PCNA inhibitors for the treatment of MYC family associated cancers

Abstract

Described herein, inter alia, is the use of PCNA inhibitors for the treatment of Myc family associated cancers.

Description

PCNA INHIBITORS FOR THE TREATMENT OF MYC FAMILY ASSOCIATED CANCERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 560,559 filed March 1, 2024, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048440- 893001WO_Sequence_Listing_ST26.xml; Size 2,557 bytes; and Date of Creation: January 22, 2025) are hereby incorporated by reference in their entirety. BACKGROUND

[0003] c-Myc (MYC), is a transcription factor and regulator that is often constitutively expressed in cancer and is a driver of the oncogenic phenotype that includes rapid proliferation and the ability to metastasize. Rapid proliferation is accompanied by high levels of transcription and replication stress often induced by transcription-replication conflicts (TRC) that can result in replication fork collapse and double-stranded DNA breaks during S phase. MYC amplification and high MYC expression have also been associated with a high metastatic phenotype. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0004] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including: (i) detecting a level of Myc family protein expression in a cancer cell sample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0005] L1is -O-, -NR7-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR7C(O)-, -C(O)NR7-, -NR7C(O)NR8-, -NR7S(O)2O-, -OS(O)2NR7-, -NR7S(O)2-, -S(O)2NR7-, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR7)-, -OP(O)(OR7)O-, -OP(O)(OR7)-, -P(O)(OR7)O-, or -CR8R9-.

[0006] R7, R8, and R9are independently hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl.

[0007] Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0008] Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.

[0009] R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0010] R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0011] R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0012] R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B, ^NHC(O)NR6CNR6AR6B,-NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0013] R3and R6may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0014] R1A, R1B, R1C, R1D, R6A, R6B, R6C, and R6Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0015] The symbol z1 is an integer from 0 to 4. The symbols m1, m6, v1, and v6 are independently 1 or 2. The symbols n1 and n6 are independently an integer from 0 to 4.

[0016] X, X1, X2, X3, and X6are independently –Cl, -Br, -I, or –F.

[0017] The symbol m is an integer from 0 to 5. The symbol n is an integer from 0 to 10.

[0018] In an aspect is provided a method of treating a cancer in a subject in need thereof, wherein the subject has a Myc family protein associated cancer, the method including administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: . Ring A, Ring B, L1, R1, z1, R2, R3, R6, m, andBRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIGS.1A-1B. MYC amplified cell lines are sensitive to AOH1996. FIG.1A: AOH1996 was submitted to the NCI Developmental Therapeutics Program (DTP) for testing in their NCI-60 Human Tumor Cell Lines Screen. The panel of cell lines were incubated with serial dilutions of AOH1996 for 48 hours. At the conclusion of the incubation period, the cells were fixed with 10% trichloroacetic acid (TCA) and cell growth was analyzed by sulforhodamine B (SRB) assay. The IC50was calculated by the NCI. The graph compares the sensitivity of MYC amplified cell lines in the NCI-60 to the rest of the cell lines in the panel. A student’s t-test performed on the datasets returned a p value of .0014 indicating a significant difference in sensitivity between the two groups. FIG.1B: A 72-hour dose response assay using AOH1996 on a set of MYC amplified cell lines (MCF7, HCT116, RKO, OVCAR8, NCI-H358, HCC827, and NCI-H1975) and two non-malignant cell lines (HSAEC and HMEC-1) was performed.

[0020] FIGS.2A-2D. AOH1996 decreases c-Myc and n-Myc and increases p21. FIG.2A: Three cancer cell lines originating from different tissues (colon, breast, and ovary) were treated with 1 µM AOH1996 for 48 or 72 hours or left untreated. Western blots on the lysates were used to look at levels of c-Myc and p21. GAPDH was used as a loading control. Treatment with AOH1996 for 48 or 72 hours resulted in decreased levels of c-Myc and increased levels of p21. FIG.2B: Additional Western blot analysis showed reduced c-Myc levels after 24 hours of 1 µM AOH1996 treatment, while the same treatment on non- malignant HMEC1 cells showed no reduction in c-Myc levels at 24 or 48 hours. FIG.2C: In neuroblastoma n-Myc amplification is associated with poor prognosis and high probability of unfavorable outcomes. Three neuroblastoma cell lines, two n-Myc amplified cell lines (BE2C and SK-N-BE2C) and one non-amplified cell line (SK-N-FI) were analyzed by Western blot analysis for n-Myc levels after treatment with 1 µM of AOH1996 for 24 and 48 hours. BE2C and SK-N-BE2C cell lines showed decreased levels of n-Myc at both 24 and 48 hours, while the low n-Myc levels in the SK-N-FI cells were not altered after AOH1996 treatment in the assay tested. FIG.2D: Western blot analysis of chromatin fractions isolated from HCT116 cells treated for 12, 24, and 36 hours demonstrated that reduced levels c-Myc are present on the chromatin after 24 hours of treatment with 1 µM AOH1996.

[0021] FIG.3. AOH1996 interferes with MYC and PCNA colocalization. A proximity ligation assay was used to identify instances of MYC and PCNA interactions. HCT116 cellswere serum starved for 36 hours before releasing into complete media with and without 1 µM of AOH1996 over a course of time. The cells were fixed and permeabilized and a proximity ligation assay using primary antibodies to MYC and PCNA was performed. The cells were counterstained with DAPI to mark the nuclei. Cells untreated by AOH1996 showed instances of MYC and PCNA interactions (light grey foci) while treatment of cells with AOH1996 for 15 minutes to 4 hours (not shown) abrogated MYC-PCNA interactions. Representative images taken at 63x and 20x for untreated and 15-minute treatment with AOH1996 are shown.

[0022] FIGS.4A-4B. PCNA and MYC colocalize in early S-phase. FIG.4A: As previously described (Schönenberger et al., 2015, Chagin et al., 2016), PCNA localization is distinct for the different stages of interphase. HCT116 cells were serum starved for 36 hours in media + .1% FBS. The cells were then released into complete media for 30 minutes, fixed, permeabilized and stained for PCNA using a monoclonal primary antibody for PCNA (PC10) and a secondary antibody conjugated to a fluorophore. The images show typical PCNA staining patterns reflective of the different stages of interphase. FIG.4B: BrdU was incorporated into replicating HCT116 cells for 30 minutes. The cells were then fixed and permeabilized. A proximity ligation assay was performed between BrdU and MYC to indicate instances where replication forks encountered MYC (light grey foci). The cells were further stained with the PC10 antibody conjugated to Alexa Fluor 488 (medium grey foci). The DNA was counterstained with DAPI (blue). PCNA as a central component of the replication fork was present at the site of MYC-BrdU foci. The replication fork encountered MYC in the early stages of S phase in areas of apparent euchromatin (unstained or lightly stained areas of DNA).

[0023] FIG.5. AOH1996 disrupts interaction of MYC with transcription elongation factor SPT5. HCT116 cells were serum starved for 36 hours before releasing into complete media with and without 1 µM of AOH1996 for 30 minutes. The cells were fixed and permeabilized and a proximity ligation assay using primary antibodies to MYC and SPT5 was performed. The cells were counterstained with DAPI (blue) to mark the nuclei. Cells untreated by AOH1996 showed instances of MYC and SPT5 interactions (light grey foci) while treatment of cells with AOH1996 for 30 minutes showed a marked reduction in MYC-SPT5 interactions.

[0024] FIG.6. AOH1996 suppresses metastatic processes. RNA seq analysis was performed on three MYC amplified and highly metastatic PDAC cell lines. Untreated and AOH1996 treated conditions for each of the cell lines were analyzed. Gene ontology analysis found biological processes related to angiogenesis, motility and migration, and proliferation were significantly decreased, while processes related to inflammation and apoptosis were significantly increased. A false discovery rate under .05 was considered significant. DETAILED DESCRIPTION I. Definitions

[0025] 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.

[0026] 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-.

[0027] 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. The alkyl may include a designated number of carbons (e.g., C1-C10means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. 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, 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-(1,4-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 (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0028] 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 herein. 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. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0029] 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 (e.g., 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) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one ormore double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0030] 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(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. 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. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0031] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0032] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0033] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0034] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

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

[0036] The term “acyl” means, unless otherwise stated, -C(O)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.

[0037] 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 and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. 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 and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). 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, benzoxazoylbenzimidazolyl, 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 -O- bonded to a ring heteroatom nitrogen.

[0038] 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.

[0039] The symbol “ ” denotes the point of attachment of a chemical moiety to theremainder of a molecule or chemical formula.

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

[0041] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: .(e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

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

[0044] Substituents for 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', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), 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 described herein 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 samenitrogen 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., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0045] 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(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', 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 described herein 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.

[0046] 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 moleculeis 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 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.

[0047] 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.

[0048] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -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'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)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 -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' arepreferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

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

[0050] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:(i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10aryl, C10aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0051] 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 C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted orunsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0052] 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 C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0053] 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.

[0054] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20alkyl, 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-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted 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-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is asubstituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0055] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

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

[0057] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0058] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0059] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group mayoptionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0060] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different.

[0061] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0062] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R1.1, R2may be substituted with one or more first substituent groups denoted by R2.1, R3may be substituted with one or more first substituent groups denoted by R3.1, R4may be substituted with one or more first substituent groups denoted by R4.1, R5may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A.1, R2Amay be substituted with one or more first substituent groups denoted by R2A.1, R3Amay be substituted with one or more first substituent groups denoted by R3A.1, R4Amay be substituted with one or more first substituent groups denoted by R4A.1, R5Amay be substituted with one or more first substituent groups denoted byR5A.1and the like up to or exceeding an R100Amay be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1may be substituted with one or more first substituent groups L2may be substituted with one or more first substituent groups denoted bybe substituted with one or more first substituent groups denoted by RL3.1, L4may be substituted with one or more first substituent groups denoted by RL4.1, L5may be substituted with one or more first substituent groups denoted by RL5.1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWWor LWWwherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1,R1A.1, R2A.1, R3A.1, R4A.1, R5A.1… R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1… RL100.1) may be… …represented herein as RWW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2.

[0063] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2… R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2… RL100.2) may be furtherR1A.3, R2A.3, R3A.3, R4A.3, R5A.3… R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3… RL100.3;represented herein as RWW.2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0064] Thus, as used herein, RWWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWWis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1,2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWWis phenyl, the said phenyl group is optionally substituted by one or more RWW.1groups as defined herein below, e.g., when RWW.1is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2is optionally substituted by one or more RWW.3. By way of example when the RWWgroup is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to: .

[0065] RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH,-SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or or unsubstituted3 membered, or 4 to 5 membered), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1is independently –F, -Cl, -Br, or –I.

[0066] RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2,-NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2is independently –F, -Cl, -Br, or –I.

[0067] RWW.3is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.33, -OCH2XWW.3, -OCHXWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3is independently –F, -Cl, -Br, or –I.

[0068] Where two different RWWsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups,to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2and RWW.3refers to the designated number of one of the twodifferent RWWsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100A.1, RWW.2is R100A.2, and RWW.3is R100A.3. Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100B.1, RWW.2is R100B.2, and RWW.3is R100B.3. RWW.1, RWW.2and RWW.3in this paragraph are as defined in the preceding paragraphs.

[0069] RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1is independently –F, -Cl, -Br, or –I.

[0070] RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted orunsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2is independently –F, -Cl, -Br, or –I.

[0071] RLWW.3is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3is independently –F, -Cl, -Br, or –I.

[0072] In the event that any R group recited in a claim or chemical formula description set forth herein (RWWsubstituent) is not specifically defined in this disclosure, then that R group (RWWgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2,-CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWWis independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).RWW.1, RWW.2, and RWW.3 are as defined above.

[0073] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWWsubstituent) is not explicitly defined, then that L group (LWWgroup) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2and RLWW.3are as defined above.

[0074] Certain compounds of the present disclosure 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 disclosure. The compounds of the presentdisclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure 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.

[0075] 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.

[0076] 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.

[0077] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0078] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0079] 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 by13C- or14C-enriched carbon are within the scope of this disclosure.

[0080] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may 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 disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0081] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0082] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimidemoiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0083] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex.

[0084] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecularentity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0085] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0086] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0087] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0088] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are notinherently 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.

[0089] 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 disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include 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 al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0090] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates,benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0091] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0092] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0093] Certain compounds of the present disclosure 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 disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0094] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, such that it is notassociated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0095] “Co-administer” 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.The compounds 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 compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0096] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0097] 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. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0098] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, 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” when referred to in this context. 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. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. 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).

[0099] “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 some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0100] “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 includingbiomolecules, 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.

[0101] 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 cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0102] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0103] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0104] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absenceof the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0105] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0106] 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 (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0107] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0108] 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, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0109] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers 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 embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0110] “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. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., a Myc family protein associated cancer).

[0111] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer,hepatocellular carcinoma, or prostate cancer.

