PCNA inhibitors as Anti-viral agents

Abstract

Described herein, inter alia, is the use of PCNA inhibitors as anti-viral agents.

Description

PATENT Attorney Docket No.: 048440-857001WO PCNA INHIBITORS AS ANTI-VIRAL AGENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 752,444 filed January 31, 2025. 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 (048440-857001WO_Sequence_Listing_ST26.xml; Size: 24,977 bytes; and Date of Creation:December 28, 2025) are hereby incorporated by reference in their entirety.BACKGROUND

[0003] Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes and it is also a proliferation biomarker in a variety of human tumors. A unique cancer-associated isoform of the protein, caPCNA, has been previously identified that potentially allows for selective therapeutic targeting of cancer cells. A number of strategies have been employed to develop agents targeting caPCNA, including peptide and small molecule-based inhibitors, but the success in developing therapeutically tractable compounds has been limited. 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 an RNA viral infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an R9-caPeptide, wherein the compound of formula (I) has 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, -CX33, -CHXJ2, -CH2X'. -OCX1., -OCHX^, -OCH^1, -CN, -SOniR1D, -SOv1NR1AR1B, -NR1CNR1AR1B. -ONR1AR1B-NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)mi, -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 and, 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, -CI I2X3. -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(0)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -0R6D, -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 zl is an integer from 0 to 4. The symbols ml, m6, vl, and v6 are independently 1 or 2. The symbols nl 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 pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIGS. 1A-1C. Inhibition of viral infection by AOH 1996 and caPepti de. Vero cells were pre-treated with the indicated concentrations of AOH 1996 (FIG. 1A) or caPeptide (FIG.1C) for 2 hours at 37 °C. After being exposed to the SARS-CoV-2 expressing GFP for 2 hours, cells were extensively washed with PBS and cultured in fresh media without virus for 24 hours. The levels of viral infection were visualized under a fluorescent microscope. FIG.IB: The abundance of GFP positive cells relative to total number of cells in triplicates were graphed plus / minus standard deviations.

[0020] FIG. 2. Docking analysis of AOH1996 analogs to RdRp subunits.

[0021] FIG. 3. Docking to Nsp 12 with special restriction. The spatial restrictions specified by the grid box were prepared in Autodock4.

[0022] FIG. 4. Effect of AOH1996 on Nsp8 and Nspl2 interaction. Nsp8 and His-tagged Nspl2 proteins bound toNiNTA beads were eluted in SDS sample buffer and analyzed by western blot.

[0023] FIG. 5. Results of cytotoxicity assay.

[0024] FIGS. 6A-6B. Inhibition of HIV infection by AOH 1996. FIG. 6A: Effect of AOH1996 on infection of CD8" PBMC by HIV NL4-3 as measured by p24 levels in supernatants (pg / mL) - Test #1. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by AOH1996 for 1 hour, cells were infected by NL4-3 HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of AOH 1996. The levels of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7, 11, and 14. FIG. 6B: Percent inhibition of HIV NL4-3 infection by AOH1996 on day 14 - Test #1.

[0025] FIGS. 7A-7B. Inhibition of HIV infection by caPeptide. FIG. 7A: Effect of caPeptide on infection of CD8" PBMC by HIV NL4-3 as measured by p24 levels in supernatants (pg / mL) - Test #1. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by caPeptide for 1 hour, cells were infected by NL4-3 HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of caPeptide. The level of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7, 10, and 14. FIG. 7B: Percent inhibition of HIV NL4-3 infection by caPeptide on day 14 - Test #1.

[0026] FIGS. 8A-8B. Inhibition of HIV infection by AOH 1996. FIG. 8A: Effect of AOH1996 on infection of CD8" PBMC by HIV NL4-3 as measured by p24 levels in supernatants (pg / mL) - Test #2. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by AOH1996 for 1 hour, cells were infected by NL4-3 HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of AOH1996. The levels of viralantigen, p24, in supernatants were measured by ELISA on day 4, 7, 11, and 14. FIG. 8B: Percent inhibition of HIV NL4-3 infection by AOH1996 on day 14 - Test #2.

[0027] FIGS. 9A-9B. Inhibition of HIV infection by caPeptide. FIG. 9A: Effect of caPeptide on infection of CD8" PBMC by HIV NL4-3 as measured by p24 levels in supernatants (pg / mL) - Test #2. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by caPeptide for 1 hour, cells were infected by NL4-3 HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of caPeptide. The level of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7, 10, and 14. FIG. 9B: Percent inhibition of HIV NL4-3 infection by caPeptide on day 14 - Test #2.

[0028] FIGS. 10A-10B. Inhibition of HIV infection by AOH1996. FIG. 10 A: Effect of AOH1996 on infection of CD8" PBMC by HIV Bal as measured by p24 levels in supernatants (pg / mL) - Test #1. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by AOH1996 for 1 hour, cells were infected by Bal HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of AOH1996. The levels of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7, 11, and 14. FIG. 10B: Percent inhibition of HIV Bal infection by AOH1996 on day 14 - Test #1.

[0029] FIGS. 11A-11B. Inhibition of HIV infection by caPeptide. FIG. 11 A: Effect of caPeptide on infection of CD8" PBMC by HIV Bal as measured by p24 levels in supernatants (pg / mL) - Test #1. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by caPeptide for 1 hour, cells were infected by Bal HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of caPeptide. The level of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7. 10. and 14. FIG. 1 IB: Percent inhibition of HIV Bal infection by caPeptide on day 14 - Test #1.

[0030] FIGS. 12A-12B. Inhibition of HIV infection by AOH1996. FIG. 12A: Effect of AOH1996 on infection of CD8" PBMC by HIV Bal as measured by p24 levels in supernatants (pg / mL) - Test #2. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by AOH1996 for 1 hour, cells were infected by Bal HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of AOH1996. The levels of viralantigen, p24, in supernatants were measured by ELISA on day 4, 7, 11, and 14. FIG. 12B: Percent inhibition of HIV Bal infection by AOH1996 on day 14 - Test #2.

[0031] FIGS. 13A-13B. Inhibition of HIV infection by caPeptide. FIG. 13 A: Effect of caPeptide on infection of CD8" PBMC by HIV Bal as measured by p24 levels in supernatants (pg / mL) - Test #2. The cells were seeded at 2 x 106cells / ml / well and activated by ActiCyte®-TC media for 48 hours. After being pre-treated by caPeptide for 1 hour, cells were infected by Bal HIV strain. After infection, cells were cultured for 14 days with half media changed twice a week in the continued presence of caPeptide. The level of viral antigen, p24, in supernatants were measured by ELISA on day 4, 7, 10, and 14. FIG. 13B: Percent inhibition of HIV Bal infection by caPeptide on day 14 - Test #2.DETAILED DESCRIPTIONI. Definitions

[0032] 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.

[0033] 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-.

[0034] 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-C10 means 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-buty l, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyL crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyL 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to theremainder 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.

[0035] 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.

[0036] 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 quatemized. 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, -0-CH3.-O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety' may' include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety’ may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety'may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl / ’ by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0037] 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, heteroalk l 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. Tdie term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkyny dene” 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 heteroalkyny dene includes one or more triple bonds.

[0038] 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.

[0039] 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 cycloalkyd 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 cycloalkyd ring of the multiple rings.

[0040] 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.

[0041] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fullysaturated. 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.

[0042] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0043] 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.

[0044] 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 quatemized. 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 heteroar l ring. A heteroarylgroup can be atached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyL pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl. 2-pyrrolyl. 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl. 2-quinoxalinyl, 5 -quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0045] Spirocyclic rings are two or more rings wherein adjacent rings are atached 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 cycloalkyd, 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.

