells. Since thapsigargin is a well-characterized inducer of ER stress, this strongly suggests that 1257 induces ER stress as part of its effect on cancer cells. 6.

[0672] Cytological profiling: Recently, the use of high-content screening has been developed as a method to rapidly discover useful and unique small molecules by computer analysis of their effects on the phenotypes of treated cells.⁵² Further development of this technique has focused on enabling its use for investigating the mode of action of biologically active compounds.⁵³

[0673] Use of cytological profiling for mechanism-of-action comparison: Cytological profiling is the use of high-content techniques to measure phenotypic parameters of cells treated with biologically active molecules and further analysis of the data aimed at developing profiles or signatures that are specific to certain molecular modes of action. Recent studies have shown that this approach can accurately cluster together profiles of cells treated with compounds with the same mode of action.⁵⁴ For example, hierarchical clustering of cytological profiles have successfully clustered etoposide and camptothecin together as topoisomerase inhibitors, as well as nocodazole and taxol together as microtubule poisons.⁵⁵ In a further extension of this technique, the effects of fractional marine plant extracts were analyzed to allow for the classification and prioritization of natural products for further exploration.⁵⁶

[0674] One advantage of cytological profiling over other fingerprint-based approaches is that in addition to measurements, profiles, and clusters, this analysis also provides images of the treated cells. Visual inspection of these images can be used to help confirm clustering results, to provide a visual rational for a certain effect, and to generally help describe the phenotypic effect on the cell by any bioactive compound.

[0675] Cytological profiling of 1257: We utilized cytological profiling to investigate the phenotypic effects of 1257. In this protocol, HeLa cells are treated with a range of compound concentrations for 24 h, fixed, and then stained with either a nuclear or cytosolic fluorescent dye set. The cytosolic dye set includes Hoechst for general DNA staining, anti-phospho-H3 fluorescent antibodies, and EdU, an alkyne-tagged thymidine analog that is later cyclized with an azide-tagged rhodamine fluorophore. The nuclear stain set consists of Hoechst to locate cells, fluorescent anti-tubulin antibody, and fluorophore-labeled phallodin for actin staining.

Approximately 250 features in each fluorescent image are measured using specialized software and these feature measurements are used to cluster with or compare to features of known cytotoxins with known modes of action. [0676] The cytological profiles of 1257 and a panel of other compounds from our lab were clustered with previously collected results from a large panel of known cytotoxins.

Unfortunately, due to apparent batch effects, most of the compounds from our lab clustered together, despite being known to have a wide diversity of molecular mechanisms. The results from cells treated with 1257 at relevant concentrations did not cluster with any of the known cytotoxins.

[0677] Upon visual inspection of the fluorescence images obtained during this experiment, some differences between the control cells and the treated cells were observed. For example, with the cytosolic stain set, there is a reduction in overall tubulin staining intensity upon treatment with 33 μΜ 1257 (green, Figure 24). No significant change is observed in the amount of actin or the number of cells undergoing mitosis (red and cyan, respectively, Figure 24).

[0678] In the cells stained with the nuclear stain set, a significant decrease in the number of cells is observed as well as a large reduction in EdU staining (cyan, Figure 25), which reflects the synthesis of new DNA. No significant change in the proportion of cells with phospho-H3 staining was observed, which is consistent with the cytosolic stain set results.

[0679] Overall, these results are consistent with our previous studies of this compound. Since 1257 causes arrest in Gl phase, this analysis was expected to show fewer S phase and G2/M phase cells, but instead there is no observable change in the amount of G2/M phase cells. No effect on tubulin by 1257 was predicted by previous experiments, although this may reflect a change in progression through the cell cycle or a general reduction in the health of the cells. The significant reduction in cells in the nuclear stain set probably reflects the amount of cell death that occurred, which should be very high based on the high concentration of 1257 used (33 μΜ). The difference in the number of cells in the cytosolic stain set versus the nuclear stain set could be due to the manipulations required for EdU incubation in the nuclear stain set. Though the cytological profile of 1257 was not successfully clustered or correlated with any known cytotoxin, its effects on a number of different phenotypic features of HeLa cells were visualized.

7.

[0680] Transcript profiling: To further characterize the effects of 1257 on cancer cells and gain information that may lead to identification of the molecular target, transcript profiling was carried out. [0681] Use of transcript profiling for mechanism-of-action characterization: In its simplest incarnation, transcript profiling involves isolation of mR A from cells, determination of the level of each transcript by microarray, and analysis of the level of different transcripts. This method gains most of its power by enabling high-quality comparisons of transcript levels between cells in various states. Transcript levels can be compared between cancer cells of the same general type isolated from different patients, between cancer cells immediately after isolation and then after culturing in vitro, between cells before and after infection with a bacteria or virus, or between cells treated with different small bioactive molecules. This example, where transcripts are analyzed after treatment with a small molecule, has potential to advance investigations of the bioactive molecules discovered.

[0682] Although a thorough inspection of the individual up-regulated and down-regulated transcripts may yield insight into the effects of a compound on a cell, this type of analysis is unlikely to reveal the molecular target in a straightforward manner. To overcome this challenge, the Broad Institute developed the Connectivity Map database (CMAP) that allows for the easy comparison of the pattern of up- and down-regulated genes in a sample to the patterns of cells treated with a large database of literature compounds.⁵⁷ The use of CMAP as a tool to identify the mode of action of a bioactive molecule has been well reviewed previously.⁵⁸ One important aspect of CMAP analysis is that it only considers whether a transcript is up- or down-regulated, not the degree to which the level is changed. Additionally, the user can decide which transcripts to include in the query.

[0683] Initial results with 1257 and U937 cells: Total RNA was isolated from U937 cells treated with 4 μΜ 1257 or DMSO and samples were submitted for hybridization to Illumina microarray chips. Microarray hybridization was performed by the Functional Genomics Unit in the Roy J. Carver Biotechnology Center and statistical analysis was performed by the High Performance Biological Computing Group in the Institute for Genomic Biology. To assess the overall ability of this experiment to detect differences in cell populations, a heat map of transcript levels from 1257-treated and GEM-1 -treated cells were compared to each other and their matched control (DMSO-treated) cells (Figure 26). Overall, the two DMSO control samples are very similar to each other with some differences in the degree of down-regulation, and each compound-treated sample is visually very different from the controls. More importantly, each compound-treated sample is very different from the other, as one would expect with two cytotoxins with different overall cellular effects. [0684] Next, the results were inspected at the transcript level, concentrating on those transcripts that were dramatically up- or down-regulated (Table 5). The top most enriched transcript is that for interferon-induced protein with tetratricopeptide repeats-2 (IFIT2) with a fold change of 11 compared to control. Two other IFIT transcripts, IFITl and IFIT3, were also enriched, though only by approximately 3 -fold. This class of proteins is mainly responsible for inhibiting viral replication, though its over-expression has been shown to inhibit cancer cell growth.⁵⁹ BCL2A1 is an anti-apoptotic Bcl-2 family protein, which may be increased in this sample due to cellular processes that work to counteract the pro-cell death effects of 1257. An increase of almost 5-fold in CCNG2, the transcript corresponding to cyclin G2 is interesting, since the over-expression of this protein is knowns to induce Gl arrest,⁶⁰ which was previously shown to occur with this concentration of 1257.