[0112] 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 generallyclinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0113] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, butare not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[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 that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0115] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or 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 that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse,carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0117] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormallung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0118] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0119] The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0120] As used herein, the term “Myc family protein associated cancer” refers to any cancer caused by aberrant activity of signaling of a Myc family protein. In embodiments, the Myc family protein associated cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, ampullary carcinoma, basal cell carcinoma, bladder cancer, bladder urothelial carcinoma, brain lower grade glioma, breast cancer, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, colon cancer, colorectal adenocarcinoma, cutaneous squamous cell carcinoma, cutaneous T cell lymphoma, diffuse glioma, diffuse large B cell lymphoma, endometrial carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastric cancer, glioblastoma, gliobastoma multiforme, glioma, head and neck squamous cell carcinoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, kidney chromophobe, kidney renal clear cell carcinoma, liverhepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, malignant peripheral nerve sheath tumor, medulloblastoma, melanoma, mesothelioma, metastatic melanoma, metastatic prostate adenocarcinoma, multiple myeloma, myelodysplastic syndromes, neuroblastoma, non-small cell lung cancer, ovarian cancer, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumors, pediatric acute lymphoid leukemia, pediatric brain cancer, pediatric Ewing sarcoma, pheochromocytoma and paraganglioma, pleural mesothelioma, prostate adenocarcinoma, prostate cancer brain metastases, osteosarcoma, retinoblastoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumors, angiosarcoma, renal cell carcinoma, urothelial carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, or uveal melanoma.

[0121] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

[0122] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0123] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0124] “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.

[0125] 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.

[0126] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0127] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, 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. 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. The compounds 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 compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0128] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0129] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0130] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. 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. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0131] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer) is causedby (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0132] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0133] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0134] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0135] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0136] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that havethe same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0137] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0138] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0139] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0140] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0141] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to His44 of PCNA when the selected residue occupies the same essential spatial or other structural relationship as His44 of PCNA. In some embodiments, where a selected protein is aligned for maximum homology with PCNA, the position in the aligned selected protein aligning with His44 is said to correspond to His44. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with PCNA and the overall structures compared. In this case, an amino acid that occupies the same essential position as His44 in the structural model is said to correspond to the His44 residue.

[0142] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.

[0143] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.

[0144] The term “Proliferating cell nuclear antigen” or “PCNA” refers to a ~29 kDa protein that self assembles into a protein complex consisting of 3 subunits of individual PCNA proteins. Together these joined PCNA molecules form a DNA clamp that acts as a processivity factor for DNA polymerase ^ in eukaryotic cells. The term “PCNA” may refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, UniProt P12004, RefSeq NM_002592, or RefSeq NP_002583). The term “PCNA” includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, “PCNA” is wild-type PCNA. In some embodiments, “PCNA” is one or more mutant forms. The term “PCNA” XYZ refers to a nucleotide sequence or protein of a mutant PCNA wherein the Y numbered amino acid of PCNA that normally has an X amino acid in the wild-type, instead has a Z amino acid in the mutant. In embodiments, a PCNA is the human PCNA. In embodiments, the PCNA has the nucleotide sequence corresponding to reference number GI:33239449. In embodiments, the PCNA has the nucleotide sequence corresponding to RefSeq NM_002592.2. In embodiments, the PCNA has the protein sequence corresponding to reference number GI:4505641. In embodiments, the PCNA has the nucleotide sequence corresponding to RefSeq NP_002583.1. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In embodiments, the PCNA has the following amino acid sequence: MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGF DTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSD YEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFS ASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLS MSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 1).

[0145] In embodiments, the PCNA is a mutant PCNA. In embodiments, the mutant PCNA is associated with a disease that is not associated with wild-type PCNA. In embodiments, the PCNA includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the sequence above. PCNA may be post-translationally modified. Modifications may include phosphorylation, methylation, methylesters of acidic amino acids, ribosylation, acetylation, glycosylation with a variety of sugars, lipidation with a variety of different lipids, poly(ADP) ribosylation, or other post-translational modifications known in the art. Differences in the extent and type of modification influences the levels (e.g., protein levels) of the ca- and nm- PCNA isoforms. In embodiments, a post-translational modification or plurality of post-translational modifications modify the inhibition of PCNA by a compound described herein or the binding of a compound described herein to PCNA, relative to PCNA without the post- translational modification(s).

[0146] The terms “cancer-associated proliferating cell nuclear antigen” or “caPCNA” as used herein refer to an isoform of PCNA having an acidic isoelectric point (e.g., peptide including protonated amine and / or carboxyl groups, acidic isoelectric point compared to a non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, prevalent PCNA isoform in non-cancerous cells, or less acidic PCNA isoform in non- cancerous cells). In embodiments, the caPCNA protein includes methylated amino acids (e.g., glutamate, aspartic acid). In embodiments, the caPCNA protein is post-translationally modified with a methylester of an acidic amino acid. In embodiments, the methylesterification of the acidic amino acid residues on PCNA exhibit a T1 / 2of approximately 20 minutes at pH 8.5. In embodiments, caPCNA is post-translationally modified as described in F. Shen, et al. J Cell Biochem.2011 Mar; 112(3): 756–760, which is incorporated by reference in its entirety for all purposes.

[0147] The terms “non-malignant Proliferating cell nuclear antigen” or “nmPCNA” as used herein refer to an isoform of PCNA having a basic isoelectric point (e.g., peptide including deprotonated amine and / or carboxyl groups, basic isoelectric point compared to a caPCNA, caPCNA in cancerous cells). In embodiments, nmPCNA is the prevalent PCNA isoform in non-cancerous cells.

[0148] The term “Myc family protein” refers to one or more of the family of regulator genes and proto-oncogenes that code for transcription factors. In embodiments, the Myc family protein is c-Myc, N-Myc, or L-Myc.

[0149] The term “c-Myc” or “MYC” refers to a proto-oncogene that plays a role in cell cycle progression, apoptosis, and cellular transformation. The term includes any recombinant or naturally-occurring form of MYC variants thereof that maintain MYC activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype MYC). In embodiments, the MYC protein encoded by the MYC gene has the amino acid sequence set forth in or corresponding to Entrez 4609, UniProt P01106, RefSeq NP_002458, or RefSeq NP_001341799. In embodiments, the MYC gene has the nucleic acid sequence set forth in RefSeq NM_002467 or RefSeq NM_001354870. In embodiments, the amino acidsequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0150] The term “N-Myc” or “MYCN” refers to a proto-oncogene that in humans is encoded by the MYCN gene. The term includes any recombinant or naturally-occurring form of N-Myc variants thereof that maintain N-Myc activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype N-Myc). In embodiments, the N-Myc protein encoded by the MYCN gene has the amino acid sequence set forth in or corresponding to Entrez 4613, UniProt P04198, RefSeq NP_001280157, RefSeq NP_001280160, RefSeq NP_001280162, or RefSeq NP_005369. In embodiments, the MYCN gene has the nucleic acid sequence set forth in RefSeq NM_005378, RefSeq NM_001293228, RefSeq NM_001293231, or RefSeq NM_001293233. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0151] The term “L-Myc” or “MYCL” refers to a proto-oncogene that in humans is encoded by the MYCL1 gene. The term includes any recombinant or naturally-occurring form of L-Myc variants thereof that maintain L-Myc activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype L-Myc). In embodiments, the L-Myc protein encoded by the MYCL1 gene has the amino acid sequence set forth in or corresponding to Entrez 4610, UniProt P12524, RefSeq NP_001028253, RefSeq NP_001028254, or RefSeq NP_005367. In embodiments, the MYCL1 gene has the nucleic acid sequence set forth in RefSeq NM_005376, RefSeq NM_001033081, or RefSeq NM_001033082. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. II. Methods of use

[0152] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including: (i) detecting a level of Myc family protein expression in a cancer cell sample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:). )O-, -OC(O)-, -NR7C(O)-, -C(O)NR7-, -NR7C(O)NR8-, -NR7S(O)2O-, -OS(O)2NR7-, -NR7S(O)2-, -S(O)2NR7-, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR7)-, -OP(O)(OR7)O-, -OP(O)(OR7)-, -P(O)(OR7)O-, or -CR8R9-.

[0154] R7, R8, and R9are independently hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).

[0155] Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0156] Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.

[0157] R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0158] R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0159] R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0160] R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B, ^NHC(O)NR6CNR6AR6B, -NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, substituted or unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0161] R3and R6may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0162] R1A, R1B, R1C, R1D, R6A, R6B, R6C, and R6Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0163] The symbol z1 is an integer from 0 to 4.

[0164] The symbols m1, m6, v1, and v6 are independently 1 or 2.

[0165] The symbols n1 and n6 are independently an integer from 0 to 4.

[0166] X, X1, X2, X3, and X6are independently –Cl, -Br, -I, or –F.

[0167] The symbol m is an integer from 0 to 5.

[0168] The symbol n is an integer from 0 to 10.

[0169] In embodiments, the level of Myc family protein expression is elevated relative to a standard control. In embodiments, the standard control is a healthy subject. In embodiments, the standard control is a subject who has cancer, but does not have a Myc family protein associated cancer.

[0170] In an aspect is provided a method of treating a cancer in a subject in need thereof, wherein the subject has a Myc family protein associated cancer, the method including administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:I). Ring A, Ring B, L1, R1, z1, R2, R3, R6, m, and diments.

[0171] In embodiments, the Myc family protein is c-Myc, N-Myc, or L-Myc. In embodiments, the Myc family protein is c-Myc. In embodiments, the Myc family protein is N-Myc. In embodiments, the Myc family protein is L-Myc.

[0172] In embodiments, the cancer is a Myc family protein associated cancer. In embodiments, the cancer is acute lymphoblastic leukemia. In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is adenoid cystic carcinoma. In embodiments, the cancer is adrenocortical carcinoma. In embodiments, the cancer is ampullary carcinoma. In embodiments, the cancer is basal cell carcinoma. In embodiments, the cancer is bladder cancer. In embodiments, the cancer is bladder urothelial carcinoma. In embodiments, the cancer is brain lower grade glioma. In embodiments, the cancer is breast cancer. In embodiments, the cancer is breast invasive carcinoma. In embodiments, the cancer is cervical squamous cell carcinoma. In embodiments, the cancer is cholangiocarcinoma. In embodiments, the cancer is chronic lymphocytic leukemia. In embodiments, the cancer is colon cancer. In embodiments, the cancer is colorectal adenocarcinoma. In embodiments, the cancer is cutaneous squamous cell carcinoma. In embodiments, the cancer is cutaneous T cell lymphoma. In embodiments, the cancer is diffuse glioma. In embodiments, the cancer is diffuse large B cell lymphoma. In embodiments, the cancer is endometrial carcinoma. In embodiments, the cancer is esophageal adenocarcinoma. In embodiments, the cancer is gastric adenocarcinoma. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is glioblastoma. In embodiments, the cancer is gliobastoma multiforme. In embodiments, the cancer is glioma. In embodiments, the cancer is head and neck squamous cell carcinoma. In embodiments, the cancer is hepatocellular carcinoma. In embodiments, the cancer is intrahepatic cholangiocarcinoma. In embodiments, the cancer is kidney chromophobe. In embodiments, the cancer is kidney renal clear cell carcinoma. In embodiments, the cancer is liver hepatocellular carcinoma. In embodiments, the cancer is lung adenocarcinoma. In embodiments, the cancer is lung squamous cell carcinoma. In embodiments, the cancer ismalignant peripheral nerve sheath tumor. In embodiments, the cancer is medulloblastoma. In embodiments, the cancer is melanoma. In embodiments, the cancer is mesothelioma. In embodiments, the cancer is metastatic melanoma. In embodiments, the cancer is metastatic prostate adenocarcinoma. In embodiments, the cancer is multiple myeloma. In embodiments, the cancer is myelodysplastic syndromes. In embodiments, the cancer is neuroblastoma. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is ovarian serous cystadenocarcinoma. In embodiments, the cancer is pancreatic adenocarcinoma. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is pancreatic ductal adenocarcinoma. In embodiments, the cancer is pancreatic neuroendocrine tumors. In embodiments, the cancer is pediatric acute lymphoid leukemia. In embodiments, the cancer is pediatric brain cancer. In embodiments, the cancer is pediatric Ewing sarcoma. In embodiments, the cancer is pheochromocytoma and paraganglioma. In embodiments, the cancer is pleural mesothelioma. In embodiments, the cancer is prostate adenocarcinoma. In embodiments, the cancer is prostate cancer brain metastases. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer is metastatic osteosarcoma. In embodiments, the cancer is retinoblastoma. In embodiments, the cancer is sarcoma. In embodiments, the cancer is skin cutaneous melanoma. In embodiments, the cancer is stomach adenocarcinoma. In embodiments, the cancer is testicular germ cell tumors. In embodiments, the cancer is angiosarcoma. In embodiments, the cancer is renal cell carcinoma. In embodiments, the cancer is urothelial carcinoma. In embodiments, the cancer is uterine carcinosarcoma. In embodiments, the cancer is uterine corpus endometrial carcinoma. In embodiments, the cancer is uveal melanoma.

[0173] In embodiments, the compound has the formula: z1, R2, R3, R6, m, and n

[0174] Ring A is phenyl or 5 to 6 membered heteroaryl.

[0175] Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl.

[0176] R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCHX42, -OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, ^NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -OC(O)NR4AR4B, -NR4AOR4C, -P(O)R4AR4B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0177] R5is independently a halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCHX52, -OCH2X5, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, ^NHC(O)NR5CNR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -OC(O)NR5AR5B, -NR5AOR5C, -P(O)R5AR5B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0178] R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0179] The symbol z4 is an integer from 0 to 5.

[0180] The symbol z5 is an integer from 0 to 7.

[0181] The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0182] The symbols n4 and n5 are independently an integer from 0 to 4.