[0046] The symbol ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0047] The term "oxo.” as used herein, means an oxygen that is double bonded to a carbon atom.

[0048] 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:3or3

[0049] An alkylarylene moiety may be substituted (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, -CCI3, -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.

[0050] 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.

[0051] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -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'+l), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound 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 same nitrogen atom, they’ can be combined yvith the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0052] 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, -R1, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-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.

[0053] 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 orspirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more 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 show n 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.

[0054] 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, tw o 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, tw o ringforming 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.

[0055] 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 and 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 isan 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-, -NR1-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0056] 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).

[0057] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I. -OCCI3, -OCF3, -OCBr3, -OCI3. -OCHC12, -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., Ci-Cs alkyl, Ci-Ce 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-C8cycloalkyl, C3-C6cycloalkyl, 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 / or(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 6membered 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:(i) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -0CH2I. -OCH2F. -CN, -OH, -NH2, -C00H, -CONH2, -N02, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH. -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), 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-C8cycloalkyl, C3-C6cycloalkyl, 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 / or (ii) 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, 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, -CC13, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -0CH2I, -OCH2F, -CN, -OH, -NH2. -COOH. -CONH2. -NO2, -SH. -SO3H, -OSO3H, -SO2NH2. -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g, Ci-C8alkyd. Ci-Cg alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, 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 / or(b) alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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.. Ce- 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, -CCI3, -CBrs. -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. -CH2C1, -CH2Br, -CH2F, -CH2I. -OCCI3, -OCF3, -OCBr3. -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3. -SF5. unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), 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).

[0058] A “size-limited substituent' ’ or “ size-limited substituent group.” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C2o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0059] A “lower substituent'’ or “ lower substituent group,’' as used herein, means a group selected from all of the substituents described above for a “substituent group.” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, 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 heteroary 1 is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0060] 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 alkyd ene, 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.

[0061] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, 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-C10aryl, 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-C20alkylene, each substituted orunsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0062] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, 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 Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7cycloalkylene, each substituted or unsubstituted heterocy cloalkylene 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.

[0063] 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, unsubstitutedcycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., 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).

[0064] 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.

[0065] 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.

[0066] 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 may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality7of lower substituent groups, each lower substituent group is different.

[0067] 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.

[0068] In a recited claim or chemical formula description herein, each R substituent or L tinker 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 tinker or an “openly substituted” R substituent or L tinker), the recited R substituent or L tinker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0069] 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 firstsubstituent groups denoted by R2A1, 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 by R5A.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 denoted by RL1.1, L2may be substituted with one or more first substituent groups denoted by RL2.1, L3may be 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, R5.1... R100 1; R1A.1 R2A.1R3A.1R4A.1R5A.1R100A.l.RL1.1RL2.1RL3.1RL4.1RL5 1RL100.1)may be further substituted with one or more second substituent groups (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. respectively). Thus, each first substituent group, which may alternatively 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

[0070] 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 further substituted with one or more third substituent groups (e.g., R1.3, R2.3, R3.3, R4.3, R5.3… R100.3; R1A.3, R2A.3, R3A.3, R4A.3, R5A.3… R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3… RL100.3. respectively). Thus, each second substituent group, which may alternatively be represented herein as RWW 2as described above, may be further substituted with one or more third substituent groups, w hich 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.

[0071] Thus, as used herein, Rwwrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the statedsuperscript number of the subject R group (1, 2, 3, 1 A, 2A, 3A, IB, 2B, 3B, etc.). Likewise, Lwwis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, ‘W’’ represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, IB, 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:

[0072] 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^-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), RWW.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), 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, -0NH2, -NHC(0)NHNH2, -NHC(O)NH2. -NHC(NH)NH2. -NHSO2H. -NHC(O)H, -NHC(0)0H. -NHOH. -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-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 Cs-Ce), 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., Ce-Ci2, Ce-Cio, 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.

[0073] RWW2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW2, -OCHXWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3. RWW.3-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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, -CHXWW22, -CH2XWW 2, -OCXWW-OCH2XWW 2, -OCHXWW 22, -CN, -OH, -NH2. -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -NHOH, -N3, unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, 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, Cs-Ce, C4-C6, or Cs-Ce), 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, Ce-Cio. 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.

[0074] 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. -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce). 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, Ce-Cio, 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.

[0075] 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, referred 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 two different 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.3Alternatively, 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.

[0076] 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, -0NH2, -NHC(0)NHNH2, -NHC(0)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-Cs, C3-Ce, C4-C6, or Cs-Ce). 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 6membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13,-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., Ci-Cs, Ci-Ce, C1-C4, or Ci-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 Cs-Ce), 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, Cs-Cio, 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.

[0077] 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(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted or unsubstituted 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 Cs-Cg), 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(0)0H. -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Ci2, Ce-Cio, 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.

[0078] 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., Ci-Cs, Ci-Cg, 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., Cs-Cg, C3-C6, C4-C6, or Cs-Cg), 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., Ce-Ci2, Cg-Cio, 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.

[0079] 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, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, Rww 1-substituted or unsubstituted alkyl (e.g., Ci-Cg, Ci-Ce, 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., Cs-Cg, C3-C6, C4-C6, or Cs-Cg), Rww^-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., Cg-Ci2, Cg-Cio, or phenyl), or Rww^-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, IB, 2B, 3B, etc.).RWW.1, RWW.2and RWW.3are as defined above.

[0080] 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(0)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-substitutedor 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 Cs-Ce), 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, Ce-Cio, 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, IB, 2B, 3B, etc ). RLWW.1, as well as RLWW.2and RLWW.3are as defined above.

[0081] 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 present disclosure 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.

[0082] As used herein, the term '‘isomers’’ refers to compounds having the same number and kind of atoms, and hence the same molecular w eight, but differing in respect to the structural arrangement or configuration of the atoms.

[0083] 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.

[0084] It w ill 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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 or 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-hydroxy succinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). 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., -sulfo-N-hydroxy succinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0090] 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 todisulfides, 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; (1) 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 avidinbiotin complex or streptavidin-biotin complex.

[0091] 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 molecular entity derived from the reaction of an unsaturated bond, such as a maleimide. and a sulfhydryl group.

[0092] “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.

[0093] 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-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0094] 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 substitutedwith 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.

[0095] 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 not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] A polypeptide, or a cell is ‘'recombinant’7when 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 other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated 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.

[0102] “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).

[0103] 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.

[0104] 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 ofdegeneration 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.

[0105] 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 “activity7increasing 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 ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003. Gennaro. Ed., Lippincott, Williams & Wilkins).

[0106] '‘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).

[0107] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 absence of 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.

[0112] 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.

[0113] 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, lipiddroplet, 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.

[0114] 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.).

[0115] 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.

[0116] '‘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 subj ect in need thereof is human.

[0117] “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 an RNA viral infection (e.g., SARS-CoV-2 infection, HIV infection, or influenza infection).

[0118] The term '‘infection” or “infectious disease” refers to a disease or condition that can be caused by organisms such as a bacterium, virus, fungi, parasite, or any other pathogenic microbial agents. In embodiments, the infectious disease is an RNA viral infection. An “RNA viral infection” is caused by an RNA virus, which is a virus that has ribonucleic acid(RNA) as its genetic material. Non-limiting RNA viral infections include the common cold, influenza, parainfluenza, coronavirus, SARS, MERS, COVID-19, HIV, Dengue Virus, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, Epstein-Barr virus, rabies, polio, mumps, measles, respirator}' syncytial virus infection, and hantaviruses.

[0119] The term “coronavirus” is used in accordance with its plain ordinary' meaning and refers to an RNA virus that in humans causes respiratory tract infections. Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria. In embodiments, the coronavirus is an enveloped viruses with a positive-sense single-stranded RNA genome.