[0685] Table 5. Significantly up- and down-regulated genes in U937 cells treated with 4 μΜ 1257 for 6 h compared to vehicle (DMSO) treatment.

[0686] Another up-regulated transcript corresponds to thioredoxin interacting protein (TXNIP), which is generally known as a tumor-suppressor gene. TXNIP is up-regulated by treatment with etoposide and has been shown to lead to an increase in reactive oxygen species.⁶¹ In an attempt to validate this transcript up-regulation, the TXNIP protein levels after treatment with 1257 were assessed. Even when treating the same cell line with the same concentration of 1257 for the same time period as assessed in the transcript profiling experiment, no significant increase in the amount of TXNIP protein was observed by western blot (Figure 27). [0687] CMAP analysis of results: Since further comparisons of 1257 to other more well- characterized cytotoxins is helpful, a CMAP analysis of these results was carried out. By inputting all transcripts that were up- or down-regulated by more than 2-fold compared to control, a CMAP result could be obtained with good mean scores with a number of pertubagens (Table 6). [0688] Since ER stress can be caused by changes in cytosolic calcium levels, the correlation of prenylamine and tetrandine, both calcium channel blockers, is not surprising. Similarly, as 1257 increases phosphorylation of eIF2a, an event that directly reduces global translation, the correlation with puromycin, a translation inhibitor, is also consistent. In addition, the HSP90 inhibitor geldanamycin, correlated with a mean score or 0.602, has also been shown to induce ER stress.⁶² In contrast, the correlation with dopamine receptor antagonists thioridazine, trifluoperazine, and prochlorperazine has no clear explanation, as a role for dopamine receptors in cancer cells is unknown, though dopamine itself may have some pro-apoptotic effects.⁶³ The correlation of benzethonium chloride and mefloquine are similarly unclear, although limited

64

studies have shown that mefloquine can induce ER stress.

[0689] Tab e 6. Compounds (or perturbagens) identified by CMAP with similar transcript patterns.

[0690] The best correlating perturbagen in this analysis was terfenadine (mean score of 0.808), an antihistamine that is no longer used due to its cardiotoxicity (Figure 28).⁶⁵ While histamine receptors are not normally thought to play a role in cancer biology, the presence of histamine H4 receptor has been demonstrated in numerous tissues and histamine may play a role in regulation of proliferation.⁶⁶ Terfenadine itself has some similarities to 1257, as it induces Gl phase arrest and apoptotic cell death, although these effects have been shown to be histamine receptor- independent but related to calcium homeostasis.⁶⁸

8.

[0691] Whole genome shRNA screening: As a general mode of action, induction of ER stress, has been assigned to 1257 further experiments to identify specific pathways key to 1257-induced cell death were investigated by conducting a positive-selection whole genome shRNA screen.

[0692] Recent uses of shRNA screens for new small molecules: Examples of the use of shRNA in either a validation experiment or to discover the mechanism of action of a bioactive molecule were well reviewed.⁵⁸ A brief summary of notable uses of shRNA screens since then is given here.

[0693] To investigate the pathways important for ER stress induced by arsenic, a functional RNAi screen was employed.⁶⁹ By utilizing an shRNA library targeting 20,000 genes, they were able to identify the gene SNAT2 (sodium-dependent neutral amino acid transporter 2) as critical for arsenic-induced ER stress and cell death, in addition to identifying known general ER stress genes. Interestingly, further investigation of the role of SNAT2 revealed that it plays a part in arsenic activation of the mTOR pathway by modulating cellular levels of certain amino acids.

[0694] Through a small phenotypic screen for changes in actin structure in glioblastoma cells and follow-up assays for selective cytotoxicity, they identified a class of quinoline-based compounds that they termed vacquinols. They further investigated the unique form of cell death induced by vacquinols through the use of the DECIPHER shRNA library, which targets a total of 5,043 genes. They found that MAP2K4 gene knock-down conferred significant protection against the activity of vacquinol-1. The MAP2K4 product, MKK4, was demonstrated to be an important node for successful formation of the macropinocytic vacuoles induced by vacquinol-1.

[0695] Although tamoxifen is known to target the estrogen receptor, further investigation of other pathways critical for its action are of interest. Thus, an shRNA screen targeting 16,487 genes was reported as a way to identify genes that can lead to tamoxifen resistance, a common problem in the clinic.⁷¹ To account for false-positives, genes enriched in the tamoxifen-treated cells were validated with siRNAs containing different target sequences than those used by the shRNA constructs. They identified 1 1 genes whose activity was essential for tamoxifen- sensitivity, and 1 1 genes whose activity decreased tamoxifen potency. [0696] Despite a growing number of successful examples of the use of shRNA screens to discovery critical pathways or molecular targets of new cytotoxins, further improvement and validation of this approach is ongoing. For example, a miniaturized shRNA screen protocol was recently developed and shown to be successful in re-discovering 40% of known drug-target interactions among a library of 28 well-characterized drugs.⁷² The shRNA library was unique in that it only targeted 368 known drug targets. This small size enabled high levels of representation for each construct, the use of many compounds (50), as well as small-format cell culture conditions (6-well plates).

[0697] Positive selection whole-genome shRNA screen with 1257 [0698] A positive-selection shRNA screen was designed in which three different ER stress- inducing cytotoxins (1257, thapsigargin, and tunicamycin) were investigated. Each compound was employed at a concentration that would induce >90% cell death and cells that were able to survive this treatment were allowed to recover, and the shRNA constructs were analyzed by next generation sequencing. By comparing the relative abundance of each shRNA construct in treated cells to those of control cells, the constructs enriched by each treatment, and thus which proteins are necessary for cytotoxin-induced cell death, can be determined (Figure 29).