[0183] X, X4, and X5are independently –Cl, -Br, -I, or -F.

[0184] In embodiments, the compound has the formula: Ring A, Ring B, R1, z1, R2, R3,in embodiments.

[0185] In embodiments, the compound has the formula:(IIIa). L1, Ring A, Ring B, R1, z1, R2, R3, ncluding in embodiments.

[0186] In embodiments, the compound has the formula: (IIIb). L1, Ring A, Ring B, R1, z1, R2, R3,in embodiments.

[0187] In embodiments, the compound has the formula: . L1, Ring A, Ring B, R1, z1, R2, R3, R4, z4, R5, z5,in embodiments.

[0188] In embodiments, the compound has the formula: ; wherein Ring A is phenyl or 5 to 6 memberedor isoquinolinyl; L1is -O- or -S-; R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCHX42, -OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, ^NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -OC(O)NR4AR4B, -NR4AOR4C, -P(O)R4AR4B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is 2 or 3; R5is independently a halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCHX52, -OCH2X5, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, ^NHC(O)NR5CNR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -OC(O)NR5AR5B, -NR5AOR5C, -P(O)R5AR5B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 7; R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B, ^NHC(O)NR6CNR6AR6B,-NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, and R6Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; m1, m4, m5, m6, v1, v4, v5, and v6 are independently 1 or 2; n1, n4, n5, and n6 are independently an integer from 0 to 4; and each X, X1, X2, X3, X4, X5, and X6is independently –Cl, -Br, -I, or –F.

[0189] In embodiments, the compound has the formula: Ring A, Ring B, R1, z1, R2, R3, R4, z4, R5,embodiments.

[0190] In embodiments, the compound has the formula: Ring A, Ring B, R1, z1, R2, R3, R4, z4, R5,embodiments.

[0191] In embodiments, the compound has the formula: . L1, Ring A, Ring B, R1, z1, R2, R3, R4, z4, in embodiments.

[0192] In embodiments, the compound has the formula: . L1, Ring A, Ring B, R1, z1, R2, R3, R4, in embodiments.

[0193] In embodiments, the compound has the formula: Ring A, Ring B, R1, z1, R2, R3, R4,embodiments.

[0194] In embodiments, the compound has the formula: R3,

[0195] In embodiments, the compound has the formula:R3,

[0196] In embodiments, the compound has the formula: Ring A, Ring B, R1, z1, R2, R3,

[0197] In embodiments, L1is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2-, -S(O)2NH-, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR9-, or -CR8R9-; wherein R8and R9are as described herein, including in embodiments. In embodiments, L1is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR9-, or -CR8R9-; and R8and R9are independently halogen or unsubstituted methyl.

[0198] In embodiments, L1is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2-, -S(O)2NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR9-, or -CR8R9-; wherein R8and R9are as described herein, including in embodiments. In embodiments, L1is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR9-, or -CR8R9-; and R8and R9are independently halogen or unsubstituted methyl.

[0199] In embodiments, L1is -O-. In embodiments, L1is –NR7-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -NH-. In embodiments, L1is -NCH3-. In embodiments, L1is -S-. In embodiments, L1is -C(O)-. In embodiments, L1is -C(O)O-. In embodiments, L1is -OC(O)-. In embodiments, L1is -NR7C(O)-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -NHC(O)-. In embodiments, L1is -C(O)NR7-, wherein R7is as described herein, including in embodiments.In embodiments, L1is -C(O)NH-. In embodiments, L1is -NR7C(O)NR8-. In embodiments, L1is -NHC(O)NH-. In embodiments, L1is -NR7S(O)2O-. In embodiments, L1is -NHS(O)2O-. In embodiments, L1is -OS(O)2NR7-. In embodiments, L1is -OS(O)2NH-. In embodiments, L1is -NR7S(O)2-. In embodiments, L1is -NHS(O)2-. In embodiments, L1is -S(O)2NR7-. In embodiments, L1is -S(O)2NH-. In embodiments, L1is –S(O)-. In embodiments, L1is –S(O)2-. In embodiments, L1is -OS(O)2O-. In embodiments, L1is -S(O)2O-. In embodiments, L1is -OS(O)2-. In embodiments, L1is -P(O)(OR7)-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -P(O)(OH)-. In embodiments, L1is -OP(O)(OR7)O-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -OP(O)(OH)O-. In embodiments, L1is -OP(O)(OR7)-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -OP(O)(OH)-. In embodiments, L1is -P(O)(OR7)O-, wherein R7is as described herein, including in embodiments. In embodiments, L1is -P(O)(OH)O-. In embodiments, L1is -CHR9-, wherein R9is as described herein, including in embodiments. In embodiments, L1is -CR8R9-, wherein R8and R9are as described herein, including in embodiments. In embodiments, L1is -CHF-. In embodiments, L1is –CF2-.

[0200] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0201] In embodiments, a substituted ring formed when two R1substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R1substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limitedsubstituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R1substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R1substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R1substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0202] In embodiments, a substituted R1A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1Ais substituted, it is substituted with at least one substituent group. In embodiments, when R1Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Ais substituted, it is substituted with at least one lower substituent group.

[0203] In embodiments, a substituted R1B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1Bis substituted, it is substituted with at least one substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one lower substituent group.

[0204] In embodiments, a substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selectedfrom substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0205] In embodiments, a substituted R1C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1Cis substituted, it is substituted with at least one substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one lower substituent group.

[0206] In embodiments, a substituted R1D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1Dis substituted, it is substituted with at least one substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one lower substituent group.

[0207] In embodiments, R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C,-OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R1substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0208] In embodiments, R1is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R1is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R1is independently halogen, -OH, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.

[0209] In embodiments, R1is independently halogen. In embodiments, R1is independently –F. In embodiments, R1is independently –Cl. In embodiments, R1is independently –Br. In embodiments, R1is independently –I. In embodiments, R1is independently -CCl3. In embodiments, R1is independently -CBr3. In embodiments, R1is independently -CF3. In embodiments, R1is independently -CI3. In embodiments, R1is independently -CH2Cl. In embodiments, R1is independently -CH2Br. In embodiments, R1is independently -CH2F. Inembodiments, R1is independently -CH2I. In embodiments, R1is independently -CHCl2. In embodiments, R1is independently -CHBr2. In embodiments, R1is independently -CHF2. In embodiments, R1is independently -CHI2. In embodiments, R1is independently –CN. In embodiments, R1is independently –OH. In embodiments, R1is independently -NH2. In embodiments, R1is independently –COOH. In embodiments, R1is independently -CONH2. In embodiments, R1is independently -NO2. In embodiments, R1is independently –SH. In embodiments, R1is independently -SO3H. In embodiments, R1is independently -OSO3H. In embodiments, R1is independently -SO2NH2. In embodiments, R1is independently ^NHNH2. In embodiments, R1is independently ^ONH2. In embodiments, R1is independently ^NHC(O)NHNH2. In embodiments, R1is independently ^NHC(O)NH2. In embodiments, R1is independently -NHSO2H. In embodiments, R1is independently -NHC(O)H. In embodiments, R1is independently -NHC(O)OH. In embodiments, R1is independently –NHOH. In embodiments, R1is independently -OCCl3. In embodiments, R1is independently -OCBr3. In embodiments, R1is independently -OCF3. In embodiments, R1is independently -OCI3. In embodiments, R1is independently -OCH2Cl. In embodiments, R1is independently -OCH2Br. In embodiments, R1is independently -OCH2F. In embodiments, R1is independently -OCH2I. In embodiments, R1is independently -OCHCl2. In embodiments, R1is independently -OCHBr2. In embodiments, R1is independently -OCHF2. In embodiments, R1is independently -OCHI2. In embodiments, R1is independently unsubstituted C1-C4alkyl. In embodiments, R1is independently unsubstituted methyl. In embodiments, R1is independently unsubstituted ethyl. In embodiments, R1is independently unsubstituted propyl. In embodiments, R1is independently unsubstituted n-propyl. In embodiments, R1is independently unsubstituted isopropyl. In embodiments, R1is independently unsubstituted butyl. In embodiments, R1is independently unsubstituted n- butyl. In embodiments, R1is independently unsubstituted isobutyl. In embodiments, R1is independently unsubstituted tert-butyl. In embodiments, R1is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R1is independently unsubstituted methoxy. In embodiments, R1is independently unsubstituted ethoxy. In embodiments, R1is independently unsubstituted propoxy. In embodiments, R1is independently unsubstituted n- propoxy. In embodiments, R1is independently unsubstituted isopropoxy. In embodiments, R1is independently unsubstituted butoxy. In embodiments, R1is independently unsubstituted n-butoxy. In embodiments, R1is independently unsubstituted isobutoxy. In embodiments, R1is independently unsubstituted tert-butoxy.

[0210] In embodiments, R1Ais independently hydrogen. In embodiments, R1Ais independently unsubstituted C1-C4 alkyl. In embodiments, R1Ais independently unsubstituted methyl. In embodiments, R1Ais independently unsubstituted ethyl. In embodiments, R1Ais independently unsubstituted propyl. In embodiments, R1Ais independently unsubstituted n-propyl. In embodiments, R1Ais independently unsubstituted isopropyl. In embodiments, R1Ais independently unsubstituted butyl. In embodiments, R1Ais independently unsubstituted n-butyl. In embodiments, R1Ais independently unsubstituted isobutyl. In embodiments, R1Ais independently unsubstituted tert-butyl.

[0211] In embodiments, R1Bis independently hydrogen. In embodiments, R1Bis independently unsubstituted C1-C4alkyl. In embodiments, R1Bis independently unsubstituted methyl. In embodiments, R1Bis independently unsubstituted ethyl. In embodiments, R1Bis independently unsubstituted propyl. In embodiments, R1Bis independently unsubstituted n-propyl. In embodiments, R1Bis independently unsubstituted isopropyl. In embodiments, R1Bis independently unsubstituted butyl. In embodiments, R1Bis independently unsubstituted n-butyl. In embodiments, R1Bis independently unsubstituted isobutyl. In embodiments, R1Bis independently unsubstituted tert-butyl.

[0212] In embodiments, R1Cis independently hydrogen. In embodiments, R1Cis independently unsubstituted C1-C4 alkyl. In embodiments, R1Cis independently unsubstituted methyl. In embodiments, R1Cis independently unsubstituted ethyl. In embodiments, R1Cis independently unsubstituted propyl. In embodiments, R1Cis independently unsubstituted n-propyl. In embodiments, R1Cis independently unsubstituted isopropyl. In embodiments, R1Cis independently unsubstituted butyl. In embodiments, R1Cis independently unsubstituted n-butyl. In embodiments, R1Cis independently unsubstituted isobutyl. In embodiments, R1Cis independently unsubstituted tert-butyl.

[0213] In embodiments, R1Dis independently hydrogen. In embodiments, R1Dis independently unsubstituted C1-C4alkyl. In embodiments, R1Dis independently unsubstituted methyl. In embodiments, R1Dis independently unsubstituted ethyl. In embodiments, R1Dis independently unsubstituted propyl. In embodiments, R1Dis independently unsubstituted n-propyl. In embodiments, R1Dis independently unsubstituted isopropyl. In embodiments, R1Dis independently unsubstituted butyl. In embodiments, R1Dis independently unsubstituted n-butyl. In embodiments, R1Dis independently unsubstituted isobutyl. In embodiments, R1Dis independently unsubstituted tert-butyl.

[0214] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4.

[0215] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2is substituted, it is substituted with at least one substituent group. In embodiments, when R2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0216] In embodiments, R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0217] In embodiments, R2is hydrogen, –CX23, -CHX22, -CH2X2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R2is hydrogen.

[0218] In embodiments, R2is hydrogen or unsubstituted C1-C4alkyl. In embodiments, R2is hydrogen. In embodiments, R2is unsubstituted C1-C4 alkyl. In embodiments, R2is unsubstituted methyl. In embodiments, R2is unsubstituted ethyl. In embodiments, R2is unsubstituted propyl. In embodiments, R2is unsubstituted n-propyl. In embodiments, R2is unsubstituted isopropyl. In embodiments, R2is unsubstituted butyl. In embodiments, R2isunsubstituted n-butyl. In embodiments, R2is unsubstituted isobutyl. In embodiments, R2is unsubstituted tert-butyl.

[0219] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0220] In embodiments, R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0221] In embodiments, R3is hydrogen, –CX33, -CHX32, -CH2X3, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R3is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R3is hydrogen.

[0222] In embodiments, R3is hydrogen or unsubstituted C1-C4alkyl. In embodiments, R3is hydrogen. In embodiments, R3is unsubstituted C1-C4 alkyl. In embodiments, R3is unsubstituted methyl. In embodiments, R3is unsubstituted ethyl. In embodiments, R3is unsubstituted propyl. In embodiments, R3is unsubstituted n-propyl. In embodiments, R3is unsubstituted isopropyl. In embodiments, R3is unsubstituted butyl. In embodiments, R3isunsubstituted n-butyl. In embodiments, R3is unsubstituted isobutyl. In embodiments, R3is unsubstituted tert-butyl.

[0223] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0224] In embodiments, a substituted ring formed when two R4substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R4substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0225] In embodiments, a substituted R4A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Ais substituted, it issubstituted with at least one substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one lower substituent group.

[0226] In embodiments, a substituted R4B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Bis substituted, it is substituted with at least one substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one lower substituent group.