[0120] The term “severe acute respiratory syndrome coronavirus” or “SARS-CoV” or “SARS-CoV-1” refers to the strain of coronavirus that causes severe acute respiratory syndrome (SARS). In embodiments, SARS-CoV-1 is an enveloped, positive-sense, singlestranded RNA virus that infects the epithelial cells within the lungs. In embodiments, the virus enters the host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.

[0121] The term “severe acute respiratory syndrome coronavirus 2” or “SARS-CoV-2” refers to the strain of coronavirus that causes coronavirus disease 2019 (COVID-19). In embodiments, SARS-CoV-2 is a positive-sense single-stranded RNA virus.

[0122] 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.

[0123] 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.

[0124] 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,123I124I,123I,131I142Pr,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.

[0125] “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, lactatedRinger'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.

[0126] 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.

[0127] 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.

[0128] 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, intraarteriole, 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 beadministered 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 trans dermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0129] 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.

[0130] 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.

[0131] 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., RNA viral infection) 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 theskill 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.

[0132] 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., RNA viral infection, SARS-CoV-2 infection, HIV infection, influenza infection) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function 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.

[0133] 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.

[0134] 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.

[0135] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0136] 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 usinganalytical 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.

[0137] 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, - carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a 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.

[0138] 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.

[0139] 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 moiety7that 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.

[0140] 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 countingfrom 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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 8 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 PCNA has the following amino acid sequence:MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGF DTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSD YEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFS ASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLS MSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 1).

[0146] 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, thePCNA 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).

[0147] 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 / 2 of 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.II. Methods of use

[0148] In an aspect is provided a method of treating an RNA viral infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an R9-caPeptide, wherein the compound of formula (I) has the formula:

[0149] 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-.

[0150] R7, R8, and R9are independently hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, C1-C4. or Ci-C2).

[0151] Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0152] Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.

[0153] R1is independently halogen, -CX’3, -CHX’2, -CH2X’, -OCX’s, -OCHX’2, -OCH2X’, -CN, -SOniR1D. -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., Ci-Cs, Ci-Ce, 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 cycloalkyd (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-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-Ce, C4-C6, or Cs-Ce), 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., Ce-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0154] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs. Ci-Ce, 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-Cs, C3-C6, C4-C6, or C3-Cg), 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., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0155] R3is hydrogen, halogen, -CX33, -CHX32, -CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, 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-Cs, C3-Cg, C4-C6, or Cs-Cg), 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., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered).

[0156] R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOvgNR6AR6B, -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., Ci-Cs, Ci-Cg, 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-Cs, C3-Cg. C4-C, or Cs-Cg), 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., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0157] 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).

[0158] 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., Ci-Cs, Ci-Ce, 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., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), 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., Ce-Cio or 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).

[0159] The symbol zl is an integer from 0 to 4.

[0160] The symbols ml, m6, vl, and v6 are independently 1 or 2.

[0161] The symbols nl and n6 are independently an integer from 0 to 4.

[0162] X, X1, X2, X3, and X6are independently -Cl, -Br, -I, or -F.

[0163] The symbol m is an integer from 0 to 5.

[0164] The symbol n is an integer from 0 to 10.

[0165] In embodiments, the RNA viral infection is a SARS-CoV-2 infection. In embodiments, the RNA viral infection is an HIV infection. In embodiments, the RNA viral infection is an influenza infection. In embodiments, the RNA viral infection is Epstein-Barr virus. In embodiments, the RNA viral infection is a parainfluenza viral infection. In embodiments, the RNA viral infection is measles. In embodiments, the RNA viral infection is mumps. In embodiments, the RNA viral infection is rabies. In embodiments, the RNA viral infection is respiratory syncytial virus infection. In embodiments, the RNA viral infection is Ebola. In embodiments, the RNA viral infection is a hantavirus.

[0166] In embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the formula:(R1)ziR2 R6 R3(I); 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)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-; R7, R8, and R9are independently hydrogen, halogen, -OH, -N₃, or substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, C1-C4, or C1-C2); 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, -SOniR1D, -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., Ci-Cs, Ci-Cg, C1-C4, or Ci-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, C?-Ce, C4-C6, or Cs-Cg), 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., Cg-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 Cs-Cg), 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., Cg-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2is hydrogen, halogen, -CX23. -CHX22, -CH2X2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, C1-C4, or Ci-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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3is hydrogen, halogen, -CX33, -CHX32, -CH2X3, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g.. 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered); R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCHX62, -OCH2X6, -CN, -SOn6R6D, -SOV6NR6AR6B, -NR6CNR6AR6B, -ONR6AR6B, -NHC(O)NR6CNR6AR6B, -NR6CC(O)NR6AR6B, -N(0)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., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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); 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); 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., Ci-Cs, Ci-Ce, 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 Cs-Ce). 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 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); the symbol zl is an integer from 0 to 4; the symbols ml, m6, vl, and v6 are independently 1 or 2; the symbols nl and n6 are independently an integer from 0 to 4; X. X1. X2. X3. and X6are independently -Cl. -Br, -I. or -F; the symbol m is an integer from 0 to 5; the symbol n is an integer from 0 to 10.

[0167] In embodiments, the compound has the formula:•(R!(II). L1, R1, zl, R2, R3, R6, m, and n are as described herein, including in embodiments.

[0168] Ring A is pheny l or 5 to 6 membered heteroaryl.

[0169] Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl.

[0170] R4is independently a halogen, -CX43, -CHX42, -CH2X4. -OCX43, -OCHX42.-OCH2X4, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NHC(O)NR4CNR4AR4B, -NR4CC(O)NR4AR4B, -N(0)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., Ci-Cs, Ci-Ce, C1-C4, or Ci-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-Cg, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered); two adjacent R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0171] R3is 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., Ci-Cs, Ci-Ce, 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-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-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 R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0172] 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., Ci-Cs, Ci-Ce, C1-C4, or Ci-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-Cs, C3-Ce, C4-C6. or Cs-Ce), 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., Ce-Cio 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 mayoptionally 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).

[0173] The symbol z4 is an integer from 0 to 5.

[0174] The symbol z5 is an integer from 0 to 7.

[0175] The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0176] The symbols n4 and n5 are independently an integer from 0 to 4.

[0177] X, X4, and X5are independently -Cl, -Br, -I, or -F.

[0178] In embodiments, the compound has the formula:(III). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R z5, and R6are as described herein, including in embodiments.

[0179] In embodiments, the compound has the formula:(Illa). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R '. z5, and R6are as described herein, including in embodiments.

[0180] In embodiments, the compound has the formula:(Illb). L1. Ring A, Ring B, R1, zl, R2, R3, R4. z4, R. z5, and R6are as described herein, including in embodiments.

[0181] In embodiments, the compound has the formula:(IV). L1, Ring A. Ring B, R1, zl. R2, R3, R4, z4. R5, z5, and R6are as described herein, including in embodiments.

[0182] In embodiments, the compound has the formula:(IVa). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0183] In embodiments, the compound has the formula:(IVb). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0184] In embodiments, the compound has the formula:(V). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0185] In embodiments, the compound has the formula:(Va). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0186] In embodiments, the compound has the formula:(Vb). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0187] In embodiments, the compound has the formula:(VI). L1, Ring A, Ring B, R1, zl, R2, R3, R4, z4, R '. z5, and R6are as described herein, including in embodiments.

[0188] In embodiments, the compound has the formula:(R1)z1?2f § (R4M A J 1 J I3C BJ-(R5) vZK_^ ><.5I_1 V V R r\° x^X(VIa)L,1 Ring A Ring BR,1zl R~2RjR4, z4, R '. z5, and R6are as described herein, including in embodiments.