[0699] MiaPaca-2 cells, a pancreatic cancer cell line, were chosen as the target cell line, as they are easily transducible, and behave similarly to U937 cells when exposed to 1257. For example, cell death occurs rapidly upon treatment with 1257, and this cell death is prevented by salubrinal (Figure 30). Additionally, 1257 has a similar potency in MiaPaca-2 cells (IC₅₀ = 8.8 μΜ) to other cell lines tested.

[0700] Our lab has previously utilized the GeneNet Human 50K siRNA Library, which contains 200,000 constructs targeting 47,500 human genes (3-5 constructs per gene).⁷⁵'⁷⁶ Since no ER stress-specific libraries are currently available, the library on hand was chosen. With a genome-wide library, this experiment benefits from the advantages of conducting a fully unbiased screen. Thus, shRNAs involved in any cellular process important for 1257 activity may be identified.

[0701] The GeneNet Human 50K siRNA Library was purchased in the plasmid format, and thus the first step was to package the library into FIV psuedoviral particles. This was accomplished by transfecting the library plasmid and pPACK-F 1 packaging plasmids (Systems Bioscinces, Inc.) into HEK293-TN, a special cell line designed for viral particle production. This cell line must be used at a very low passage number and cannot be allowed to reach full confluency, so proper advance planning and daily monitoring of this cell line is required for success. To ensure that all 200,000 constructs were well-represented in the final pool of viral particles, at least 50 μg must be packaged at a time. Viral particles were harvested at both 48 and 72 h post-transfection, concentrated with PEG-it, pooled, and aliquoted before storing at -80 °C. The transduction efficiency was assessed by small-scale transduction of MiaPaca-2 cells with varying amounts of viral particle solution and measurement of the percent GFP-positive cells by flow cytometry.

[0702] Once the transduction efficiency of the FIV pseudoviral particles was established, 10 million MiaPaca-2 cells were transduced and after 72 h were determined to be 50% GFP positive. Previous efforts to sort similar populations of MiaPaca-2 cells had demonstrated that efficient cell sorting was only possible with very low concentrations of cells (to avoid cell clumping), but that this low concentration made collecting 2 million cells, the minimum number needed, unfeasible. Thus, this population of 50% transduced cells was used in all three replicates without removal of the untransduced cells.

[0703] For each replicate of the screen, 4 million MiaPaca-2 cells (corresponding to 10-fold representation of each shRNA construct) were plated for each treatment and exposed to 1257, thapsigargin, tunicamycin, or DMSO. The size and representation of each replication was chosen to accommodate limitations in cell culture space and compound quanitites (both synthetic and commercial). Concentrations and exposure times were optimized for each cytotoxin and, after wash-out of the cytoxoin cells, were allowed to recover and grow to near-confluency. Genomic DNA was isolated from each sample and the shRNA inserts were amplified by nested PCR (Figure 31). In the first round of PCR, primers complementary to flanking regions were used and the cDNA product obtained from this reaction was used in a further round of PCR with nested primers.

[0704] The nested primers were designed, in conjunction with Dr. Alvaro Hernandez in the DNA Services Facility, to provide end sequences complementary to Illumina sequencing chips and were partially based on the primers used by Caporaso and coworkers.⁷⁶ The nested forward primer contains a sequence complementary to the loop sequence and a P5 Illumina adapter sequence, and the same primer was used for all 12 samples. The nested reverse primer contains a sequence complementary to the long terminal repeat region, a 12-base pair barcode sequence, and a P7 Illumina adapter sequence. The barcode sequence must be different for each sample, thus a unique nested reverse primer was designed for each sample.

[0705] The final PCR products were checked for quality and purity using a Bioanalyzer (performed by the Functional Genomics Facility) and quantified by Qubit (performed by the Functional Genomics Facility). Equal amounts of DNA from each sample were mixed together and submitted for Illumina HiSeq analysis in single-read mode (performed by the DNA Services Facility).

[0706] Preliminary shRNA screen results: Sequencing of the amplified shRNA constructs resulted in over 1 18 million reads, each 50 nucleotides in length, with excellent quality over the constructs. Out of the approximately 200,000 constructs present in the library, over 62,000 were observed in the final samples. Loss of some constructs is expected due to the toxicity of certain constructs. Due to experimental limitations that kept the total fold-representation of each construct at 10, some constructs could have been lost during transduction or subsequent culturing of cells. [0707] Statistical analysis of the sequencing results is currently being carried out by the High- Performance Biological Computing group. Once the constructs which are significantly enriched in each compound-treated sample set are identified, they were individually validated for their ability to prevent compound-induced cell death in MiaPaca-2 cells containing the identified shRNA construct. 9.

[0708] Hemolysis assay

[0709] To assess the translational potential of 1257, an in vitro hemolysis assay was utilized to determine whether this compound has any toxicity in human red blood cells.

[0710] Applicability of hemolysis assay: In the clinic, drug- induced hemolytic anemia can be induced via immune system-mediated and immune system-independent mechanisms. Although rare, drug-induced immune hemolytic anemia is known to occur with certain commonly -used drugs, such as cefotetan, ceftriaxone, penicillin, and piperacillin. The general mechanism in these cases is thought to be binding of the drug to the outer membrane of red blood cells, which causes the production of antibodies against the bound drug and subsequent destruction of red blood cells by the immune system.⁷⁶ [0711] Most drug-induced non-immune hemolysis occurs via oxidative pathways, though some drug-induced hemolysis mechanisms have not been fully elucidated. The ability of primaquine, an antimalarial, to induce an increase in hydrogen peroxide within blood cells leading to Heinz body formation and cell lysis is well known.⁷⁶'⁷⁷ The mechanism of dapsone- induced hemolysis occurs through N-hydroxylation that leads to the formation of

methemoglobin, which can then lead to hemolysis.⁷⁸ The biggest risk for oxidative hemolytic anemia is faced by individuals harboring an inactivating glucose-6-phosphate dehydrogenase (G6PD) mutation, though this condition can occur even in people with wild-type G6PD. Within red blood cells, G6PD is a major producer of NADPH, which is required for various antioxidant processes that help prevent the formation of methemoglobin. Other mechanism for the induction of hemolysis can also by envisioned, such as inhibition of key anti-oxidant enzymes, interference with the function of hemoglobin to induce greater superoxide formation, as well as inhibition or over-activation of ion channels that regulate cellular volume.