[0227] In embodiments, a substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0228] In embodiments, a substituted R4C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Cis substituted, it is substituted with at least one substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one lower substituent group.

[0229] In embodiments, a substituted R4D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Dis substituted, it is substituted with at least one substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one lower substituent group.

[0230] In embodiments, R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCHX42, -OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, ^NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -OC(O)NR4AR4B, -NR4AOR4C, -P(O)R4AR4B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R4substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0231] In embodiments, R4is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstitutedC1-C8alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R4is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R4is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1- C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, or unsubstituted methoxy.

[0232] In embodiments, R4is independently halogen. In embodiments, R4is independently –F. In embodiments, R4is independently –Cl. In embodiments, R4is independently –Br. In embodiments, R4is independently –I. In embodiments, R4is independently -CCl3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2Cl. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHCl2. In embodiments, R4is independently -CHBr2. In embodiments, R4is independently -CHF2. In embodiments, R4is independently -CHI2. In embodiments, R4is independently –CN. In embodiments, R4is independently –OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently –COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. In embodiments, R4is independently –SH. In embodiments, R4is independently -SO3H. In embodiments, R4is independently -OSO3H. In embodiments, R4is independently -SO2NH2. In embodiments, R4is independently ^NHNH2. In embodiments, R4is independently ^ONH2. In embodiments, R4is independently ^NHC(O)NHNH2. In embodiments, R4is independently ^NHC(O)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently –NHOH. In embodiments, R4is independently -OCCl3. In embodiments, R4is independently -OCBr3. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2Cl. In embodiments, R4isindependently -OCH2Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCl2. In embodiments, R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently unsubstituted C1-C4alkyl. In embodiments, R4is independently unsubstituted methyl. In embodiments, R4is independently unsubstituted ethyl. In embodiments, R4is independently unsubstituted propyl. In embodiments, R4is independently unsubstituted n-propyl. In embodiments, R4is independently unsubstituted isopropyl. In embodiments, R4is independently unsubstituted butyl. In embodiments, R4is independently unsubstituted n- butyl. In embodiments, R4is independently unsubstituted isobutyl. In embodiments, R4is independently unsubstituted tert-butyl. In embodiments, R4is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4is independently unsubstituted methoxy. In embodiments, R4is independently unsubstituted ethoxy. In embodiments, R4is independently unsubstituted propoxy. In embodiments, R4is independently unsubstituted n- propoxy. In embodiments, R4is independently unsubstituted isopropoxy. In embodiments, R4is independently unsubstituted butoxy. In embodiments, R4is independently unsubstituted n-butoxy. In embodiments, R4is independently unsubstituted isobutoxy. In embodiments, R4is independently unsubstituted tert-butoxy.

[0233] In embodiments, R4is independently –OR4D, wherein R4Dis as described herein, including in embodiments. In embodiments, R4Dis hydrogen or substituted or unsubstituted alkyl. In embodiments, R4Dis independently hydrogen or unsubstituted alkyl. In embodiments, R4Dis independently hydrogen or unsubstituted C1-C5alkyl. In embodiments, R4Dis independently hydrogen or unsubstituted methyl.

[0234] In embodiments, R4Ais independently hydrogen. In embodiments, R4Ais independently unsubstituted C1-C4alkyl. In embodiments, R4Ais independently unsubstituted methyl. In embodiments, R4Ais independently unsubstituted ethyl. In embodiments, R4Ais independently unsubstituted propyl. In embodiments, R4Ais independently unsubstituted n-propyl. In embodiments, R4Ais independently unsubstituted isopropyl. In embodiments, R4Ais independently unsubstituted butyl. In embodiments, R4Ais independently unsubstituted n-butyl. In embodiments, R4Ais independently unsubstituted isobutyl. In embodiments, R4Ais independently unsubstituted tert-butyl.

[0235] In embodiments, R4Bis independently hydrogen. In embodiments, R4Bis independently unsubstituted C1-C4 alkyl. In embodiments, R4Bis independently unsubstituted methyl. In embodiments, R4Bis independently unsubstituted ethyl. In embodiments, R4Bis independently unsubstituted propyl. In embodiments, R4Bis independently unsubstituted n-propyl. In embodiments, R4Bis independently unsubstituted isopropyl. In embodiments, R4Bis independently unsubstituted butyl. In embodiments, R4Bis independently unsubstituted n-butyl. In embodiments, R4Bis independently unsubstituted isobutyl. In embodiments, R4Bis independently unsubstituted tert-butyl.

[0236] In embodiments, R4Cis independently hydrogen. In embodiments, R4Cis independently unsubstituted C1-C4alkyl. In embodiments, R4Cis independently unsubstituted methyl. In embodiments, R4Cis independently unsubstituted ethyl. In embodiments, R4Cis independently unsubstituted propyl. In embodiments, R4Cis independently unsubstituted n-propyl. In embodiments, R4Cis independently unsubstituted isopropyl. In embodiments, R4Cis independently unsubstituted butyl. In embodiments, R4Cis independently unsubstituted n-butyl. In embodiments, R4Cis independently unsubstituted isobutyl. In embodiments, R4Cis independently unsubstituted tert-butyl.

[0237] In embodiments, R4Dis independently hydrogen. In embodiments, R4Dis independently unsubstituted C1-C4 alkyl. In embodiments, R4Dis independently unsubstituted methyl. In embodiments, R4Dis independently unsubstituted ethyl. In embodiments, R4Dis independently unsubstituted propyl. In embodiments, R4Dis independently unsubstituted n-propyl. In embodiments, R4Dis independently unsubstituted isopropyl. In embodiments, R4Dis independently unsubstituted butyl. In embodiments, R4Dis independently unsubstituted n-butyl. In embodiments, R4Dis independently unsubstituted isobutyl. In embodiments, R4Dis independently unsubstituted tert-butyl.

[0238] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5.

[0239] In embodiments, a substituted R4.1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowersubstituent group may optionally be different. In embodiments, when R4.1is substituted, it is substituted with at least one substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.1is substituted, it is substituted with at least one lower substituent group.

[0240] In embodiments, a substituted R4.2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.2is substituted, it is substituted with at least one substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.2is substituted, it is substituted with at least one lower substituent group.

[0241] In embodiments, a substituted R4.3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.3is substituted, it is substituted with at least one substituent group. In embodiments, when R4.3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4.3is substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, a substituted R4.4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4.4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4.4is substituted, it is substituted with at least one substituent group. In embodiments, when R4.4is substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R4.4is substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, R4.1, R4.2, R4.3, and R4.4are independently a halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0244] In embodiments, R4.1is halogen. In embodiments, R4.1is –F. In embodiments, R4.1is –Cl. In embodiments, R4.1is –Br. In embodiments, R4.1is –I. In embodiments, R4.1is -CCl3. In embodiments, R4.1is -CBr3. In embodiments, R4.1is -CF3. In embodiments, R4.1is -CI3. In embodiments, R4.1is -CH2Cl. In embodiments, R4.1is -CH2Br. In embodiments, R4.1is -CH2F. In embodiments, R4.1is -CH2I. In embodiments, R4.1is -CHCl2. In embodiments, R4.1is -CHBr2. In embodiments, R4.1is -CHF2. In embodiments, R4.1is -CHI2. In embodiments, R4.1is –CN. In embodiments, R4.1is –OH. In embodiments, R4.1is -NH2. In embodiments, R4.1is –COOH. In embodiments, R4.1is -CONH2. In embodiments, R4.1is -NO2. In embodiments, R4.1is –SH. In embodiments, R4.1is -SO3H. In embodiments, R4.1is -OSO3H. In embodiments, R4.1is -SO2NH2. In embodiments, R4.1is ^NHNH2. In embodiments, R4.1is ^ONH2. In embodiments, R4.1is ^NHC(O)NHNH2. In embodiments, R4.1is ^NHC(O)NH2. In embodiments, R4.1is -NHSO2H. In embodiments, R4.1is -NHC(O)H. In embodiments, R4.1is -NHC(O)OH. In embodiments, R4.1is –NHOH. In embodiments, R4.1is -OCCl3. In embodiments, R4.1is -OCBr3. In embodiments, R4.1is -OCF3. In embodiments, R4.1is -OCI3. In embodiments, R4.1is -OCH2Cl. In embodiments, R4.1is -OCH2Br. In embodiments, R4.1is -OCH2F. In embodiments, R4.1is -OCH2I. In embodiments, R4.1is -OCHCl2. In embodiments, R4.1is -OCHBr2. In embodiments, R4.1is -OCHF2. In embodiments, R4.1is -OCHI2. In embodiments, R4.1isunsubstituted C1-C4alkyl. In embodiments, R4.1is unsubstituted methyl. In embodiments, R4.1is unsubstituted ethyl. In embodiments, R4.1is independently unsubstituted propyl. In embodiments, R4.1is unsubstituted n-propyl. In embodiments, R4.1is unsubstituted isopropyl. In embodiments, R4.1is unsubstituted butyl. In embodiments, R4.1is unsubstituted n-butyl. In embodiments, R4.1is unsubstituted isobutyl. In embodiments, R4.1is unsubstituted tert- butyl. In embodiments, R4.1is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4.1is unsubstituted methoxy. In embodiments, R4.1is unsubstituted ethoxy. In embodiments, R4.1is unsubstituted propoxy. In embodiments, R4.1is unsubstituted n- propoxy. In embodiments, R4.1is unsubstituted isopropoxy. In embodiments, R4.1is unsubstituted butoxy. In embodiments, R4.1is unsubstituted n-butoxy. In embodiments, R4.1is unsubstituted isobutoxy. In embodiments, R4.1is unsubstituted tert-butoxy.

[0245] In embodiments, R4.2is halogen. In embodiments, R4.2is –F. In embodiments, R4.2is –Cl. In embodiments, R4.2is –Br. In embodiments, R4.2is –I. In embodiments, R4.2is -CCl3. In embodiments, R4.2is -CBr3. In embodiments, R4.2is -CF3. In embodiments, R4.2is -CI3. In embodiments, R4.2is -CH2Cl. In embodiments, R4.2is -CH2Br. In embodiments, R4.2is -CH2F. In embodiments, R4.2is -CH2I. In embodiments, R4.2is -CHCl2. In embodiments, R4.2is -CHBr2. In embodiments, R4.2is -CHF2. In embodiments, R4.2is -CHI2. In embodiments, R4.2is –CN. In embodiments, R4.2is –OH. In embodiments, R4.2is -NH2. In embodiments, R4.2is –COOH. In embodiments, R4.2is -CONH2. In embodiments, R4.2is -NO2. In embodiments, R4.2is –SH. In embodiments, R4.2is -SO3H. In embodiments, R4.2is -OSO3H. In embodiments, R4.2is -SO2NH2. In embodiments, R4.2is ^NHNH2. In embodiments, R4.2is ^ONH2. In embodiments, R4.2is ^NHC(O)NHNH2. In embodiments, R4.2is ^NHC(O)NH2. In embodiments, R4.2is -NHSO2H. In embodiments, R4.2is -NHC(O)H. In embodiments, R4.2is -NHC(O)OH. In embodiments, R4.2is –NHOH. In embodiments, R4.2is -OCCl3. In embodiments, R4.2is -OCBr3. In embodiments, R4.2is -OCF3. In embodiments, R4.2is -OCI3. In embodiments, R4.2is -OCH2Cl. In embodiments, R4.2is -OCH2Br. In embodiments, R4.2is -OCH2F. In embodiments, R4.2is -OCH2I. In embodiments, R4.2is -OCHCl2. In embodiments, R4.2is -OCHBr2. In embodiments, R4.2is -OCHF2. In embodiments, R4.2is -OCHI2. In embodiments, R4.2is unsubstituted C1-C4 alkyl. In embodiments, R4.2is unsubstituted methyl. In embodiments, R4.2is unsubstituted ethyl. In embodiments, R4.2is independently unsubstituted propyl. In embodiments, R4.2is unsubstituted n-propyl. In embodiments, R4.2is unsubstituted isopropyl. In embodiments, R4.2is unsubstituted butyl. In embodiments, R4.2is unsubstituted n-butyl.In embodiments, R4.2is unsubstituted isobutyl. In embodiments, R4.2is unsubstituted tert- butyl. In embodiments, R4.2is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4.2is unsubstituted methoxy. In embodiments, R4.2is unsubstituted ethoxy. In embodiments, R4.2is unsubstituted propoxy. In embodiments, R4.2is unsubstituted n- propoxy. In embodiments, R4.2is unsubstituted isopropoxy. In embodiments, R4.2is unsubstituted butoxy. In embodiments, R4.2is unsubstituted n-butoxy. In embodiments, R4.2is unsubstituted isobutoxy. In embodiments, R4.2is unsubstituted tert-butoxy.