[0189] In embodiments, the compound has the formula:(R5)Z5(VIb). L1, Ring A, Ring B, R1, zl, R2, R?, R4, z4, R\ z5, and R6are as described herein, including in embodiments.

[0190] 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.

[0191] 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.

[0192] 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-.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] In embodiments, R1is independently halogen. -CX13, -CHXS, -CH2X1. -OCX63, -OCHX, -OCH2X1, -CN, -SOniR1D, -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., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or 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 Cs-Ce), 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.. Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0201] In embodiments, 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. In embodiments, R1is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4alkyl, 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.

[0202] 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 -CCI3. 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 -OCCI3. In embodiments, R1is independently -OCBr3. In embodiments, R1is independently -OCF3. In embodiments, R1is independently -OCI3. In embodiments, R1is independently -OCH2CI. 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-C4 alkyl. 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.

[0203] In embodiments, zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In embodiments, zl is 4.

[0204] 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.

[0205] 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., Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0206] In embodiments, R2is hydrogen, -CX23, -CHX22, -CH2X2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R2is hydrogen.

[0207] In embodiments, R2is hydrogen or unsubstituted C1-C4 alkyl. 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.

[0208] 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.

[0209] 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., Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0210] In embodiments, R3is hydrogen, -CX33, -CHX32, -CH2X3, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R3is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R3is hydrogen.

[0211] In embodiments, R3is hydrogen or unsubstituted C1-C4 alkyl. 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] In embodiments, a substituted R4C(e.g., substituted alkyd, 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.

[0218] 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.

[0219] 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., Ce-Cio 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 Cs-Ce), 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., Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0220] In embodiments, R4is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstitutedCi-Cs 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, 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. In embodiments, R4is independently halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4is independently halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, or unsubstituted methoxy.

[0221] 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 -CCI3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2C1. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHC12. 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 -OCCI3. In embodiments, R4is independently -OCBr3. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2C1. In embodiments, R4isindependently -OCH₂Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCh. In embodiments. R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently unsubstituted C1-C4 alkyl. 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.

[0222] 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-C5 alkyl. In embodiments, R4Dis independently hydrogen or unsubstituted methyl. In embodiments, R4Dis independently hydrogen. In embodiments, R4Dis independently unsubstituted C1-C5 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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 issubstituted with at least one substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

[0227] 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.

[0228] 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.

[0229] 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 lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent 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.

[0230] 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.

[0231] 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., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or 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 Cs-Ce), 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., Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0232] In embodiments, R5is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstitutedCi-Cs 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, R5is independently halogen, -CF3, -CN, -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. In embodiments, R5is independently halogen, -CF3, CHF2, CH2F, -OCF3, -OCHF2, -OCH2F, -CN,-OH, -NH2, -SH, unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted phenyl. In embodiments, R5is independently halogen, -CF3, -CHF2, -CH2F, -OCF3,-OCHF2, -OCH2F, -CN, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

[0233] 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 -CH2C1. In embodiments, R5is independently -CH2Br. In embodiments, R5is independently -CH2F. In embodiments, R5is independently -CH2I. In embodiments. R5is independently -CHCh. 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 -OCCI3. In embodiments, R5is independently -OCBr3. In embodiments, R5is independently -OCF3. In embodiments, R5isindependently -OCI3. In embodiments, R5is independently -OCH2CI. 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.

[0234] 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.

[0236] In embodiments, a substituted R6(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 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.

[0237] 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 issubstituted 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.

[0238] 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.

[0239] 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 R6Bsubstituents 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 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.

[0240] 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 lowersubstituent 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.

[0241] 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.

[0242] 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., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0243] In embodiments, R6is hydrogen, halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R6is substituted or unsubstituted Ci-Ce alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0244] 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 -CH2CI. In embodiments. R6is -CH2Br. In embodiments, R6is -CH2F. In embodiments, R6is -CH2I. In embodiments, R6is -CHCh. 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 -OCCI3. In embodiments, R6is -OCBr3. In embodiments, R6is -OCF3. In embodiments, R6is -OCI3. In embodiments, R6is -OCH2CI. In embodiments, R6is -OCH2Br. In embodiments, R6is -OCH2F. In embodiments, R6is -OCH2I. In embodiments, R6is -OCHCh. In embodiments, R6is -OCHBr2. In embodiments, R6is -OCHF2. In embodiments, R6is -OCHI2. In embodiments, R6is substituted or unsubstituted C1-C4 alkyl. In embodiments, R6is substituted C1-C4 alkyl. 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, R6isunsubstituted 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.

[0245] 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.

[0246] 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 an L-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.

[0247] 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.

[0248] In embodiments, R6is hydrogen, unsubstituted methyl, unsubstituted isopropyl,

[0249] 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 is substituted 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.

[0250] 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).

[0251] 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.

[0252] 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, sizelimited 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.

[0253] In embodiments, R7is hy drogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce. 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. In embodiments, R7is unsubstituted n-butyl. In embodiments, R7is unsubstituted isobutyl. In embodiments, R7is unsubstituted tert-butyl.

[0254] 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, sizelimited 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. Inembodiments, 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.

[0255] In embodiments, R8is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyd (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2). In embodiments, R8is hydrogen,halogen, -OH, -N3, or unsubstituted alkyl (e g., Ci-Cs, Ci-Ce, 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.

[0256] 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, sizelimited 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.

[0257] In embodiments, R9is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce. 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-C4 alkyl. In embodiments, R9is unsubstituted C1-C4 alkyl. In embodiments, R9is unsubstituted methyl. In embodiments, R9is unsubstituted ethyl. Inembodiments, 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.

[0258] 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.

[0259] 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 substituted 3-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. In embodiments, Ring A is a substituted pyrrolyl. In embodiments, Ring A is an unsubstituted pyrrolyl. In embodiments, Ring A is a substituted furanyl. In embodiments, Ring A is an unsubstituted 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. In embodiments, 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.

[0260] 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. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is triazolyl.In embodiments. Ring A isIn embodiments, RingA isembodiments, Ring A isRing A is OCH3 jnembodiments, Ring A isOH. In embodiments, Ring A is F In embodiments. Ring A is CF3 |nembodiments, RingA isCH3. In embodiments. Ring A isIn embodiments,CH3Ring A is. In embodiments, Ring A isH3CO CH3In embodiments,Ring Ais

[0262] In embodiments, a substituted Ring B (e g., substituted phenyl, substituted naphthyl, 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, sizelimited 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.

[0263] 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 an unsubstituted 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 isoquinolinyl. In embodiments. Ring B is anunsubstituted 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.

[0264] 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 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. In embodiments, Ring B is ON inembodiments, Ring B is. In embodiments, Ring B is. In embodiments, Ring B is’ « — V. Inembodiments, RingB is. In embodiments, Ring Bis. Inembodiments, RingB is

[0266] In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5.

[0267] 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.

[0268] In embodiments, the compound has the formula:R2R6Ol\ iL I A IInN■o° *3R1, zl, R2, R3, R4, z4, R3, and R6are as described herein. including in embodiments.

[0269] In embodiments, the compound has the formula:R1, zl, R2, R3, R4, z4, and R6are as described herein, including in embodiments.

[0270] In embodiments, the compound has the formula:R1, zl, R2, R3, R4, z4, and R6are as described herein, including in embodiments.

[0271] In embodiments, the compound has the formula:R2R6O” N IO O R3r>5R. R2, R3, R4, z4, R5, and R6are as described herein, including in embodiments.

[0272] In embodiments, the compound has the formula:embodiments.

[0273] In embodiments, the compound has the formula:. R2, R3, R4, z4, and R6are as described herein, including in embodiments.