[0712] Simple in vitro hemolysis assays can be used to assess the potential for drug-induced hemolysis with lead compounds.⁷⁶ The type of hemolysis observed in this assay is necessarily immune system-independent, as the red blood cells are prepared by pelleting and washing to remove the serum, which contains white bloods cells and antibodies. Hemolysis measurements have also been found to be good predictors of in vivo effects.⁷⁷

[0713] Analysis of 1257 and related compounds: Dose-response curves for lysis of whole human red blood cells were generated for each 1257 analog with anticancer activity. Most analogs with anticancer activity did not induce significant hemolysis (>10%) until 100 μΜ compound was reached, but high levels of hemolysis were induced by 1257 starting at 30 μΜ (Figure 32). Additionally, none of the analogs without anticancer activity caused more than 15% hemolysis at 100 μΜ. [0714] Unfortunately, due to the small difference between the concentrations of 1257 required for activity and those that induce hemolysis, the translational potential of this compound is very low. However, the low levels of hemolysis induced by the other compounds in this series suggest that this structural class is not necessarily predisposed to high levels of hemolysis and a suitable active but non-toxic analog may be developed. [0715] Due to the high hemolytic activity of 1257, recent efforts focused on analog 1258 and its activity. This compound induces cancer cell death with a somewhat reduced potency compared to 1257, and also displays the steep slope and high E_max values that characterize 1257 (Figure 33). Additionally, cell death induced by 1258 is similarly counteracted by salubrinal in U937 human lymphoma cells (Figure 34).

10.

[0716] Synthesis of compounds described herein.

[0717]

25

[0718] (lS/R,5S/R,12R/S)-2-AUyl-6,6-bis((benzyloxy)methyl)-2,3,4,5,6,7-hexahydro-lH- 5,l-ethanoazocino[4,3-Z>]indol-12-yl acetate (25). Acetic anhydride (27 μΐ_^, 0.29 mmol) was added to a solution of alcohol 24 (30 mg, 0.057 mmol) and pyridine (24 μΐ,, 0.29 mmol) in

CH₂Ci2 (0.3 mL). A solution of 4-dimethylaminopyridine (3.5 mg, 0.029 mmol) in CH₂C1₂ (0.1 mL) was added, and the reaction was stirred for 1 h at room temperature. The mixture was partitioned between H₂0 (3 mL) and CH₂C1₂ (3 mL), and the layers were separated. The aqueous layer was extracted with CH₂C1₂ (2 x 3 mL), and the combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (6 : 4) containing 1% Et₃N to provide 25 (27 mg, 83%) as a tan solid: mp 143-145 °C; ^XH NMR (400 MHz) δ 9.34 (s, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.35-7.24 (comp, 1 1 H), 7.14 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 7.08 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.06-5.96 (m, 1 H), 5.54 (ddd, J = 9.2, 9.2, 2.4 Hz, 1 H), 5.30 (dd, J = 17.2, 1.6 Hz, 1 H), 5.19 (dd, J = 10.0, 1.2 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.59 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 5.2 Hz, 1 H), 4.00 (d, J = 9.2 Hz, 1 H), 3.93 (d, J = 8.4 Hz, 1 H), 3.85 (d, J = 9.2 Hz, 1 H), 3.76 (d, J = 8.4 Hz, 1 H), 3.26 (dd, J = 14.0, 6.8 Hz, 1 H), 3.03 (dd, J = 14.4, 5.6 Hz, 1 H), 2.84-2.77 (comp, 2 H), 2.50 (dd, J = 12.8, 4.0 Hz, 1 H), 2.26 (ddd, J = 13.2, 13.2, 3.6 Hz, 1 H), 2.01-1.91 (comp, 2 H), 1.85 (s, 3 H), 1.83-1.78 (m, 1 H); ¹³C NMR (100 MHz) δ 170.5, 139.0, 138.6, 137.9, 137.7, 135.0, 128.7, 128.5, 128.0, 127.8, 127.6, 127.1, 121.6, 119.4, 118.3, 117.0, 110.8, 110.6, 77.6, 77.4, 74.2, 73.9, 73.1, 72.0, 61.9, 52.4, 49.0, 46.3, 41.3, 40.0, 29.9, 21.5; IR (neat) 1927, 2868, 1729, 1250, 1105, 736, 698 cm^"1; mass spectrum (ESI) m/z 565.3065 [C₃₆H41 2O4 (M+l) requires 565.3061]. [0719]

26

[0720] (lS/R,5S/R,12R/S)-2-AUyl-6,6-bis((benzyloxy)methyl)-2,3,4,5,6,7-hexahydro-lH- 5,l-ethanoazocino[4,3-Z>]indol-12-yl benzoate (26). Benzoic anhydride (65 mg, 0.29 mmol) was added to a solution of alcohol 24 (30 mg, 0.057 mmol) and pyridine (24 μΐ,, 0.29 mmol) in CH₂C1₂ (0.3 mL). A solution of 4-dimethylaminopyridine (3.5 mg, 0.029 mmol) in CH₂C1₂ (0.1 mL) was added, and the reaction was stirred for 1 h at room temperature. The mixture was partitioned between H₂0 (3 mL) and CH₂C1₂ (3 mL), and the layers were separated. The aqueous layer was extracted with CH₂C1₂ (2 x 3 mL), and the combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant yellow oil was purified by flash column chromatography eluting with hexanes/EtOAc (7 : 3) containing 1% Et₃N to provide 26 (27 mg, 74%) as a tan solid: ^XH NMR (400 MHz) δ 9.31 (s, 1 H), 7.91-7.89 (comp, 2 H), 7.53 (d, J= 6.8 Hz, 1 H), 7.47-7.44 (m, 1 H), 7.30-6.93 (comp, 15 H), 6.08-5.95 (m, 1 H), 5.79-5.75 (m, 1 H), 5.32 (d, J= 17.2 Hz, 1 H), 5.21 (d, J= 10.0 Hz, 1 H), 4.57 (s, 2 H), 4.47 (d, J= 4.4 Hz, 1 H), 4.22 (d, J= 12.0 Hz, 1 H), 4.11 (d, J = 12.0 Hz, 1 H), 4.02 (d, J= 8.4 Hz, 1 H), 3.96-3.93 (comp, 2 H), 3.75 (d, J= 8.4 Hz, 1 H), 3.29 (dd, J= 12.8, 6.0 Hz, 1 H), 3.08- 2.90 (comp, 3 H), 2.56-2.54 (m, 1 H), 2.36-2.29 (m, 1 H), 2.22-2.16 (m, 1 H), 1.89-1.86 (m, 1 H); ¹³C NMR (100 MHz) δ 166.0, 139.1, 138.3, 137.9, 137.7, 135.0, 132.7, 130.8, 129.6, 128.7, 128.25, 128.19, 128.1, 128.0, 127.8, 127.3, 127.2, 121.6, 119.4, 118.3, 117.0, 110.8, 110.7, 78.4, 74.0, 73.9, 73.0, 72.2, 61.9, 52.5, 49.1, 46.3, 41.1, 40.2, 29.9; IR (neat) 2928, 2870, 1713, 1276, 1116, 735, 713 cm^"1; mass spectrum (ESI) m/z 627.3222 [C₄iH₄₃N₂0₄ (M+l) requires 627.3217].