[0246] In embodiments, R4.3is halogen. In embodiments, R4.3is –F. In embodiments, R4.3is –Cl. In embodiments, R4.3is –Br. In embodiments, R4.3is –I. In embodiments, R4.3is -CCl3. In embodiments, R4.3is -CBr3. In embodiments, R4.3is -CF3. In embodiments, R4.3is -CI3. In embodiments, R4.3is -CH2Cl. In embodiments, R4.3is -CH2Br. In embodiments, R4.3is -CH2F. In embodiments, R4.3is -CH2I. In embodiments, R4.3is -CHCl2. In embodiments, R4.3is -CHBr2. In embodiments, R4.3is -CHF2. In embodiments, R4.3is -CHI2. In embodiments, R4.3is –CN. In embodiments, R4.3is –OH. In embodiments, R4.3is -NH2. In embodiments, R4.3is –COOH. In embodiments, R4.3is -CONH2. In embodiments, R4.3is -NO2. In embodiments, R4.3is –SH. In embodiments, R4.3is -SO3H. In embodiments, R4.3is -OSO3H. In embodiments, R4.3is -SO2NH2. In embodiments, R4.3is ^NHNH2. In embodiments, R4.3is ^ONH2. In embodiments, R4.3is ^NHC(O)NHNH2. In embodiments, R4.3is ^NHC(O)NH2. In embodiments, R4.3is -NHSO2H. In embodiments, R4.3is -NHC(O)H. In embodiments, R4.3is -NHC(O)OH. In embodiments, R4.3is –NHOH. In embodiments, R4.3is -OCCl3. In embodiments, R4.3is -OCBr3. In embodiments, R4.3is -OCF3. In embodiments, R4.3is -OCI3. In embodiments, R4.3is -OCH2Cl. In embodiments, R4.3is -OCH2Br. In embodiments, R4.3is -OCH2F. In embodiments, R4.3is -OCH2I. In embodiments, R4.3is -OCHCl2. In embodiments, R4.3is -OCHBr2. In embodiments, R4.3is -OCHF2. In embodiments, R4.3is -OCHI2. In embodiments, R4.3is unsubstituted C1-C4 alkyl. In embodiments, R4.3is unsubstituted methyl. In embodiments, R4.3is unsubstituted ethyl. In embodiments, R4.3is independently unsubstituted propyl. In embodiments, R4.3is unsubstituted n-propyl. In embodiments, R4.3is unsubstituted isopropyl. In embodiments, R4.3is unsubstituted butyl. In embodiments, R4.3is unsubstituted n-butyl. In embodiments, R4.3is unsubstituted isobutyl. In embodiments, R4.3is unsubstituted tert- butyl. In embodiments, R4.3is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4.3is unsubstituted methoxy. In embodiments, R4.3is unsubstituted ethoxy. In embodiments, R4.3is unsubstituted propoxy. In embodiments, R4.3is unsubstituted n-propoxy. In embodiments, R4.3is unsubstituted isopropoxy. In embodiments, R4.3is unsubstituted butoxy. In embodiments, R4.3is unsubstituted n-butoxy. In embodiments, R4.3is unsubstituted isobutoxy. In embodiments, R4.3is unsubstituted tert-butoxy.

[0247] In embodiments, R4.4is halogen. In embodiments, R4.4is –F. In embodiments, R4.4is –Cl. In embodiments, R4.4is –Br. In embodiments, R4.4is –I. In embodiments, R4.4is -CCl3. In embodiments, R4.4is -CBr3. In embodiments, R4.4is -CF3. In embodiments, R4.4is -CI3. In embodiments, R4.4is -CH2Cl. In embodiments, R4.4is -CH2Br. In embodiments, R4.4is -CH2F. In embodiments, R4.4is -CH2I. In embodiments, R4.4is -CHCl2. In embodiments, R4.4is -CHBr2. In embodiments, R4.4is -CHF2. In embodiments, R4.4is -CHI2. In embodiments, R4.4is –CN. In embodiments, R4.4is –OH. In embodiments, R4.4is -NH2. In embodiments, R4.4is –COOH. In embodiments, R4.4is -CONH2. In embodiments, R4.4is -NO2. In embodiments, R4.4is –SH. In embodiments, R4.4is -SO3H. In embodiments, R4.4is -OSO3H. In embodiments, R4.4is -SO2NH2. In embodiments, R4.4is ^NHNH2. In embodiments, R4.4is ^ONH2. In embodiments, R4.4is ^NHC(O)NHNH2. In embodiments, R4.4is ^NHC(O)NH2. In embodiments, R4.4is -NHSO2H. In embodiments, R4.4is -NHC(O)H. In embodiments, R4.4is -NHC(O)OH. In embodiments, R4.4is –NHOH. In embodiments, R4.4is -OCCl3. In embodiments, R4.4is -OCBr3. In embodiments, R4.4is -OCF3. In embodiments, R4.4is -OCI3. In embodiments, R4.4is -OCH2Cl. In embodiments, R4.4is -OCH2Br. In embodiments, R4.4is -OCH2F. In embodiments, R4.4is -OCH2I. In embodiments, R4.4is -OCHCl2. In embodiments, R4.4is -OCHBr2. In embodiments, R4.4is -OCHF2. In embodiments, R4.4is -OCHI2. In embodiments, R4.4is unsubstituted C1-C4 alkyl. In embodiments, R4.4is unsubstituted methyl. In embodiments, R4.4is unsubstituted ethyl. In embodiments, R4.4is independently unsubstituted propyl. In embodiments, R4.4is unsubstituted n-propyl. In embodiments, R4.4is unsubstituted isopropyl. In embodiments, R4.4is unsubstituted butyl. In embodiments, R4.4is unsubstituted n-butyl. In embodiments, R4.4is unsubstituted isobutyl. In embodiments, R4.4is unsubstituted tert- butyl. In embodiments, R4.4is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4.4is unsubstituted methoxy. In embodiments, R4.4is unsubstituted ethoxy. In embodiments, R4.4is unsubstituted propoxy. In embodiments, R4.4is unsubstituted n- propoxy. In embodiments, R4.4is unsubstituted isopropoxy. In embodiments, R4.4is unsubstituted butoxy. In embodiments, R4.4is unsubstituted n-butoxy. In embodiments, R4.4is unsubstituted isobutoxy. In embodiments, R4.4is unsubstituted tert-butoxy.

[0248] In embodiments, a substituted R5(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5is substituted, it is substituted with at least one substituent group. In embodiments, when R5is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5is substituted, it is substituted with at least one lower substituent group.

[0249] In embodiments, a substituted ring formed when two R5substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R5substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R5substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0250] In embodiments, a substituted R5A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R5Ais substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

[0251] In embodiments, a substituted R5B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Bis substituted, it is substituted with at least one substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one lower substituent group.

[0252] In embodiments, a substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0253] In embodiments, a substituted R5C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowersubstituent group may optionally be different. In embodiments, when R5Cis substituted, it is substituted with at least one substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one lower substituent group.

[0254] In embodiments, a substituted R5D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Dis substituted, it is substituted with at least one substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one lower substituent group.

[0255] In embodiments, R5is independently a halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCHX52, -OCH2X5, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, ^NHC(O)NR5CNR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -OC(O)NR5AR5B, -NR5AOR5C, -P(O)R5AR5B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R5substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0256] In embodiments, R5is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R5is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R5is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1- C4alkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted phenyl. In embodiments, R5is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

[0257] In embodiments, R5is independently halogen. In embodiments, R5is independently –F. In embodiments, R5is independently –Cl. In embodiments, R5is independently –Br. In embodiments, R5is independently –I. In embodiments, R5is independently -CCl3. In embodiments, R5is independently -CBr3. In embodiments, R5is independently -CF3. In embodiments, R5is independently -CI3. In embodiments, R5is independently -CH2Cl. In embodiments, R5is independently -CH2Br. In embodiments, R5is independently -CH2F. In embodiments, R5is independently -CH2I. In embodiments, R5is independently -CHCl2. In embodiments, R5is independently -CHBr2. In embodiments, R5is independently -CHF2. In embodiments, R5is independently -CHI2. In embodiments, R5is independently –CN. In embodiments, R5is independently –OH. In embodiments, R5is independently -NH2. In embodiments, R5is independently –COOH. In embodiments, R5is independently -CONH2. In embodiments, R5is independently -NO2. In embodiments, R5is independently –SH. In embodiments, R5is independently -SO3H. In embodiments, R5is independently -OSO3H. In embodiments, R5is independently -SO2NH2. In embodiments, R5is independently ^NHNH2. In embodiments, R5is independently ^ONH2. In embodiments, R5is independently ^NHC(O)NHNH2. In embodiments, R5is independently ^NHC(O)NH2. In embodiments, R5is independently -NHSO2H. In embodiments, R5is independently -NHC(O)H. In embodiments, R5is independently -NHC(O)OH. In embodiments, R5is independently –NHOH. In embodiments, R5is independently -OCCl3. In embodiments, R5is independently -OCBr3. In embodiments, R5is independently -OCF3. In embodiments, R5is independently -OCI3. In embodiments, R5is independently -OCH2Cl. In embodiments, R5is independently -OCH2Br. In embodiments, R5is independently -OCH2F. In embodiments, R5is independently -OCH2I. In embodiments, R5is independently -OCHCl2. In embodiments, R5is independently -OCHBr2. In embodiments, R5is independently -OCHF2. In embodiments, R5is independently -OCHI2. In embodiments, R5is independently unsubstituted C1-C4 alkyl. In embodiments, R5is independently unsubstituted methyl. In embodiments, R5is independently unsubstituted ethyl. In embodiments, R5is independently unsubstituted propyl. In embodiments, R5is independently unsubstituted n-propyl. In embodiments, R5is independently unsubstituted isopropyl. In embodiments, R5is independently unsubstituted butyl. In embodiments, R5is independently unsubstituted n- butyl. In embodiments, R5is independently unsubstituted isobutyl. In embodiments, R5is independently unsubstituted tert-butyl. In embodiments, R5is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R5is independently unsubstituted methoxy. In embodiments, R5is independently unsubstituted ethoxy. In embodiments, R5is independently unsubstituted propoxy. In embodiments, R5is independently unsubstituted n- propoxy. In embodiments, R5is independently unsubstituted isopropoxy. In embodiments, R5is independently unsubstituted butoxy. In embodiments, R5is independently unsubstituted n-butoxy. In embodiments, R5is independently unsubstituted isobutoxy. In embodiments, R5is independently unsubstituted tert-butoxy. In embodiments, R5is independently substituted or unsubstituted phenyl. In embodiments, R5is independently substituted phenyl. In embodiments, R5is independently unsubstituted phenyl.

[0258] In embodiments, R5Ais independently hydrogen. In embodiments, R5Ais independently unsubstituted C1-C4 alkyl. In embodiments, R5Ais independently unsubstituted methyl. In embodiments, R5Ais independently unsubstituted ethyl. In embodiments, R5Ais independently unsubstituted propyl. In embodiments, R5Ais independently unsubstituted n-propyl. In embodiments, R5Ais independently unsubstituted isopropyl. In embodiments, R5Ais independently unsubstituted butyl. In embodiments, R5Ais independently unsubstituted n-butyl. In embodiments, R5Ais independently unsubstituted isobutyl. In embodiments, R5Ais independently unsubstituted tert-butyl.

[0259] In embodiments, R5Bis independently hydrogen. In embodiments, R5Bis independently unsubstituted C1-C4alkyl. In embodiments, R5Bis independently unsubstituted methyl. In embodiments, R5Bis independently unsubstituted ethyl. In embodiments, R5Bis independently unsubstituted propyl. In embodiments, R5Bis independently unsubstituted n-propyl. In embodiments, R5Bis independently unsubstitutedisopropyl. In embodiments, R5Bis independently unsubstituted butyl. In embodiments, R5Bis independently unsubstituted n-butyl. In embodiments, R5Bis independently unsubstituted isobutyl. In embodiments, R5Bis independently unsubstituted tert-butyl.

[0260] In embodiments, R5Cis independently hydrogen. In embodiments, R5Cis independently unsubstituted C1-C4 alkyl. In embodiments, R5Cis independently unsubstituted methyl. In embodiments, R5Cis independently unsubstituted ethyl. In embodiments, R5Cis independently unsubstituted propyl. In embodiments, R5Cis independently unsubstituted n-propyl. In embodiments, R5Cis independently unsubstituted isopropyl. In embodiments, R5Cis independently unsubstituted butyl. In embodiments, R5Cis independently unsubstituted n-butyl. In embodiments, R5Cis independently unsubstituted isobutyl. In embodiments, R5Cis independently unsubstituted tert-butyl.

[0261] In embodiments, R5Dis independently hydrogen. In embodiments, R5Dis independently unsubstituted C1-C4alkyl. In embodiments, R5Dis independently unsubstituted methyl. In embodiments, R5Dis independently unsubstituted ethyl. In embodiments, R5Dis independently unsubstituted propyl. In embodiments, R5Dis independently unsubstituted n-propyl. In embodiments, R5Dis independently unsubstituted isopropyl. In embodiments, R5Dis independently unsubstituted butyl. In embodiments, R5Dis independently unsubstituted n-butyl. In embodiments, R5Dis independently unsubstituted isobutyl. In embodiments, R5Dis independently unsubstituted tert-butyl.

[0262] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6. In embodiments, z5 is 7.substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substitutedheteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6is substituted, it is substituted with at least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group.

[0265] In embodiments, a substituted R6A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6Ais substituted, it is substituted with at least one substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one lower substituent group.

[0266] In embodiments, a substituted R6B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6Bis substituted, it is substituted with at least one substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one lower substituent group.

[0267] In embodiments, a substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R6Aand R6Bsubstituentsbonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0268] In embodiments, a substituted R6C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6Cis substituted, it is substituted with at least one substituent group. In embodiments, when R6Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Cis substituted, it is substituted with at least one lower substituent group.