[0274] In embodiments, the compound has the formula:N NH. R4, z4, R5, and R6are as described herein, including in embodiments.

[0275] In embodiments, the compound has the formula:.. R6ON JHR4, z4, and R6are as described herein, including in embodiments.

[0276] In embodiments, the compound has the formula:N JHR4, z4, and R6are as described herein, including in embodiments.

[0277] In embodiments, the compound has the formula:embodiments.

[0278] In embodiments, the compound has the formula:R4, z4, and R6are as described herein, including in embodiments.

[0279] In embodiments, the compound has the formula:R6is as described herein, including in embodiments.

[0280] In embodiments, the compound has the formula:R6is as described herein, including in embodiments.

[0281] In embodiments, the compound has the formula:R6is as described herein, including in embodiments.

[0282] In embodiments, the compound has the formula:R6is as described herein, including in embodiments.

[0283] In embodiments, the compound has the formula:R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0284] In embodiments, the compound has the formula:R2, R3, R4, z4, R5, z5, and R6are as described herein, including in embodiments.

[0285] In embodiments, the compound has the formula:R4, R5, z5, and R6are as described herein, including in embodiments.

[0286] In embodiments, the compound has the formula:. R4, R5, z5, and R6are as described herein, including in embodiments.

[0287] In embodiments, the compound has the formula:R4, R5, z5, and R6are as described herein, including in

[0288] In embodiments, the compound has the formula:R4, R5, z5, and R6are as described herein, including in

[0289] In embodiments, the compound has the formula:. R5, z5, and R6are as described herein, including in embodiments.

[0290] In embodiments, the compound has the formula:R6ON JH. R5, z5, and R6are as described herein, including in embodiments.

[0291] In embodiments, the compound has the formula:.. R6ONn N■0 °H. R5, z5, and R6are as described herein, including in embodiments.

[0292] In embodiments, the compound has the formula:N. R5, z5, and R6are as described herein, including in embodiments.

[0293] In embodiments, the compound has the formula:. Inembodiments, the compound has the formula:. In embodiments,Hl\L,X NOthe compound has the formula:In embodiments, the compoundhas the formula:In 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:In embodiments, the compound has the formula:In embodiments, the compound has the formula:. In embodiments, the compound has the formula: O« N o°HOCH3. In embodiments, the compound has the formula:o 0 °HOCH3. 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^OH 0. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:NH2H 5 oN^N HO °. In embodiments, the compound has the formula: NH2H o N NHs °. In embodiments, the compound has the formula: NH2O H N N HS °. 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:HOCH3. 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:HOCH3. 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: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: H ONV-Ns oH. 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: 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: HN. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:5o. In embodiments, the compound has the formula: O H N N HS ° F. In embodiments, the compound has the formula: F. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:CF3. In embodiments, the compound has the formula:o. In embodiments, the compound has the formula: 0. In embodiments, the compound has the formula: CH3in 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:5o JH3OH H CO CH3. In embodiments, the compound has the formula:H o N0 °CNH3CO CH3

[0294] In embodiments, the compound has the formula:R1, zl, R2. R4, and z4 are as described herein, including in

[0295] In embodiments, the compound has the formula:R1, zl, R2, R4, and z4 are as described herein, including in

[0296] In embodiments, the compound has the formula:embodiments.

[0297] In embodiments, the compound has the formula:R2, R4, and z4 are as described herein, including in embodiments.

[0298] In embodiments, the compound has the formula:H NO. R4is as described herein, including in embodiments.

[0299] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0300] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0301] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0302] In embodiments, the compound has the formula:embodiments, the compound has the formula:the compound has the formula:In embodiments, the compound has theformula:

[0303] In embodiments, the compound has the formula:R1, zl, R2, R4, and z4 are as described herein, including

[0304] In embodiments, the compound has the formula:R1, zl, R2, R4, and z4 are as described herein, including in embodiments.

[0305] In embodiments, the compound has the formula:R2, R4, and z4 are as described herein, including in

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

[0307] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0308] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0309] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0310] In embodiments, the compound has the formula:R4is as described herein, including in embodiments.

[0311] embodiments, the compound has the formula: embodiments, the compound has the formula:embodiments, the compound has the formula:. Inembodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:

[0312] In embodiments, when R1is substituted, R1is 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 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 R12substituent 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 A, R12, and R13have values corresponding to the values of Rww. R^W 1, Rw-2;and Rww-3,reSpecpVely, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRww-25and RWW 3correspond to R1, R1 1, R1 2, and R13, respectively.

[0313] 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 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 R12substituent group is substituted, the R1 2substituent group is substituted with one or more third substituent groups denoted by R1 1as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R1. R1 A, R12, and R13have values corresponding to the values of Rww, RwwRww-2, and RWW3respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww'2, and RWW3correspond to R1, R1 1, R1 2, and R1 3, respectively.

[0314] 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 R1A3as expiaineciintpedefinitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A l, R1A 2, and R1A3have values corresponding to the values of Rww, RWW 1?RWW2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’; wherein Rww, RwR™ and RWW 3correspond to R1A, R1A 1, R1A2, and R1A3, respectively.

[0315] 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, RW W 1, Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rwi;Rww-2, and RWW3correspond to R1B, R1B 1, R1B 2, and R1B 3. respectively.

[0316] 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 R1A3as explained in the definitions section above in the description of “first substituent group(s)7’. In the above embodiments, R1A 1, R1A 2and R1A3have values corresponding to the values of RWW 1, RWW2anj RWW.3,reSpectiveiy5explained in the definitions section above in the description of “first substituent group(s)”, wherein Rw", Rww-2, and RWW 3correspond to RIA I. R1A'2, and R1A3, respectively.

[0317] 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, RW 2anj RWW.3,reSpectiveiy,asexplained in the definitions section above in thedescription of “first substituent group(s)”, wherein Rw%R^W.2,ANC| RW.3correSpOnc| (0R1B 1, R1B 2, and R1B 3, respectively.

[0318] 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 the description 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 RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRWW-2, and RWW 3correspond to R1C, R1C 1, R1C 2, and R1C 3, respectively.

[0319] 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)7’. 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,anc| Rww-3,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1;RW2and RWW3correspond to R1D, R1D 1, R1D 2, and R1D, respectively.

[0320] 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 R22as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22substituent group is substituted,the R22substituent group is substituted with one or more third substituent groups denoted by R23as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R2, R2 1, R22, and R23have values corresponding to the values of Rww, RWW4, Rww-2,anc| RWW; reSpectiVely, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rwi;RWW.2, and RWW3correspond to R2, R2R22. and R23, respectively.

[0321] 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 R32as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R32substituent 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 A, R32, and R33have values corresponding to the values of Rww. R^W 1, RWW2anjRwwreSpecpVely, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww?RwwRWW 2and RWW 3correspond to R3, R3R32, and R33, respectively.

[0322] 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)7’. In embodiments, when an R4 1substituent group is substituted, the R4 1substituent group is substituted with one or more second substituent groups denoted by R42as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R42substituent group is substituted, the R42substituent group is substituted with one or more third substituent groups denoted by R43as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4 1, R42, and R43have values corresponding to the values of Rww, Rww A, 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 RWW3correspond to R4, R4', R42, and R43, respectively.

[0323] 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 substituent groups denoted by R42as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R42substituent group is substituted, the R42substituent group is substituted with one or more third substituent groups denoted by R43as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R44. R42, and R43have values corresponding to the values of Rww, RWW 1, RWW 2.anc|respectively, as explained in the definitions section above in the description of “first substituent group(s)". wherein Rw w. RWW 1, RWW-2, and RWW 3correspond to R4, R4 1, R42, and R43, respectively.