[0721]

27

[0722] (lS/R,5S/R,12R/S)-2-AUyl-6,6-bis((benzyloxy)methyl)-12-methoxy-7-methyl- 2,3,4,5,6,7-hexahydro-lH-5,l-ethanoazocino[4,3-6]indole (27) (1258). A solution of 24 (30 mg, 0.057 mmol) in DMF (0.15 mL) was added dropwise to a suspension of NaH (18 mg, 0.45 mmol) in DMF (0.1 mL) at 0 °C. The reaction was stirred for 0.5 h at 0 °C, whereupon a solution of methyl -toluenesulfonate (42 mg, 0.23 mmol) was added. The reaction was warmed to room temperature and stirred for 18 h. The reaction was cooled to 0 °C, diluted with Et₂0 (5 mL) and quenched with saturated aqueous aHC03 (5 mL). The layers were separated, and the aqueous layer was extracted with Et₂0 (2 x 5 mL). The combined organic layers were washed with brine (1 x 15 mL), dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant yellow residue was purified by flash column chromatography eluting with EtOAc to give 27 (17 mg, 54%) as a clear gum: ^XH NMR (400 MHz) δ 7.43 (d, J= 7.6 Hz, 1 H), 7.26-7.07 (comp, 12 H), 7.02-6.98 (m, 1 H), 6.03-5.93 (m, 1 H), 5.23 (d, J= 17.6 Hz, 1 H), 5.14 (d, J= 10.0 Hz, 1 H), 4.47 (d, J= 12.0 Hz, 1 H), 4.44 (s, 2 H), 4.38 (d, J= 6.4 Hz, 1 H), 4.25 (d, J= 12.0 Hz, 1 H), 4.21 (d, J= 10.4 Hz, 1 H), 3.95-3.90 (m, 1 H), 3.86 (d, J= 9.2 Hz, 1 H), 3.80 (d, J = 10.4 Hz, 1 H), 3.66 (s, 3 H), 3.66-3.65 (m, 1 H), 3.28 (s, 3 H), 3.20 (dd, J= 14.4, 7.2 Hz, 1 H), 2.97 (dd, J = 14.4, 3.6 Hz, 1 H), 2.90 (br s, 1 H), 2.76-2.69 (m, 1 H), 2.41-2.38 (comp, 2 H), 2.15-2.05 (comp, 2 H), 1.77-1.69 (m, 1 H); ¹³C NMR (100 MHz) δ 207.0, 138.6, 138.5, 137.8, 137.4, 128.3, 128.2, 128.1, 127.5, 127.4, 121.2, 118.8, 118.1, 116.7, 113.1, 108.6, 85.4, 77.6, 74.2, 73.3, 72.7, 61.8, 56.9, 52.4, 40.0, 48.9, 44.7, 40.5, 32.4, 31.4, 30.9; IR (neat) 2928, 2862, 1098, 740, 698 cm^"1; mass spectrum (ESI) m/z 551.3271 [C36H43N2O3 ( +l) requires 551.3268].

[0723]

30

[0724] (lS/R,5S/R,12R/S)-6,6-bis((benzyloxy)methyl)-2-methyl-2,3,4,5,6,7-hexahydro-lH- 5,l-ethanoazocino[4,3-Z>]indol-12-ol (30). Sodium triacetoxyborohydride (17 mg, 0.080 mmol) was added to a solution of 29 (19 mg, 0.039 mmol) and formaldehyde (6.5 μΐ, of a 37% by weight solution, 0.080 mmol) in 1,2-dichloroethane (0.4 mL) at 0 °C, and the reaction was stirred for 2 h at 0 °C. The mixture was partitioned between saturated aqueous aHC03 (3 mL) and CH2CI2 (3 mL), and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 3 mL), and the combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The resultant brown residue was purified by flash column

chromatography eluting with toluene/EtOAc/MeOH (3 : 3 : 4) to give 30 (16 mg, 83%) as a clear gum: *H NMR (400 MHz) δ 9.30 (s, 1 H), 7.44 (d, J= 7.6 Hz, 1 H), 7.35-7.02 (comp, 13 H), 4.59 (d, J= 12.0 Hz, 1 H), 4.53 (d, J= 12.0 Hz, 1 H), 4.44-4.39 (comp, 3 H), 4.31 (d, J= 5.2 Hz, 1 H), 4.10-3.98 (m, 1 H), 3.97 (s, 2 H), 3.85 (d, J= 8.8 Hz, 1 H), 3.62 (d, J= 8.8 Hz, 1 H), 2.97 (ddd, J= 14.4, 9.2, 6.4 Hz, 1 H), 2.48-2.41 (comp, 2 H), 2.41 (s, 3 H), 2.19 (ddd, J= 13.2, 13.2, 4.0 Hz, 1 H), 1.93-1.86 (comp, 2 H), 1.73-1.69 (m, 1 H); ¹³C NMR (100 MHz) δ 138.8, 137.5, 137.4, 134.8, 128.7, 128.4, 128.1, 127.9, 127.8, 127.7, 121.6, 119.5, 118.1, 110.6, 109.5, 77.2, 75.0, 74.8, 73.9, 73.4, 72.5, 55.7, 50.2, 47.1, 46.3, 46.0, 41.6, 29.4; IR (neat) 3411, 2929, 1456, 1100, 1073, 734 cm^"1; mass spectrum (ESI) m/z 497.2802 [C₃2H₃7N2O₃ (M+l) requires

497.2799]. VII. References

[0725] 1. Palchaudhuri, R.; Nesterenko, V.; Hergenrother, P. J. The complex role of the triphenymethyl motif in anti-cancer compounds. J. Am. Chem. Soc. 2008, 130, 10274-10281.