[0269] In embodiments, a substituted R6D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6Dis substituted, it is substituted with at least one substituent group. In embodiments, when R6Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Dis substituted, it is substituted with at least one lower substituent group.

[0270] In embodiments, R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B,^NHC(O)NR6CNR6AR6B, -NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0271] In embodiments, R6is hydrogen, halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R6is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0272] In embodiments, R6is hydrogen. In embodiments, R6is halogen. In embodiments, R6is –F. In embodiments, R6is –Cl. In embodiments, R6is –Br. In embodiments, R6is –I. In embodiments, R6is -CCl3. In embodiments, R6is -CBr3. In embodiments, R6is -CF3. In embodiments, R6is -CI3. In embodiments, R6is -CH2Cl. In embodiments, R6is -CH2Br. In embodiments, R6is -CH2F. In embodiments, R6is -CH2I. In embodiments, R6is -CHCl2. In embodiments, R6is -CHBr2. In embodiments, R6is -CHF2. In embodiments, R6is -CHI2. In embodiments, R6is –CN. In embodiments, R6is –OH. In embodiments, R6is -NH2. In embodiments, R6is –COOH. In embodiments, R6is -CONH2. In embodiments, R6is -NO2. In embodiments, R6is –SH. In embodiments, R6is -SO3H. In embodiments, R6is -OSO3H. In embodiments, R6is -SO2NH2. In embodiments, R6is ^NHNH2. In embodiments, R6is ^ONH2. In embodiments, R6is ^NHC(O)NHNH2. In embodiments, R6is ^NHC(O)NH2. In embodiments, R6is -NHSO2H. In embodiments, R6is -NHC(O)H. In embodiments, R6is -NHC(O)OH. In embodiments, R6is –NHOH. In embodiments, R6is -OCCl3. In embodiments, R6is -OCBr3. In embodiments, R6is -OCF3. In embodiments, R6is -OCI3. In embodiments, R6is -OCH2Cl. In embodiments, R6is -OCH2Br. In embodiments, R6is -OCH2F. In embodiments, R6is -OCH2I. In embodiments, R6is -OCHCl2. Inembodiments, R6is -OCHBr2. In embodiments, R6is -OCHF2. In embodiments, R6is -OCHI2. In embodiments, R6is substituted or unsubstituted C1-C4 alkyl. In embodiments, R6is substituted C1-C4alkyl. In embodiments, R6is substituted methyl. In embodiments, R6is substituted ethyl. In embodiments, R6is substituted propyl. In embodiments, R6is substituted n-propyl. In embodiments, R6is substituted isopropyl. In embodiments, R6is substituted butyl. In embodiments, R6is substituted n-butyl. In embodiments, R6is substituted isobutyl. In embodiments, R6is substituted tert-butyl. In embodiments, R6is unsubstituted C1-C4 alkyl. In embodiments, R6is unsubstituted methyl. In embodiments, R6is unsubstituted ethyl. In embodiments, R6is unsubstituted propyl. In embodiments, R6is unsubstituted n-propyl. In embodiments, R6is unsubstituted isopropyl. In embodiments, R6is unsubstituted butyl. In embodiments, R6is unsubstituted n-butyl. In embodiments, R6is unsubstituted isobutyl. In embodiments, R6is unsubstituted tert-butyl. In embodiments, R6is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R6is substituted 2 to 4 membered heteroalkyl. In embodiments, R6is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R6is unsubstituted methoxy. In embodiments, R6is unsubstituted ethoxy. In embodiments, R6is unsubstituted propoxy. In embodiments, R6is unsubstituted n-propoxy. In embodiments, R6is unsubstituted isopropoxy. In embodiments, R6is unsubstituted butoxy. In embodiments, R6is unsubstituted n-butoxy. In embodiments, R6is unsubstituted isobutoxy. In embodiments, R6is unsubstituted tert-butoxy.

[0273] In embodiments, R6is an amino acid side chain. In embodiments, R6is a glycine side chain. In embodiments, R6is an alanine side chain. In embodiments, R6is a valine side chain. In embodiments, R6is a leucine side chain. In embodiments, R6is an isoleucine side chain. In embodiments, R6is a methionine side chain. In embodiments, R6is a serine side chain. In embodiments, R6is a threonine side chain. In embodiments, R6is a cysteine side chain. In embodiments, R6is an aspartic acid side chain. In embodiments, R6is a glutamic acid side chain. In embodiments, R6is an asparagine side chain. In embodiments, R6is a glutamine side chain. In embodiments, R6is a histidine side chain. In embodiments, R6is a phenylalanine side chain. In embodiments, R6is a tyrosine side chain. In embodiments, R6is a tryptophan side chain. In embodiments, R6is an arginine side chain. In embodiments, R6is a lysine side chain.

[0274] In embodiments, R6is an amino acid side chain. In embodiments, R6is an L- glycine side chain. In embodiments, R6is an L-alanine side chain. In embodiments, R6is anL-valine side chain. In embodiments, R6is an L-leucine side chain. In embodiments, R6is an L-isoleucine side chain. In embodiments, R6is an L-methionine side chain. In embodiments, R6is an L-serine side chain. In embodiments, R6is an L-threonine side chain. In embodiments, R6is an L-cysteine side chain. In embodiments, R6is an L-aspartic acid side chain. In embodiments, R6is an L-glutamic acid side chain. In embodiments, R6is an L-asparagine side chain. In embodiments, R6is an L-glutamine side chain. In embodiments, R6is an L-histidine side chain. In embodiments, R6is an L-phenylalanine side chain. In embodiments, R6is an L-tyrosine side chain. In embodiments, R6is an L-tryptophan side chain. In embodiments, R6is an L-arginine side chain. In embodiments, R6is an L-lysine side chain.

[0275] In embodiments, R6is an amino acid side chain. In embodiments, R6is a D-glycine side chain. In embodiments, R6is a D-alanine side chain. In embodiments, R6is a D-valine side chain. In embodiments, R6is a D-leucine side chain. In embodiments, R6is a D- isoleucine side chain. In embodiments, R6is a D-methionine side chain. In embodiments, R6is a D-serine side chain. In embodiments, R6is a D-threonine side chain. In embodiments, R6is a D-cysteine side chain. In embodiments, R6is a D-aspartic acid side chain. In embodiments, R6is a D-glutamic acid side chain. In embodiments, R6is a D-asparagine side chain. In embodiments, R6is a D-glutamine side chain. In embodiments, R6is a D-histidine side chain. In embodiments, R6is a D-phenylalanine side chain. In embodiments, R6is a D- tyrosine side chain. In embodiments, R6is a D-tryptophan side chain. In embodiments, R6is a D-arginine side chain. In embodiments, R6is a D-lysine side chain.

[0276] In embodiments, R6is hydrogen, unsubstituted methyl, unsubstituted isopropyl, ,alkyl. In embodiments, R6Ais unsubstituted methyl. In embodiments, R6Ais unsubstituted ethyl. In embodiments, R6Ais unsubstituted propyl. In embodiments, R6Ais unsubstituted n-propyl. In embodiments, R6Ais unsubstituted isopropyl. In embodiments, R6Ais unsubstituted butyl. In embodiments, R6Ais unsubstituted n-butyl. In embodiments, R6Ais unsubstituted isobutyl. In embodiments, R6Ais unsubstituted tert-butyl.

[0278] In embodiments, R6Bis hydrogen. In embodiments, R6Bis unsubstituted C1-C4alkyl. In embodiments, R6Bis unsubstituted methyl. In embodiments, R6Bis unsubstituted ethyl. In embodiments, R6Bis unsubstituted propyl. In embodiments, R6Bis unsubstituted n- propyl. In embodiments, R6Bis unsubstituted isopropyl. In embodiments, R6Bis unsubstituted butyl. In embodiments, R6Bis unsubstituted n-butyl. In embodiments, R6Bis unsubstituted isobutyl. In embodiments, R6Bis unsubstituted tert-butyl.

[0279] In embodiments, R6Cis hydrogen. In embodiments, R6Cis unsubstituted C1-C4 alkyl. In embodiments, R6Cis unsubstituted methyl. In embodiments, R6Cis unsubstituted ethyl. In embodiments, R6Cis unsubstituted propyl. In embodiments, R6Cis unsubstituted n- propyl. In embodiments, R6Cis unsubstituted isopropyl. In embodiments, R6Cis unsubstituted butyl. In embodiments, R6Cis unsubstituted n-butyl. In embodiments, R6Cis unsubstituted isobutyl. In embodiments, R6Cis unsubstituted tert-butyl.

[0280] In embodiments, R6Dis hydrogen. In embodiments, R6Dis unsubstituted C1-C4alkyl. In embodiments, R6Dis unsubstituted methyl. In embodiments, R6Dis unsubstituted ethyl. In embodiments, R6Dis unsubstituted propyl. In embodiments, R6Dis unsubstituted n- propyl. In embodiments, R6Dis unsubstituted isopropyl. In embodiments, R6Dis unsubstituted butyl. In embodiments, R6Dis unsubstituted n-butyl. In embodiments, R6Dis unsubstituted isobutyl. In embodiments, R6Dis unsubstituted tert-butyl.

[0281] In embodiments, a substituted ring formed when R3and R6substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3and R6substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R3and R6substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3and R6substituents bonded to the same nitrogen atom are joined is substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3and R6substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0282] In embodiments, R3and R6may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0283] In embodiments, R3and R6are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R3and R6are joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, R3and R6are joined to form an unsubstituted pyrrolidinyl. In embodiments, R3and R6are joined to form an unsubstituted piperidinyl.

[0284] In embodiments, a substituted R7(e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R7is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0285] In embodiments, R7is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R7is hydrogen, halogen, -OH, -N3, or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R7is hydrogen. In embodiments, R7is halogen. In embodiments, R7is –F. In embodiments, R7is –Cl. In embodiments, R7is –Br. In embodiments, R7is –I. In embodiments, R7is -OH. In embodiments, R7is -N3. In embodiments, R7is substituted or unsubstituted C1-C4 alkyl. In embodiments, R7is unsubstituted C1-C4 alkyl. In embodiments, R7is unsubstituted methyl. In embodiments, R7is unsubstituted ethyl. In embodiments, R7is unsubstituted propyl. In embodiments, R7is unsubstituted n-propyl. In embodiments, R7is unsubstituted isopropyl. In embodiments, R7is unsubstituted butyl. Inembodiments, R7is unsubstituted n-butyl. In embodiments, R7is unsubstituted isobutyl. In embodiments, R7is unsubstituted tert-butyl.

[0286] In embodiments, a substituted R8(e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0287] In embodiments, R8is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R8is hydrogen, halogen, -OH, -N3, or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R8is hydrogen. In embodiments, R8is halogen. In embodiments, R8is –F. In embodiments, R8is –Cl. In embodiments, R8is –Br. In embodiments, R8is –I. In embodiments, R8is -OH. In embodiments, R8is -N3. In embodiments, R8is substituted or unsubstituted C1-C4 alkyl. In embodiments, R8is unsubstituted C1-C4 alkyl. In embodiments, R8is unsubstituted methyl. In embodiments, R8is unsubstituted ethyl. In embodiments, R8is unsubstituted propyl. In embodiments, R8is unsubstituted n-propyl. In embodiments, R8is unsubstituted isopropyl. In embodiments, R8is unsubstituted butyl. In embodiments, R8is unsubstituted n-butyl. In embodiments, R8is unsubstituted isobutyl. In embodiments, R8is unsubstituted tert-butyl.

[0288] In embodiments, a substituted R9(e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R9is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R9is substituted, it is substituted with at least one substituent group. In embodiments, when R9is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R9is substituted, it is substituted with at least one lower substituent group.

[0289] In embodiments, R9is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R9is hydrogen, halogen, -OH, -N3, or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R9is hydrogen. In embodiments, R9is halogen. In embodiments, R9is –F. In embodiments, R9is –Cl. In embodiments, R9is –Br. In embodiments, R9is –I. In embodiments, R9is -OH. In embodiments, R9is -N3. In embodiments, R9is substituted or unsubstituted C1-C4alkyl. In embodiments, R9is unsubstituted C1-C4alkyl. In embodiments, R9is unsubstituted methyl. In embodiments, R9is unsubstituted ethyl. In embodiments, R9is unsubstituted propyl. In embodiments, R9is unsubstituted n-propyl. In embodiments, R9is unsubstituted isopropyl. In embodiments, R9is unsubstituted butyl. In embodiments, R9is unsubstituted n-butyl. In embodiments, R9is unsubstituted isobutyl. In embodiments, R9is unsubstituted tert-butyl.

[0290] In embodiments, a substituted Ring A (e.g., substituted phenyl and / or substituted 5 to 6 membered heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when Ring A is substituted, it is substituted with at least one substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent group.