[0324] 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 R4A2as 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 R4A3have values corresponding to the values of Rww, RWW 1, R -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 RWW3correspond to R4A, R4A 1, R4A 2, and R4A3, respectively.

[0325] 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 R4B4substituent 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 substituentgroup(s)'’. In the above embodiments, R4B, R4B 1, R4B 2, and R4B 3have values corresponding to the values of R, Rw-1. Rw-2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRww-2, and RWW 3correspond to R4B, R4B 1, R4B 2, and R4B 3, respectively.

[0326] 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 R4A2substituent group is substituted, the R4A 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, R4A 1, R4A 2, and R4A 3have values corresponding to the values of RW 1, RWW'2, and Rww'3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein RW V-1, RA W 2_ and RWW 3correspond to R4A 1, R4A-2, and R4A3, respectively.

[0327] 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 I. R4B 2, and R4B Jhave values corresponding to the values ofRWW 1,anc|Rw.sreSpecpvely, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RV / W 1, RWW.2,ancjRww3correspond to R4B-1, R4B 2, and R4B 3, respectively.

[0328] 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 substituent groups 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, R%W2,ANC| RWW3,reSpectjVely, as explained in the definitions section above in the description of “first substituent group(s)’; wherein Rw w. RWW 1, RWW-2, and RWW 3correspond to R4C, R4C 1, R4C 2, and R4C3, respectively.

[0329] 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\ R4D 2, and R4D 3have values corresponding to the values of Rww, RWW 1, R -2. and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww-2, and RWW3correspond to R4D, R4D l, R4D 2, and R4D 3, respectively.

[0330] 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 R3 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 R52substituent group is substituted, the R3 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 substituentgroup(s)'’. In the above embodiments, R5, R5 1. R52, and R53have values corresponding to the values of Rww. Rw A, Rww'2, and Rwwrespectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRww-2, and RWW 3correspond to R3, R3 1, R52, and R53, respectively.

[0331] In embodiments, when two adjacent R3substituents 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 R3 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 R52substituent group is substituted, the R3 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 A, R52, and R53have values corresponding to the values of Rww. R^W 1, RWW2anjRww.3,reSpecpVely, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww?RwwRww-25and RWW 3correspond to R5, R3 1, R52, and R53, respectively.

[0332] 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 the description of “first substituent group(s)7’. In embodiments, when an R5A 1substituent group is substituted, the R5A 1substituent group is substituted with one or more second substituent groups denoted by R3A2as 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 R5A3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A, R5A I. R3A2, and R5A3have values corresponding to the values of R"w, RWW 1, Rww-2,anc| 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 RWW3correspond to R5A, R5A-1, R5A 2, and R5A3, respectively.

[0333] 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 thedescription 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\ R5B 2, and R5B 3have values corresponding to the values of R'J". Rw WJ, Rww-2, and Rww'3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww-2, and RWW3correspond to R5B, R5B', R5B 2, and R5B 3. respectively.

[0334] 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 R5A2as 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 R5A3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A 1, R5A2, and R5A3have values corresponding to the values of Rww.i, RWW.2,ANC[ RWW.3,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rw% 1, R^W.2,ANC| RWW3correspond to R5A 1R5A.2anj R5A.3, respectively.

[0335] 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 R3B 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 ofRWW. I,anc[Rww.3,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW 1, R W.2,ANC| RWW3correspond to R5B 1R5B 2ailj RSB.3 respectively.

[0336] 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 R3C 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 R3C 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, R5CR5C 2, and R5C 3have values corresponding to the values of Rw^, 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?RwwRWW 2and RWW 3correspond to R5C, R5C 1, R5C 2, and R5C3, respectively.

[0337] 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 the description of “first substituent group(s)7’. 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 expiainec[ inthe definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5D, R5D 1, R3D 2, and R5D 3have values corresponding to the values of R%w, 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 RWW3correspond to R5D, R5D 1, R5D 2, and R5D 3, respectively.

[0338] In embodiments, when R6is substituted, R6is substituted with one or more first substituent groups denoted by R6 1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R6 1substituent group is substituted, the R6 1substituent group is substituted with one or more second substituent groups denoted by R62as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R62substituent group is substituted, the R62substituent group is substituted with one or more third substituent groups denoted by R63as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R6, R6 1, R62, and R63have values corresponding to the values of Rww, RWWJ, Rxv-2. and RWW.3,reSpectiVely, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww-2, and RWW3correspond to R6, R6’, R62, and R63, respectively.

[0339] In embodiments, when R6Ais substituted, R6Ais substituted with one or more first substituent groups denoted by R6A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A 1substituent group is substituted, the R6A 1substituent group is substituted with one or more second substituent groups denoted by R6A2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A2substituent group is substituted, the R6A2substituent group is substituted with one or more third substituent groups denoted by R6A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6A, R6A I. R6A 2, and R6A Jhave values corresponding to the values of Rw, RwwRWW2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRww-2, and RWW 3correspond to R6A, R6A 1, R6A 2, and R6 3, respectively.

[0340] In embodiments, when R6Bis substituted, R6Bis substituted with one or more first substituent groups denoted by R6B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 1substituent group is substituted, the R6B 1substituent group is substituted with one or more second substituent groups denoted by R6B 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R6B 2substituent group is substituted, the R6B 2substituent group is substituted with one or more third substituent groups denoted by R6B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6B, R6B 1, R6B 2, and R6B 3have values corresponding to the values of R"'w, Rww-1, Rww-2, and Rww-3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein Rww, R% W l. Rww-2, and RW3correspond to R6B, R6B l, R6B 2, and R6B 3. respectively.

[0341] In embodiments, when R6Aand R6Bsubstituents 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 R6A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A 1substituent group is substituted, the R6A 1substituent group is substituted with one or more second substituent groups denoted by R6A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A 2substituent group is substituted, the R6A 2substituent group is substituted with one or more third substituent groups denoted by R6A 3as explained in the definitions section above in the description of “first substituent group(s)7’. In the above embodiments, R6A 1, R6A 2and R6A 3have values corresponding to the values of RWW 1, RWW.2anj RWW.3, respectively^ as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rw" ', R"W2, and RWW3correspond to R6A I. R6A 2and R6A3, respectively.

[0342] In embodiments, when R6Aand R6Bsubstituents 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 R6B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 1substituent group is substituted, the R6B 1substituent group is substituted with one or more second substituent groups denoted by R6B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 2substituent group is substituted, the R6B 2substituent group is substituted with one or more third substituent groups denoted by R6B 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R6B-1, R6R2, and R6BBhave values corresponding to the values of RWW. I, RWW.2,anj RWW.3,reSpectivety5explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW 1, R% W 2, and RWW3correspond to R6B R6B 2, and R6B 3, respectively.

[0343] In embodiments, when R6Cis substituted, R6Cis substituted with one or more first substituent groups denoted by R6C 1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R6C 1substituent group is substituted, the R6C 1substituent group is substituted with one or more second substituent groups denoted by R6C 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6C 2substituent group is substituted, the R6C 2substituent group is substituted with one or more third substituent groups denoted by R6C 3as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R6C, R6C 1, R6C 2, and R6Q3have values corresponding to the values of R'J". Rw WJ, Rww-2, and Rww'3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww-2, and RWW3correspond to R6C, R6C', R6C 2, and R6 3. respectively.

[0344] In embodiments, when R6Dis substituted, R6Dis substituted with one or more first substituent groups denoted by R6D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6D 1substituent group is substituted, the R6111substituent group is substituted with one or more second substituent groups denoted by R6D 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6D 2substituent group is substituted, the R6D 2substituent group is substituted with one or more third substituent groups denoted by R6D 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6D, R6I ) I. R6D 2, and R6D■’ have values corresponding to the values of Rw, RwwRWW2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwWW.2, and RWW 3correspond to R6D, R6D 1, R6D 2, and R6D 3, respectively.