[0726] 2. Bair, J. S.; Palchaudhuri, R.; Hergenrother, P. J. Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell death. J. Am. Chem. Soc. 2010, 132, 5469- 5478. [0727] 3. Gatza, M. L.; Lucas, J. E.; Barry, W. T.; Kim, J. W.; Wang, Q.; Crawford, M. D.; Datto, M. B.; Kelley, M.; Mathey-Prevot, B.; Potti, A.; Nevins, J. R. A pathway-based classification of human breast cancer. Proc. Natl. Acad. Sci. 2010, 107, 6994-6999.

[0728] 4. Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Prot. 2006, 1, 1 112-11 16.

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Claims

WHAT IS CLAIMED IS:

1. A compound having the formula:

wherein:

R¹ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^1A, -OR^1A, - NR^1AR^1B, -C(0)OR^1A, -C(0)NR^1A R^1B, -N0₂, -SR^1A, -S(0)„iR^1A, -S(0)„iOR^1A, -S(0)„iNR^1AR^1B, -NHNR^1AR^1B, -ONR^1AR^1B, -NHC(0)NHNR^1AR^1B, 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;

R² is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^2A, -OR^2A, - NR^2AR^2B, -C(0)OR^1A, -C(0)NR^2AR^2B, -N0₂, -SR^2A, -S(0)_n2R^2A, -S(0)_n2OR^2A, -S(0)_niNR^2AR^2B, -NHNR^2AR^2B, -ONR^2AR^2B, -NHC(0)NHNR^2AR^2B, 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;

R³ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^3A, -OR^3A, - NR^3AR^3B, -C(0)OR^3A, -C(0)NR^3AR^3B, -N0₂, -SR^3A, -S(0)„₃R^3A, -S(0)„₃OR^3A, -S(0)„₃NR^3AR^3B, -NHNR^3AR^3B, -ONR^3AR^3B, -NHC(0)NHNR^3AR^3B, 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;

R⁴ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^4A, -OR^4A, - NR^4AR^4B, -C(0)OR^4A, -C(0)NR^4AR^4B, -N0₂, -SR^4A, -S(0)_n4R^4A, -S(0)_n4OR^4A, -S(0)_n4NR^4AR^4B, -NHNR^4AR^4B, -ONR^4AR^4B, -NHC(0)NHNR^4AR^4B, 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;

R⁵ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^5A, -OR^5A, - NR^5AR^5B, -C(0)OR^5A, -C(0)NR^5AR^5B, -N0₂, -SR^5A, -S(0)„₅R^5A, -S(0)„₅OR^5A, -S(0)„₅NR^5AR^5B, -NHNR^5AR^5B, -ONR^5AR^5B, -NHC(0)NHNR^5AR^5B, 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;

R⁶ is hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, -C(0)R^6A, -OR^6A, - NR^6AR^6B, -C(0)OR^6A, -C(0)NR^6AR^6B, -N0₂, -SR^6A, -S(0)„₆R^6A, -S(0)„₆OR^6A, -S(0)„₆NR^6AR^6B, -NHNR^6AR^6B, -ONR^6AR^6B, -NHC(0)NHNR^6AR^6B, 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;

R⁷ is independently hydrogen, halogen, -N₃, -CF₃, -CC1₃, -CBr₃, -CI₃, -CN, - C(0)R^7A, -OR^7A, -NR^7AR^7B, -C(0)OR^7A, -C(0)NR^7AR^7B, -N0₂, -SR^7A, -S(0)_n7R^7A, -S(0)_n7OR^7A, -S(0)_n7NR^7AR^7B, -NHNR^7AR^7B, -ONR^7AR^7B, -NHC(0)NHNR^7AR^7B, 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;

L¹ and L² are independently -0-, -C(0)0-. -C(0)NH-, -NH-. -S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene;

nl, n2, n3, n4, n5, n6 and n7 are independently 1 or 2;

n is 1, 2, 3, 4 or 5;

m is 1 or 2; and

R^1A, R^1B, R^2A, R^2B, R^3A, R^3B, R^4A, R^4B, R^5A, R^5B, R^6A, R^6B, R^7A, R^7B are independently hydrogen, oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, - S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, - NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, -Si(CH₃)₃ 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,

wherein the compound is not actinophyllic acid.

2. The compound of claim 1, wherein

R⁴ is hydrogen, -OR^4A, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;

R⁵ is hydrogen, -OR^5A, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. 3. The compound of claim 1, wherein

R⁴ is hydrogen, -OR^4A, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl, R^4C-substituted or unsubstituted cycloalkyl or R^4C-substituted or unsubstituted heterocycloalkyl;

R is hydrogen, -OR , R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl, R^5C-substituted or unsubstituted cycloalkyl or R^5C-substituted or unsubstituted heterocycloalkyl;

wherein R^4C and R^5C are independently halogen, hydroxyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl or unsubstituted heterocycloalkyl. 4. The compound of claim 1, wherein

R⁴ is hydrogen, -OR^4A, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl, R^4C-substituted or unsubstituted cycloalkyl or R^4C-substituted or unsubstituted heterocycloalkyl;

5 5A. 5C 5C R is hydrogen, -OR , R -substituted or unsubstituted aryl, R -substituted or unsubstituted heteroaryl, R^5C-substituted or unsubstituted cycloalkyl or R^5C-substituted or unsubstituted heterocycloalkyl;

wherein R^4C and R^5C are unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl or unsubstituted heterocycloalkyl. 5. The compound of claim 1, wherein R⁴ is -OR^4A and R⁵ is -OR^5A. 6. The compound of claim 1 having the structure:

7. The compound of claim 6, wherein R³ is halogen, -OR^3A, 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. 8. The compound of claim 6, wherein R³ is -OR^3A.

9. The compound of claim 1 having the structure:

10. The compound of claim 1, wherein R¹ is hydrogen, halogen, -C(0)R^1A, - C(0)OR^1A, -NR^1AR^1B, -OR^1A, 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. 1 1. The compound of claim 10, wherein R^1B is hydrogen.