[0291] In embodiments, Ring A is unsubstituted phenyl or unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted phenyl. In embodiments, Ring A is an unsubstituted phenyl. In embodiments, Ring A is a substituted 5 to 6 membered heteroaryl. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted thienyl. In embodiments, Ring A is an unsubstituted thienyl. In embodiments, Ring A is a substituted 2-thienyl. In embodiments, Ring A is an unsubstituted 2-thienyl. In embodiments, Ring A is a substituted 3-thienyl. In embodiments, Ring A is an unsubstituted 3-thienyl. In embodiments, Ring A is a substituted pyridyl. In embodiments, Ring A is an unsubstituted pyridyl. In embodiments, Ring A is a substituted 2-pyridyl. In embodiments, Ring A is an unsubstituted 2-pyridyl. In embodiments, Ring A is a substituted3-pyridyl. In embodiments, Ring A is an unsubstituted 3-pyridyl. In embodiments, Ring A is a substituted 4-pyridyl. In embodiments, Ring A is an unsubstituted 4-pyridyl. Inembodiments, Ring A is a substituted pyrrolyl. In embodiments, Ring A is an unsubstitutedpyrrolyl. In embodiments, Ring A is a substituted furanyl. In embodiments, Ring A is anunsubstituted furanyl. In embodiments, Ring A is a substituted pyrazolyl. In embodiments,Ring A is an unsubstituted pyrazolyl. In embodiments, Ring A is a substituted imidazolyl. Inembodiments, Ring A is an unsubstituted imidazolyl. In embodiments, Ring A is a substituted oxazolyl. In embodiments, Ring A is an unsubstituted oxazolyl. In embodiments, Ring A is a substituted isoxazolyl. In embodiments, Ring A is an unsubstituted isoxazolyl. In embodiments, Ring A is a substituted thiazolyl. In embodiments, Ring A is an unsubstituted thiazolyl. In embodiments, Ring A is a substituted triazolyl. In embodiments, Ring A is an unsubstituted triazolyl.

[0292] In embodiments, Ring A is phenyl. In embodiments, Ring A is 5 to 6 membered heteroaryl. In embodiments, Ring A is thienyl. In embodiments, Ring A is 2-thienyl. In embodiments, Ring A is 3-thienyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is 2-pyridyl. In embodiments, Ring A is 3-pyridyl. In embodiments, Ring A is 4-pyridyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is furanyl. Inembodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl. In embodiments,Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is triazolyl. , .In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Inembodiments, Ring A . In embodiments, Ring A In.. R4.1, R4.2, R4.3, and R4.4are independently any value of R4as describedin embodiments.

[0295] R4.1, R4.2, R4.3, and R4.4are independently a halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCHX42, -OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, ^NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -OC(O)NR4AR4B, -NR4AOR4C, -P(O)R4AR4B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In ., . ., , hthyl, substituted quinolinyl, and / or substituted isoquinolinyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when Ring B is substituted, it is substituted with at least one substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one lower substituent group.

[0298] In embodiments, Ring B is unsubstituted phenyl, unsubstituted naphthyl, unsubstituted quinolinyl, or unsubstituted isoquinolinyl. In embodiments, Ring B is a substituted phenyl. In embodiments, Ring B is an unsubstituted phenyl. In embodiments, Ring B is a substituted naphthyl. In embodiments, Ring B is an unsubstituted naphthyl. In embodiments, Ring B is a substituted 1-naphthyl. In embodiments, Ring B is an unsubstituted 1-naphthyl. In embodiments, Ring B is a substituted 2-naphthyl. In embodiments, Ring B is an unsubstituted 2-naphthyl. In embodiments, Ring B is a substituted quinolinyl. In embodiments, Ring B is an unsubstituted quinolinyl. In embodiments, Ring B is a substituted 2-quinolinyl. In embodiments, Ring B is anunsubstituted 2-quinolinyl. In embodiments, Ring B is a substituted 3-quinolinyl. In embodiments, Ring B is an unsubstituted 3-quinolinyl. In embodiments, Ring B is a substituted 4-quinolinyl. In embodiments, Ring B is an unsubstituted 4-quinolinyl. In embodiments, Ring B is a substituted 5-quinolinyl. In embodiments, Ring B is an unsubstituted 5-quinolinyl. In embodiments, Ring B is a substituted 6-quinolinyl. In embodiments, Ring B is an unsubstituted 6-quinolinyl. In embodiments, Ring B is a substituted 7-quinolinyl. In embodiments, Ring B is an unsubstituted 7-quinolinyl. In embodiments, Ring B is a substituted 8-quinolinyl. In embodiments, Ring B is an unsubstituted 8-quinolinyl. In embodiments, Ring B is a substituted isoquinolinyl. In embodiments, Ring B is an unsubstituted isoquinolinyl. In embodiments, Ring B is a substituted 1-isoquinolinyl. In embodiments, Ring B is an unsubstituted 1-isoquinolinyl. In embodiments, Ring B is a substituted 3-isoquinolinyl. In embodiments, Ring B is an unsubstituted 3-isoquinolinyl. In embodiments, Ring B is a substituted 4-isoquinolinyl. In embodiments, Ring B is an unsubstituted 4-isoquinolinyl. In embodiments, Ring B is a substituted 5-isoquinolinyl. In embodiments, Ring B is an unsubstituted 5-isoquinolinyl. In embodiments, Ring B is a substituted 6-isoquinolinyl. In embodiments, Ring B is an unsubstituted 6-isoquinolinyl. In embodiments, Ring B is a substituted 7-isoquinolinyl. In embodiments, Ring B is an unsubstituted 7-isoquinolinyl. In embodiments, Ring B is a substituted 8-isoquinolinyl. In embodiments, Ring B is an unsubstituted 8-isoquinolinyl.

[0299] In embodiments, Ring B is phenyl. In embodiments, Ring B is naphthyl. In embodiments, Ring B is 1-naphthyl. In embodiments, Ring B is 2-naphthyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is 2-quinolinyl. In embodiments, Ring B is 3-quinolinyl. In embodiments, Ring B is 4-quinolinyl. In embodiments, Ring B is 5-quinolinyl. In embodiments, Ring B is 6-quinolinyl. In embodiments, Ring B is 7-quinolinyl. In embodiments, Ring B is 8-quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is 1-isoquinolinyl. In embodiments, Ring B is 3-isoquinolinyl. In embodiments, Ring B is 4-isoquinolinyl. In embodiments, Ring B is 5-isoquinolinyl. In embodiments, Ring B is 6-isoquinolinyl. In embodiments, Ring B is 7-isoquinolinyl. In embodiments, Ring B is 8-isoquinolinyl.In embodiments, embodiments, In embodiments,isembodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5.

[0302] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10.

[0303] In embodiments, the compound has the formula: z1, R2, R3, R4, z4, and R6are as described herein,

[0304] In embodiments, the compound has the formula:1, z1, R2, R3, R4, z4, and R6are as described herein,

[0305] In embodiments, the compound has the formula: in

[0306] In embodiments, the compound has the formula: . R2, R3, R4, z4, and R6are as described herein, including in

[0307] In embodiments, the compound has the formula: . R4, z4, and R6are as described herein, including inthe compound has the formula:. R4, z4, and R6are as described herein, including in

[0309] In embodiments, the compound has the formula: are as described herein, including in

[0310] In embodiments, the compound has the formula: . R4, z4, and R6are as described herein, including in

[0311] In embodiments, the compound has the formula: described herein, including in embodiments.has the formula:as described herein, including in embodiments. pound has the formula: . R6is as described herein, including in embodiments.the compound has the formula: herein,

[0316] In embodiments, the compound has the formula:. R2, R3, R4, z4, R5, z5, and R6are as described herein,

[0317] In embodiments, the compound has the formula: . R4, R5, z5, and R6are as described herein, including in

[0318] In embodiments, the compound has the formula: . R4, R5, z5, and R6are as described herein, including in

[0319] In embodiments, the compound has the formula: . R4, R5, z5, and R6are as described herein, including in

[0320] In embodiments, the compound has the formula:. R4, R5, z5, and R6are as described herein, including in

[0321] In embodiments, the compound has the formula: in inin. R5, z5, and R6are as described herein, including in

[0325] In embodiments, the compound has the formula: , wherein L1, R4.2, and R4.4are as described herein, including inembodiments. In embodiments, the compound has the , wherein L1, R4.2, and R4.3are as described herein, including inembodiments, the compound has the , wherein L1, R4.2, R4.3, and R4.4are as described herein,the compound has the , wherein L1, R4.1, and R4.3are asdescribed herein, including in embodiments. In embodiments, the compound has the , wherein L1, R4.1, and R4.4are as described herein, the compound has the formula:, wherein L1, R1, R4.2, and R4.4are as described herein,embodiments, the compound has the formula: , wherein L1, R1, R4.2, and R4.3are as described herein,embodiments, the compound has the formula: , wherein L1, R1, R4.2, R4.3, and R4.4are as described herein,embodiments, the compound has the formula:including in embodiments. In embodiments, the compound has the formula: , wherein L1, R1, R4.1, and R4.4are as described herein,

[0326] In embodiments, the compound has the formula: O H N N are as described herein, including inembodiments. In embodiments, the compound has the , wherein R4.2and R4.3are as described herein, including inthe compound has the as described herein, including informula , wherein R4.1and R4.3are as described herein, including in embo , the compound has the formula: , wherein R1, R4.2, and R4.3are as described herein, including inthe compound has the formula: , wherein R1, R4.1, and R4.4are as described herein, including in

[0327] In embodiments, the compound has the formula: R6

[0328] In embodiments, the compound has the formula:). Ring A, R1, z1, R2, R3, R4, z4, and R6are as described .

[0329] In embodiments, the compound has the formula: . Ring A, R1, z1, R2, R3, R4, z4, and R6are as described

[0330] In embodiments, the compound has the formula: , wherein R4is as described herein, including in embodiments. Inembodiments, the compound has the , wherein R4is as described herein, including inhas the , wherein R4is as described herein, including inembodiments. In embodiments, the compound has the formul , wherein R4is as described herein, including in embodiments.

[0331] In embodiments, the compound has the Inembodiments, the compound has the In embodiments,the compound has the . In embodiments, the compoundhas the embodiments, the compound has theformula . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:la:la:la:la:la:la:la:la:la:la:la:la:la:la: la: la:la:la:la:la:la:la:la:la:la:la:la:la:la:la:la:la: la: la: la:ula: ula: 5n embodiments, the compound has the formula: n embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:n embodiments, the compound has the formula:n embodiments, the compound has the formula:la:la: la: la:la:la:. In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: O H N N N H O ON. In embodiments, the compound has the formula: . In embodiments, the compound has the formula:. In embodiments, the compound has the formula: .

[0332] Inembodiments, the compound has the In embodiments,the compound has the . In embodiments, thecompound has the formula . In embodiments, the compound has the . In embodiments, the compound has the formula:O H N N. In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: .

[0333] Inembodiments, the compound has the . In embodiments,the compound has the formula . In embodiments, the compound. In embodiments, the compound has the formula: . In embodiments, the compound has the formula:la: mula: N. R1, z1, R2, R4, and z4 are as described herein, including in

[0335] In embodiments, the compound has the formula: . R1, z1, R2, R4, and z4 are as described herein, including in

[0336] In embodiments, the compound has the formula: are as described herein, including in

[0337] In embodiments, the compound has the formula: . R2, R4, and z4 are as described herein, including in

[0338] In embodiments, the compound has the formula:

[0342] In embodiments, the compound has the formul In embodiments, the compound has thethe compound has the . In embodiments, the compound HN has the .

[0343] Inthe formula:. R1, z1, R2, R4, and z4 are as described herein, including

[0345] In embodiments, the compound has the formula: O R2N in in

[0348] In embodiments, the compound has the formula:. R4is as described herein, including in embodiments.

[0351] In embodiments, the compound has the Inembodiments, the compound has the Inembodiments, the compound has the . Inembodiments, the compound has the . Inembodiments, the compound has the formul In embodiments, the compound has the . Inembodiments, the compound has the .

[0352] In embodiments, when R1isfirst substituent groups denoted by R1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1substituent group is substituted, the R1.1substituent group is substituted with one or more second substituent groups denoted by R1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0353] In embodiments, when two adjacent R1substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1substituent group issubstituted, the R1.1substituent group is substituted with one or more second substituent groups denoted by R1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0354] In embodiments, when R1Ais substituted, R1Ais substituted with one or more first substituent groups denoted by R1A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1substituent group is substituted, the R1A.1substituent group is substituted with one or more second substituent groups denoted by R1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2substituent group is substituted, the R1A.2substituent group is substituted with one or more third substituent groups denoted by R1A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A.1, R1A.2, and R1A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1A, R1A.1, R1A.2, and R1A.3, respectively.

[0355] In embodiments, when R1Bis substituted, R1Bis substituted with one or more first substituent groups denoted by R1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1substituent group is substituted, the R1B.1substituent group is substituted with one or more second substituent groups denoted by R1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2substituent group is substituted, the R1B.2substituent group is substituted with one or more third substituent groups denoted by R1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B.1, R1B.2, and R1B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1B, R1B.1, R1B.2, and R1B.3, respectively.

[0356] In embodiments, when R1Aand R1Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1substituent group is substituted, the R1A.1substituent group is substituted with one or more second substituent groups denoted by R1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2substituent group is substituted, the R1A.2substituent group is substituted with one or more third substituent groups denoted by R1A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A.1, R1A.2, and R1A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R1A.1, R1A.2, and R1A.3, respectively.

[0357] In embodiments, when R1Aand R1Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1substituent group is substituted, the R1B.1substituent group is substituted with one or more second substituent groups denoted by R1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2substituent group is substituted, the R1B.2substituent group is substituted with one or more third substituent groups denoted by R1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B.1, R1B.2, and R1B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R1B.1, R1B.2, and R1B.3, respectively.