[0345] In embodiments, when R3and R6substituents 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 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 R32substituent 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 aboveembodiments, R' R3 2, and R3' have values corresponding to the values of RWW 1, Rw" -2, and RW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RwwR0-2, and R"Wcorrespond to R3 1, R32, and R3 3, respectively.

[0346] In embodiments, when R3and R6substituents 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 R6 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6 1substituent group is substituted, the R6 1substituent group is substituted with one or more second substituent groups denoted by R62as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R62substituent group is substituted, the R62substituent group is substituted with one or more third substituent groups denoted by R6'3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6R62, and R6" have 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,ANC| WW.3C0rreSp0nd t0R6 1,62ANC| R63, respectively.

[0347] In embodiments, when R7is substituted, R7is substituted with one or more first substituent groups denoted by R7 1as explained in the definitions section above in the description of “first substituent group(s)7’. In embodiments, when an R7 1substituent group is substituted, the R7 1substituent group is substituted with one or more second substituent groups denoted by R72as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R72substituent group is substituted, the R72substituent group is substituted with one or more third substituent groups denoted by R73as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7, R7 1, R72, and R73have values corresponding to the values of Rww, Rww A, Rww'2, and RWW, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW 2, and RWW3correspond to R7, R7 1, R72, and R73, respectively.

[0348] In embodiments, when R8is substituted, R8is substituted with one or more first substituent groups denoted by R8 1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R8 1substituent group is substituted, the R8 1substituent group is substituted with one or more second substituent groups denoted by R82as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R82substituent group is substituted, the R82substituent group is substituted with one or more third substituent groups denoted by R83as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R8, R8 1, R82, and R83have values corresponding to the values of Rww, RWWJ, Rxv-2.afK| RWW.3,reSpectiVely, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRww-2, and RWW3correspond to R8, R8’, R82, and R83, respectively.

[0349] In embodiments, when R9is substituted, R9is substituted with one or more first substituent groups denoted by R9 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9 1substituent group is substituted, the R9 1substituent group is substituted with one or more second substituent groups denoted by R92as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R92substituent group is substituted, the R92substituent group is substituted with one or more third substituent groups denoted by R93as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9, R9 1, R92, and R93have values corresponding to the values of Rww. Rww A, Rww'2, and Rww'3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRww-2, and RWW 3correspond to R9, R9 1, R92, and R93, respectively.

[0350] In embodiments, when Ring A is substituted, Ring A is substituted with one or more first substituent groups denoted by RA 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RA 1substituent group is substituted, the RA 1substituent group is substituted with one or more second substituent groups denoted by RA2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an RA 2substituent group is substituted, the RA 2substituent group is substituted with one or more third substituent groups denoted by RA 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, Ring A, RA 1, RA2, and RA 3have values corresponding to the values of Rww, Rww A, Rww'2, and Rww'3, respectively, as explained inthe definitions section above in the description of “first substituent group(s)’', wherein Rww, RWW 1, RWW.2,anj j^ww.scorreSpOncito Ring A, RA 1, RA2, and RA3, respectively.

[0351] In embodiments, when Ring B is substituted, Ring B is substituted with one or more first substituent groups denoted by RB 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB 1substituent group is substituted, the RB 1substituent group is substituted with one or more second substituent groups denoted by RB 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB 2substituent group is substituted, the RB 2substituent group is substituted with one or more third substituent groups denoted by RB 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, Ring B, RB, RB 2, and RB 3have values corresponding to the values of Rww, RWW 1, Rww-2, and RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRWW-2, and RWW 3correspond to Ring B, RB-1, RB 2, and RB 3, respectively.

[0352] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

[0353] In embodiments, the R9-caPeptide includes the amino acid sequence QLGIPEQEYSC (residues 125-135 of SEQ ID NO: 1), VEQLGIPEQEY (residues 123-133 of SEQ ID NO: 1), LGIPEQEYSCVVK (residues 126-138 of SEQ ID NO: 1), LGIPEQEYSCVVKMPSG (residues 126-142 of SEQ ID NO: 1), EQLGIPEQEY (residues 124-133 of SEQ ID NO: 1), QLGIPEQEY (residues 125-133 of SEQ ID NO: 1).LGIPEQEYSCVVKMPS (residues 126-141 of SEQ ID NO: 1), LGIPEQEYSCVVKMP (residues 126-140 of SEQ ID NO: 1), LGIPEQEYSCVVKM (residues 126-139 of SEQ ID NO: 1), LGIPEQEYSCVV (residues 126-137 of SEQ ID NO: 1), LGIPEQEYSCV (residues 126-136 of SEQ ID NO: 1), LGIPEQEYSC (residues 126-135 of SEQ ID NO: 1), QLGIPEQEYSC (residues 125-135 of SEQ ID NO: 1), or LGIPEQEYS (residues 126-134 of SEQ ID NO: 1). In embodiments, the R9-caPeptide includes the amino acid sequence LGIPEQEY (residues 126-133 of SEQ ID NO: 1), LAIPEQEY (SEQ ID NO: 2), LGIAEQEY (SEQ ID NO: 3), LGIPAQEY (SEQ ID NO: 4), LGIPEAEY (SEQ ID NO: 5), LGIPEQAY (SEQ ID NO: 6), LGIAEAEY (SEQ ID NO: 7), LGIPEAAY (SEQ ID NO: 8), LGIAEQAY (SEQ ID NO: 9), or LGIAEAAY (SEQ ID NO: 10). In embodiments, the R9-caPeptide includes the amino acid sequence LGIPEQEY (residues 126-133 of SEQ ID NO: 1). In embodiments, the R9-caPeptide includes an N-terminal modification. In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIPEQEY (SEQ ID NO: 11). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCAGIPEQEY (SEQ ID NO: 12). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLAI PEQEY (SEQ ID NO: 13). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGAPEQEY (SEQ ID NO: 14). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIAEQEY (SEQ ID NO: 15). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIPAQEY (SEQ ID NO: 16). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIPEAEY (SEQ ID NO: 17). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIPEQAY (SEQ ID NO: 18). In embodiments, the R9-caPeptide includes the amino acid sequence RRRRRRRRRCCLGIPEQEA (SEQ ID NO: 19). In embodiments, the R9-caPeptide is as described in WO 2010 / 011890 and WO 2011 / 044374, which are incorporated herein by reference in their entirety for all purposes.

[0354] In embodiments, the R9-caPeptide includes an amino acid sequence of a region that is similar to a portion of PCNA or of a PCNA homolog. In embodiments, the R9-caPeptide includes an amino acid sequence of a region that is identical to a portion of PCNA or of a PCNA homolog. In embodiments, the R9-caPeptide includes at least one chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group. A chemical modification includes adding chemical moieties, creating new bonds, and removing chemical moieties. Modifications at amino acid side groups include acylation of lysine, e-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine. Modifications of the terminal amino include the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications, wherein a lower alkyl is a C1-C4 alkyl. In embodiments, one or more side groups, or terminal groups, may be protected by protective groups known to a person havingordinary skill in the art. In embodiments, the a-carbon of an amino acid is mono-or dimethylated.

[0355] A person having ordinary skill in the art will recognize that peptides may be substantially similar to the peptides described above in that an amino acid residue may be substituted with another amino acid residue having a similar side chain without substantially affecting the inhibitory functions of the peptide variants disclosed herein. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. In embodiments, conservative amino acid substitution groups include: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine. Thus, the peptide inhibitors disclosed herein may have one or more conservative amino acid substitutions without substantially affecting the inhibitory functions of the peptide.