12. The compound of claim 10, wherein R¹ is hydrogen, -C(0)R^1A, - C(0)OR^1A, R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^lc-substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl;

R^1A is R^lc-substituted or unsubstituted alkyl, R^lc-substituted or unsubstituted heteroalkyl, R^lc-substituted or unsubstituted cycloalkyl, R^lc-substituted or unsubstituted heterocycloalkyl, R^lc-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl; and

R^1C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^1D- substituted or unsubstituted alkyl, R^1D-substituted or unsubstituted heteroalkyl, R^1D-substituted or unsubstituted cycloalkyl, R^1D-substituted or unsubstituted heterocycloalkyl, R^1D-substituted or unsubstituted aryl, or R^1D-substituted or unsubstituted heteroaryl; and

R^1D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 13. The compound of claim 10, wherein R¹ is hydrogen, halogen, -C(0)R^1A, - C(0)OR^1A, 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. 14. The compound of claim 10, wherein R^1A is hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C₃ to Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C₃ to Cio aryl or substituted or unsubstituted 5 or 6 membered heteroaryl. 15. The compound of claim 10, wherein R^1A is R^lc-substituted or unsubstituted alkyl, or R^lc-substituted or unsubstituted heteroalkyl; and R is halogen, unsubstituted alkyl or unsubstituted cycloalkyl. 16. The compound of claim 10, wherein R¹ is hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl, R^1D-substituted or unsubstituted aryl, R^1D- substituted or unsubstituted heteroaryl, R^1D-substituted or unsubstituted cycloalkyl, or R^1D- substituted or unsubstituted heterocycloalkyl; and

R^1D is halo gen or unsubstituted alkyl. 17. The compound of claim 10, wherein R¹ is hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl. 18. The compound of claim 10, wherein R¹ is hydrogen, methyl, ethyl, propyl, '^^^OH ^ _{or allyl} 19. The compound of claim 10, wherein R¹ is hydrogen. 20. The compound of claim 1 having the structure:

The compound of claim 20, wherein m is 1. The compound of claim 1 having the structure:

The compound of claim 1 having the structure:

24. The compound of claim 1, wherein L¹ and L² are independently substituted or unsubstituted alkylene. 25. The compound of claim 1, wherein L¹ and L² are independently unsubstituted alkylene. 26. The compound of claim 1, wherein L¹ and L² are independently unsubstituted Ci to C₁₀ alkylene. 27. The compound of claim 1, wherein L¹ and L² are independently unsubstituted Ci to C5 alkylene. 28. The compound of claim 1, wherein L¹ and L² are methylene. 29. The compound of claim 1, wherein

R^4A is hydrogen, R^4C-substituted or unsubstituted alkyl, R^4C-substituted or unsubstituted heteroalkyl, R^4C-substituted or unsubstituted cycloalkyl, R^4C-substituted or unsubstituted heterocycloalkyl, R^4C-substituted or unsubstituted aryl, R^4C-substituted or unsubstituted heteroaryl;

R^4C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D- substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl;

R^4D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; R is hydrogen, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R^5C-substituted or unsubstituted aryl, R^5C-substituted or unsubstituted heteroaryl;

R^5L is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NFTNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D- substituted or unsubstituted alkyl, R^5D-substituted or unsubstituted heteroalkyl, R^5D-substituted or unsubstituted cycloalkyl, R^5D-substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D-substituted or unsubstituted heteroaryl; and

R^5D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 30. The compound of claim 29, wherein

R^4A is R^4C-substituted or unsubstituted alkyl, wherein R^4C is R^4D-substituted or unsubstituted aryl; and

R^5A is R^5C-substituted or unsubstituted alkyl, wherein R^5C is R^5D-substituted or unsubstituted aryl. 31. The compound of claim 29, wherein

, wherein z4 is an integer from 1 to 5; and

, wherein z5 is an integer from

32. The compound of claim 29, wherein z4 is 1 or 2 and z5 is 1 or 2.

33. The compound of claim 29, wherein z4 and z5 are 0.

34. The compound of claim 1, wherein R⁶ is hydrogen, halogen, -C(0)R^6A, - C(0)OR^6A, -NR^6AR^6B, -OR^6A, 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. 35. The compound of claim 34, wherein R^6B is hydrogen. 36. The compound of claim 34, wherein

R⁶ is hydrogen, -C(0)R^6A, -C(0)OR^6A, R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C- substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^6C- substituted or unsubstituted heteroaryl;

R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted heteroalkyl, R^6C-substituted or unsubstituted cycloalkyl, R^6C-substituted or unsubstituted heterocycloalkyl, R^6C-substituted or unsubstituted aryl, or R^lc-substituted or unsubstituted heteroaryl;

R^6C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D- substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and

R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 37. The compound of claim 36, wherein R⁶ is R^6C-substituted or unsubstituted alkyl, wherein R^6C is R^6D-substituted or unsubstituted aryl. 38. The compound of claim 36, wherein R⁶ is -C(0)OR^6A and R^6A is R^6C- substituted or unsubstituted aryl.

39. The compound of claim 36, wherein R⁶ is hydrogen, unsubstituted C1-C5

alkyl, -C(0)OR^6A or

z6 is an integer from 1 to 5 and R^6A is R^6C- substituted or unsubstituted alkyl. 40. The compound of claim 36, wherein R⁶ is -C(0)OR^6A and R^6A is unsubstituted alkyl. 41. The compound of claim 36, wherein z6 is 1 or 2. 42. The compound of claim 1, wherein R⁶ is hydrogen, halogen, -C(0)R^6A, - C(0)OR^6A, 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. 43. The compound of claim 42, wherein R^6A is hydrogen, substituted or unsubstituted Ci to Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3 to Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C3 to C₁₀ aryl or substituted or unsubstituted 5 or 6 membered heteroaryl. 44. The compound of claim 42, wherein R^6A is R^6C-substituted or unsubstituted alkyl, R^6C-substituted or unsubstituted aryl, or R^6C-substituted or unsubstituted heteroalkyl; and

R^6C is halogen, unsubstituted alkyl or unsubstituted cycloalkyl. 45. The compound of claim 34, wherein R⁶ is hydrogen or R^6C-substituted or unsubstituted Ci to C5 alkyl, wherein R^6C is hydroxyl, R^6D-substituted or unsubstituted aryl, R^6D- substituted or unsubstituted heteroaryl, R^6D-substituted or unsubstituted cycloalkyl, or R^6D- substituted or unsubstituted heterocycloalkyl; and

R^6D is halo gen or unsubstituted alkyl. 46. The compound of claim 34, wherein R⁶ is -C(0)OR^6A; R^6A is R^6C- substituted or unsubstituted alkyl; and R^6C is unsubstituted alkyl or halogen.