[0358] In embodiments, when R1Cis substituted, R1Cis substituted with one or more first substituent groups denoted by R1C.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R1C.1substituent group is substituted, the R1C.1substituent group is substituted with one or more second substituent groups denoted by R1C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.2substituent group is substituted, the R1C.2substituent group is substituted with one or more third substituent groups denoted by R1C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1C, R1C.1, R1C.2, and R1C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1C, R1C.1, R1C.2, and R1C.3, respectively.

[0359] In embodiments, when R1Dis substituted, R1Dis substituted with one or more first substituent groups denoted by R1D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.1substituent group is substituted, the R1D.1substituent group is substituted with one or more second substituent groups denoted by R1D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.2substituent group is substituted, the R1D.2substituent group is substituted with one or more third substituent groups denoted by R1D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D.1, R1D.2, and R1D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1D, R1D.1, R1D.2, and R1D.3, respectively.

[0360] In embodiments, when R2is substituted, R2is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0361] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0362] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0363] In embodiments, when two adjacent R4substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituentgroups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0364] In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4A, R4A.1, R4A.2, and R4A.3, respectively.

[0365] In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4B.1, R4B.2, and R4B.3, respectively.

[0366] In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to

[0367] In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R4B.1, R4B.2, and R4B.3, respectively.

[0368] In embodiments, when R4Cis substituted, R4Cis substituted with one or more first substituent groups denoted by R4C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.1substituent group is substituted, the R4C.1substituent group is substituted with one or more second substituentgroups denoted by R4C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.2substituent group is substituted, the R4C.2substituent group is substituted with one or more third substituent groups denoted by R4C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4C, R4C.1, R4C.2, and R4C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4C, R4C.1, R4C.2, and R4C.3, respectively.

[0369] In embodiments, when R4Dis substituted, R4Dis substituted with one or more first substituent groups denoted by R4D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.1substituent group is substituted, the R4D.1substituent group is substituted with one or more second substituent groups denoted by R4D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.2substituent group is substituted, the R4D.2substituent group is substituted with one or more third substituent groups denoted by R4D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4D, R4D.1, R4D.2, and R4D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4D, R4D.1, R4D.2, and R4D.3, respectively.

[0370] In embodiments, when R4.1is substituted, R4.1is substituted with one or more first substituent groups denoted by R4.1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.1substituent group is substituted, the R4.1.1substituent group is substituted with one or more second substituent groups denoted by R4.1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1.2substituent group is substituted, the R4.1.2substituent group is substituted with one or more third substituent groups denoted by R4.1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.1, R4.1.1, R4.1.2, and R4.1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.1, R4.1.1, R4.1.2, and R4.1.3, respectively.

[0371] In embodiments, when R4.2is substituted, R4.2is substituted with one or more first substituent groups denoted by R4.2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.1substituent group is substituted, the R4.2.1substituent group is substituted with one or more second substituent groups denoted by R4.2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2.2substituent group is substituted, the R4.2.2substituent group is substituted with one or more third substituent groups denoted by R4.2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.2, R4.2.1, R4.2.2, and R4.2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.2, R4.2.1, R4.2.2, and R4.2.3, respectively.

[0372] In embodiments, when R4.3is substituted, R4.3is substituted with one or more first substituent groups denoted by R4.3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.3.1substituent group is substituted, the R4.3.1substituent group is substituted with one or more second substituent groups denoted by R4.3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.3.2substituent group is substituted, the R4.3.2substituent group is substituted with one or more third substituent groups denoted by R4.3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.3, R4.3.1, R4.3.2, and R4.3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.3, R4.3.1, R4.3.2, and R4.3.3, respectively.

[0373] In embodiments, when R4.4is substituted, R4.4is substituted with one or more first substituent groups denoted by R4.4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.4.1substituent group is substituted, the R4.4.1substituent group is substituted with one or more second substituent groups denoted by R4.4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.4.2substituent group is substituted, the R4.4.2substituent group is substituted with one or more third substituent groups denoted by R4.4.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R4.4, R4.4.1, R4.4.2, and R4.4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4.4, R4.4.1, R4.4.2, and R4.4.3, respectively.

[0374] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0375] In embodiments, when two adjacent R5substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0376] In embodiments, when R5Ais substituted, R5Ais substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5A, R5A.1, R5A.2, and R5A.3, respectively.

[0377] In embodiments, when R5Bis substituted, R5Bis substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5B, R5B.1, R5B.2, and R5B.3, respectively.

[0378] In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. Inthe above embodiments, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5A.1, R5A.2, and R5A.3, respectively.

[0379] In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5B.1, R5B.2, and R5B.3, respectively.

[0380] In embodiments, when R5Cis substituted, R5Cis substituted with one or more first substituent groups denoted by R5C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.1substituent group is substituted, the R5C.1substituent group is substituted with one or more second substituent groups denoted by R5C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.2substituent group is substituted, the R5C.2substituent group is substituted with one or more third substituent groups denoted by R5C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5C, R5C.1, R5C.2, and R5C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5C, R5C.1, R5C.2, and R5C.3, respectively.

[0381] In embodiments, when R5Dis substituted, R5Dis substituted with one or more first substituent groups denoted by R5D.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R5D.1substituent group is substituted, the R5D.1substituent group is substituted with one or more second substituent groups denoted by R5D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5D.2substituent group is substituted, the R5D.2substituent group is substituted with one or more third substituent groups denoted by R5D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5D, R5D.1, R5D.2, and R5D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5D, R5D.1, R5D.2, and R5D.3, respectively. [...

Claims

WHAT IS CLAIMED IS:

1. A method of treating a cancer in a subject in need thereof, said method comprising: (i) detecting a level of Myc family protein expression in a cancer cellsample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt thereof, having the formula: , 2-,or unsubstituted alkyl; Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl; Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R1substituents may optionally be joinedto form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B, ^NHC(O)NR6CNR6AR6B, -NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3and R6may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R6A, R6B, R6C, and R6Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4; m1, m6, v1, and v6 are independently 1 or 2; n1 and n6 are independently an integer from 0 to 4; X, X1, X2, X3, and X6are independently –Cl, -Br, -I, or –F;m is an integer from 0 to 5; and n is an integer from 0 to 10.

2. The method of claim 1, wherein the level of Myc family protein expression is elevated relative to a standard control.

3. A method of treating a cancer in a subject in need thereof, wherein the subject has a Myc family protein associated cancer, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: , 2-,or unsubstituted alkyl; Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl; Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; R1is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCHX12, -OCH2X1, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, ^NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -OC(O)NR1AR1B, -NR1AOR1C, -P(O)R1AR1B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R1substituents may optionally be joinedto form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2is hydrogen, halogen, -CX23, –CHX22, –CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3is hydrogen, halogen, -CX33, –CHX32, –CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOv6NR6AR6B, ^NR6CNR6AR6B, ^ONR6AR6B, ^NHC(O)NR6CNR6AR6B, -NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -OC(O)NR6AR6B, -NR6AOR6C, -P(O)R6AR6B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3and R6may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R6A, R6B, R6C, and R6Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4; m1, m6, v1, and v6 are independently 1 or 2; n1 and n6 are independently an integer from 0 to 4; X, X1, X2, X3, and X6are independently –Cl, -Br, -I, or –F;m is an integer from 0 to 5; and n is an integer from 0 to 10.

4. The method of one of claims 1 to 3, wherein the Myc family protein is c-Myc, N-Myc, or L-Myc.

5. The method of one of claims 1 to 3, wherein the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, ampullary carcinoma, basal cell carcinoma, bladder cancer, bladder urothelial carcinoma, brain lower grade glioma, breast cancer, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, colon cancer, colorectal adenocarcinoma, cutaneous squamous cell carcinoma, cutaneous T cell lymphoma, diffuse glioma, diffuse large B cell lymphoma, endometrial carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastric cancer, glioblastoma, gliobastoma multiforme, glioma, head and neck squamous cell carcinoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, kidney chromophobe, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, malignant peripheral nerve sheath tumor, medulloblastoma, melanoma, mesothelioma, metastatic melanoma, metastatic prostate adenocarcinoma, multiple myeloma, myelodysplastic syndromes, neuroblastoma, non-small cell lung cancer, ovarian cancer, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumors, pediatric acute lymphoid leukemia, pediatric brain cancer, pediatric Ewing sarcoma, pheochromocytoma and paraganglioma, pleural mesothelioma, prostate adenocarcinoma, prostate cancer brain metastases, osteosarcoma, retinoblastoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumors, angiosarcoma, renal cell carcinoma, urothelial carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, or uveal melanoma.

6. The method of one of claims 1 to 3, wherein the compound has the formula:II); wherein Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl; R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCHX42, -OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, ^NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -OC(O)NR4AR4B, -NR4AOR4C, -P(O)R4AR4B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5is independently a halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCHX52, -OCH2X5, -CN, -SOn5R5D, -SOv5NR5AR5B, ^NR5CNR5AR5B, ^ONR5AR5B, ^NHC(O)NR5CNR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -OC(O)NR5AR5B, -NR5AOR5C, -P(O)R5AR5B, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R5substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5; z5 is an integer from 0 to 7; m4, m5, v4, and v5 are independently 1 or 2; n4 and n5 are independently an integer from 0 to 4; and X4and X5are independently –Cl, -Br, -I, or -F.

7. The method of claim 6, wherein the compound has the formula: .has the formula: (IIIa).has the formula: (IIIb).

10. The method of claim 6, wherein the compound has the formula: .

11. The method of claim 6, wherein the compound has the formula:V). pound has the formula: .L1is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2-, -S(O)2NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR9-, or -CR8R9-; and R8and R9are independently halogen or unsubstituted methyl.

14. The method of one of claims 1 to 3, wherein L1is -O-.

15. The method of one of claims 1 to 3, wherein L1is –S-.

16. The method of one of claims 1 to 3, wherein L1is –S(O)2-.

17. The method of one of claims 1 to 3, wherein R1is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

18. The method of one of claims 1 to 3, wherein R1is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

19. The method of one of claims 1 to 3, wherein R1is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1- C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

20. The method of one of claims 1 to 3, wherein R1is independently halogen, -OH, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.

21. The method of one of claims 1 to 3, wherein z1 is 1.

22. The method of one of claims 1 to 3, wherein z1 is 0.

23. The method of one of claims 1 to 3, wherein R2is hydrogen, –CX23, -CHX22, -CH2X2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

24. The method of one of claims 1 to 3, wherein R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

25. The method of one of claims 1 to 3, wherein R2is hydrogen.

26. The method of one of claims 1 to 3, wherein R3is hydrogen, –CX33, -CHX32, -CH2X3, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

27. The method of one of claims 1 to 3, wherein R3is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

28. The method of one of claims 1 to 3, wherein R3is hydrogen.

29. The method of one of claims 1 to 3, wherein R6is hydrogen, halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted 2 to 8membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

30. The method of one of claims 1 to 3, wherein R6is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

31. The method of one of claims 1 to 3, wherein R6is hydrogen, ,form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

33. The method of one of claims 1 to 3, wherein R3and R6are joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

34. The method of one of claims 1 to 3, wherein R3and R6are joined to form an unsubstituted pyrrolidinyl.

35. The method of one of claims 1 to 3, wherein R3and R6are joined to form an unsubstituted piperidinyl.

36. The method of claim 6, wherein R4is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

37. The method of claim 6, wherein R4is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

38. The method of claim 6, wherein R4is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

39. The method of claim 6, wherein R4is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, or unsubstituted methoxy.

40. The method of claim 6, wherein R4is independently –OR4D.

41. The method of claim 40, wherein R4Dis independently hydrogen or substituted or unsubstituted alkyl.

42. The method of claim 40, wherein R4Dis independently hydrogen or unsubstituted alkyl.

43. The method of claim 40, wherein R4Dis independently hydrogen or unsubstituted C1-C5 alkyl.

44. The method of claim 40, wherein R4Dis independently hydrogen or unsubstituted methyl.

45. The method of claim 40, wherein R4Dis independently unsubstituted methyl.

46. The method of claim 6, wherein z4 is 1.

47. The method of claim 6, wherein z4 is 0.

48. The method of claim 6, wherein R5is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

49. The method of claim 6, wherein R5is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

50. The method of claim 6, wherein R5is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted phenyl.

51. The method of claim 6, wherein R5is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

52. The method of claim 6, wherein z5 is 1.

53. The method of claim 6, wherein z5 is 0.

54. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted phenyl.

55. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 5 to 6 membered heteroaryl.

56. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted thienyl.

57. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 2-thienyl.

58. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 3-thienyl.

59. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted pyridyl.

60. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 2-pyridyl.

61. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 3-pyridyl.

62. The method of one of claims 1 to 3, wherein Ring A is a substituted or unsubstituted 4-pyridyl.

63. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted phenyl.

64. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted naphthyl.

65. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 1-naphthyl.

66. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 2-naphthyl.

67. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted quinolinyl.

68. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 2-quinolinyl.

69. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 3-quinolinyl.

70. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 4-quinolinyl.

71. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted isoquinolinyl.

72. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 1-isoquinolinyl.

73. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 3-isoquinolinyl.

74. The method of one of claims 1 to 3, wherein Ring B is a substituted or unsubstituted 4-isoquinolinyl.

75. The method of claim 6, wherein the compound has the formula:

77. The method of claim 6, wherein the compound has the formula: .

78. The method of one of claims 1 to 3, wherein the compound has the formula:, ,,15 or 16

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