47. The compound of claim 34, wherein R⁶ is hydrogen, methyl, ethyl or propyl. 48. The compound of claim 34, wherein R⁶ is hydrogen. 49. The compound of claim 34, wherein R⁶ is methyl. 50. The compound of claim 49, wherein

R⁷ is hydrogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -S(0)₂C1, - S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, - NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^7C-substituted or unsubstituted alkyl, R^7C-substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl;

R 7 A. is R 7C -substituted or unsubstituted alkyl, R 7C -substituted or unsubstituted heteroalkyl, R^7C-substituted or unsubstituted cycloalkyl, R^7C-substituted or unsubstituted heterocycloalkyl, R^7C-substituted or unsubstituted aryl, or R^7C-substituted or unsubstituted heteroaryl;

R^7C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^7D- substituted or unsubstituted alkyl, R^7D-substituted or unsubstituted heteroalkyl, R^7D-substituted or unsubstituted cycloalkyl, R^7D-substituted or unsubstituted heterocycloalkyl, R^7D-substituted or unsubstituted aryl, or R^7D-substituted or unsubstituted heteroaryl; and

R^7D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 51. The compound of claim 49, wherein R⁷ is hydrogen. 52. The compound of claim 51 , wherein R is hydrogen, -Si(CH₃)₃, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R^3C-substituted or unsubstituted aryl, R^3C-substituted or unsubstituted heteroaryl;

R^3C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^3D- substituted or unsubstituted alkyl, R^3D-substituted or unsubstituted heteroalkyl, R^3D-substituted or unsubstituted cycloalkyl, R^3D-substituted or unsubstituted heterocycloalkyl, R^3D-substituted or unsubstituted aryl, or R^3D-substituted or unsubstituted heteroaryl; and

R^3D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 53. The compound of claim 51 , wherein

R is hydrogen, R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R^3C-substituted or unsubstituted cycloalkyl, R^3C-substituted or unsubstituted heterocycloalkyl, R^3C-substituted or unsubstituted aryl, R^3C-substituted or unsubstituted heteroaryl;

R^3C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^3D- substituted or unsubstituted alkyl, R^3D-substituted or unsubstituted heteroalkyl, R^3D-substituted or unsubstituted cycloalkyl, R^3D-substituted or unsubstituted heterocycloalkyl, R^3D-substituted or unsubstituted aryl, or R^3D-substituted or unsubstituted heteroaryl; and

R^3D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. The compound of claim 52, wherein R is hydrogen or unsubstituted

The compound of claim 52, wherein R^3A is hydrogen or methyl. The compound of claim 1 , having the structure:

The compound of claim 1, having the structure:

58. The compound of claim 57, wherein

R^4A is , wherein z4 is an integer from 1 to 5;

R^5A is

, wherein z5 is an integer from 1 to 5;

R^4C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D- substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl; R^4D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NH H₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D- substituted or unsubstituted alkyl, R^5D-substituted or unsubstituted heteroalkyl, R^5D-substituted or unsubstituted cycloalkyl, R^5D-substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D-substituted or unsubstituted heteroaryl; and

R^5D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 59. The compound of claim 58, wherein z4 and z5 are 1. 60. The compound of claim 58, wherein R^4C and R^4C are hydrogen. 61. The compound of claim 57, wherein R⁶ is hydrogen, unsubstituted C1-C5

alkyl, -C(0)OR^6A or "* , wherein z6 is an integer from 1 to 5;

R^6C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D- substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and

R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

62. The compound of claim 61, wherein R^6C is hydrogen.

63. The compound of claim 61 wherein z6 is 1.

64. The compound of claim 57, wherein L¹ and L² are unsubstituted Ci to C5 alkylene.

65. The compound of claim 64, wherein L¹ and L² are methylene.

66. The compound of claim 57, wherein R^3A is hydrogen or methyl.

67. The compound of claim 65, wherein R^3A is hydrogen.

68. The compound of claim 67, wherein R¹ is substituted or unsubstituted alkyl.

69. The compound of claim 68, wherein

R¹ is hydrogen or R^lc-substituted or unsubstituted Ci to C5 alkyl, wherein R^1C is hydroxyl.

ΌΗ

wherein R¹ is hydrogen, methyl, ethyl, propyl, or allyl.

70. The compound of claim 68, wherein

R¹ is hydrogen, methyl, ethyl, propyl, OH or allyl.

71. The compound of claim 68, wherein

T)H

R¹ is methyl, ethyl, propyl, or allyl. 72. The compound of claim 68, wherein R¹ is allyl. 73. The compound of claim 1, having the structure:

The compound of claim 1, having the structure:

75. The compound of claim 74, wherein

, wherein z4 is an integer from 1 to 5;

, wherein z5 is an integer from 1 to 5;

R^4L is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^4D- substituted or unsubstituted alkyl, R^4D-substituted or unsubstituted heteroalkyl, R^4D-substituted or unsubstituted cycloalkyl, R^4D-substituted or unsubstituted heterocycloalkyl, R^4D-substituted or unsubstituted aryl, or R^4D-substituted or unsubstituted heteroaryl;

R^4D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R^5C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^5D- substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R^5D-substituted or unsubstituted heterocycloalkyl, R^5D-substituted or unsubstituted aryl, or R^5D-substituted or unsubstituted heteroaryl; and

R^5D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 76. The compound of claim 75, wherein z4 and z5 are 1. 77. The compound of claim 75, wherein R^4C and R^4C are hydrogen. 78. The compound of claim 77, wherein

R⁶ is hydrogen, unsubstituted C1-C5 alkyl, -RC(0)OR^6A or

, wherein z6 is an integer from 1 to 5;

R^6A is R^6C-substituted or unsubstituted alkyl;

R^6C is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂, R^6D- substituted or unsubstituted alkyl, R^6D-substituted or unsubstituted heteroalkyl, R^6D-substituted or unsubstituted cycloalkyl, R^6D-substituted or unsubstituted heterocycloalkyl, R^6D-substituted or unsubstituted aryl, or R^6D-substituted or unsubstituted heteroaryl; and

R^6D is independently oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, - N0₂, -SH, -S(0)₂C1, -S(0)₃H, -S(0)₄H, -S(0)₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(O) NH₂, -NHS(0)₂H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF₃, -OCHF₂,

unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

79. The compound of claim 78, wherein R is

80. The compound of claim 61, wherein R^6C is hydrogen.

81. The compound of claim 61, wherein z6 is 1. 82. The compound of claim 78, wherein R⁶ is -C(0)OR^6A and R^6A is unsubstituted alkyl. 83. The compound of claim 82, wherein R^6A is tertiary butyl. 84. A method of treating cancer in a subject in need thereof, said method comprising administering an effective amount of a compound of claim 1 to said subject, thereby treating said cancer. 85. The method of claim 84, wherein said cancer is lung cancer, lymphoma, breast cancer, cervical cancer, or brain cancer.