[0356] Non-naturally occurring variants of the caPCNA-derived peptides can readily be generated using recombinant techniques or chemically synthesized. Such variants include, but are not limited to deletions, additions and substitutions in the amino acid sequence of the disclosed peptides. For example, one class of substitutions is conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in the disclosed caPCNA-derived peptides by another amino acid of like characteristics. Typically accepted as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Vai, and Leu; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gin; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr.III. Pharmaceutical compositions

[0357] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0358] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. In embodiments, the compound is a compound of formula (I), (II), (III), (Illa), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), or (VIb), including embodiments thereof.

[0359] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0360] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component (e.g., a compound provided herein). In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% to 70% of the active compound.

[0361] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0362] Dragees cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.

[0363] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0364] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0365] When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampules are convenient unit dosages. The compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the present invention are well-known to those of skill in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are hereby incorporated by reference.

[0366] Aqueous solutions suitable for oral use can be prepared by dissolving the active component (e.g., compounds described herein) in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g.. lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one ormore preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0367] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0368] Oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto. J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsify ing agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.IV. Embodiments

[0369] Embodiment Pl. A method of treating an RNA viral infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an R9-caPeptide; wherein the compound of formula (I) has the formula:R2R6R3(I); whereinL1is -0-, -NR7-, -S-, -C(0)-, -C(0)0-, -0C(0)-, -NR7C(O)-, -C(O)NR7-. -NR7C(O)NR8-, -NR7S(O)2O-, -OS(O)2NR7-. -NR7S(O)2-, -S(O)2NR7-, -S(0)-, -S(0)2-, -0S(0)20-, -S(0)20-, -0S(0)2-, -P(O)(OR7)-, -OP(O)(OR7)O-, -OP(O)(OR7)-, -P(O)(OR7)O-, or -CR8R9-;R7, R8, and R9are independently hydrogen, halogen, -OH, -N3, or substituted 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, -CX1?, -CHX^, -CH2X'. -OCX13, -OCHX1?,-OCH2X1, -CN, -SOniR1D, -SOv1NR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)mi, -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; 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, -CX3s, -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(0)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C,-C(O)NR6AR6B, -0R6D, -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;zl is an integer from 0 to 4;ml, m6, vl, and v6 are independently 1 or 2;nl 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; andn is an integer from 0 to 10.

[0370] Embodiment P2. The method of embodiment Pl, wherein the RNA viral infection is a SARS-CoV-2 infection.

[0371] Embodiment P3. The method of embodiment Pl, wherein the RNA viral infection is an HIV infection.

[0372] Embodiment P4. The method of embodiment Pl, wherein the RNA viral infection is an influenza infection.1

[0373] Embodiment P5. The method of embodiment Pl. wherein the RNA viral infection is a parainfluenza infection.

[0374] Embodiment P6. The method of embodiment Pl, wherein the RNA viral infection is a respiratory syncytial virus infection.

[0375] Embodiment P7. The method of embodiment Pl, wherein the RNA viral infection is a hantavirus.

[0376] Embodiment P8. The method of one of embodiments Pl to P7, wherein the compound has the formula:(11); whereinRing A is phenyl or 5 to 6 membered heteroaryl;Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl;R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX63, -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 unsubstitutedcycloalkyl, 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 may optionally 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; andX4and X5are independently -Cl, -Br, -I, or -F.

[0377] Embodiment P9. The method of embodiment P8, wherein the compound has the formula:(III).

[0378] Embodiment PIO. The method of embodiment P8, wherein the compound has the formula:(Illa).

[0379] Embodiment P 11. The method of embodiment P8. wherein the compound has the formula:(nib).

[0380] Embodiment Pl 2. The method of embodiment P8, wherein the compound has the formula:

[0381] Embodiment Pl 3. The method of embodiment P8, wherein the compound has the formula:zRix R2R6O(R4)Z4- t A 5(V).

[0382] Embodiment Pl 4. The method of embodiment P8, wherein the compound has the formula:- ^L1R(VI)

[0383] Embodiment Pl 5. The method of one of embodiments Pl to P14, wherein 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-; andR8and R9are independently halogen or unsubstituted methyl.

[0384] Embodiment P 16. The method of one of embodiments Pl to P14, wherein L1is -O-.

[0385] Embodiment P 17. The method of one of embodiments P 1 to P 14. wherein L1is -S-.

[0386] Embodiment P18. The method of one of embodiments Pl to P14, wherein L1is -S(O)2-.

[0387] Embodiment P 19. The method of one of embodiments Pl to Pl 8, wherein R1is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2. -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

[0388] Embodiment P20. The method of one of embodiments Pl to Pl 8, 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-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0389] Embodiment P21. The method of one of embodiments Pl to Pl 8, wherein R1is independently halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0390] Embodiment P22. The method of one of embodiments Pl to Pl 8, wherein R1is independently halogen, -OH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.

[0391] Embodiment P23. The method of one of embodiments Pl to P22, wherein zl is 1.

[0392] Embodiment P24. The method of one of embodiments Pl to Pl 8, wherein zl is 0.

[0393] Embodiment P25. The method of one of embodiments Pl to P24, wherein R2is hydrogen, -CX23, -CHX22, -CH2X2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0394] Embodiment P26. The method of one of embodiments Pl to P24, wherein R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

[0395] Embodiment P27. The method of one of embodiments Pl to P24, wherein R2is hydrogen.

[0396] Embodiment P28. The method of one of embodiments Pl to P27, wherein R3is hydrogen, -CX3?, -CHX32. -CH2X3, -CN, -C(O)H, -C(O)OH, -C(O)NH2. substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0397] Embodiment P29. The method of one of embodiments P 1 to P27. wherein R3is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

[0398] Embodiment P30. The method of one of embodiments Pl to P27, wherein R3is hydrogen.

[0399] Embodiment P31. The method of one of embodiments Pl to P30, wherein R6is hydrogen, halogen. -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-Cs cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted Cg-Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

[0400] Embodiment P32. The method of one of embodiments Pl to P30, wherein R6is substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0401] Embodiment P33. The method of one of embodiments Pl to P30, wherein R6is

[0402] Embodiment P34. The method of one of embodiments Pl to P27, wherein R3and R6are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0403] Embodiment P35. The method of one of embodiments Pl to P27, wherein R3and R6are joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

[0404] Embodiment P36. The method of one of embodiments Pl to P27, wherein R3and R6are joined to form an unsubstituted pyrrolidinyl.

[0405] Embodiment P37. The method of one of embodiments Pl to P27, wherein R3and R6are joined to form an unsubstituted piperidinyl.

[0406] Embodiment P38. The method of one of embodiments P8 to P37, wherein R4is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs 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-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

[0407] Embodiment P39. The method of one of embodiments P8 to P37, wherein R4is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4alkyl, 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.

[0408] Embodiment P40. The method of one of embodiments P8 to P37. wherein R4is independently halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0409] Embodiment P41. T...

Claims

1. WHAT IS CLAIMED IS:

1. A method of treating an RNA viral infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an R9-caPeptide;wherein the compound of formula (I) has the formula:' (I); wherein 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-;R7, R8, and R9are independently hydrogen, halogen. -OH, -N3, or substituted 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, -CX^, -CHX1^ -CH2X -OCX^, -OCHX1^ -OCI LX1. -CN, -SOniR1D, -S0V1NR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NHC(O)NR1CNR1AR1B, -NR1CC(O)NR1AR1B, -N(O)mi, -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: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;RIARIBRicRIDR6AR6B^R6CanjR6Dare Inc[epenc|en(|y hydrogen, halogen, -CX3, -CHX2, -CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyd, 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 heteroarvl;zl is an integer from 0 to 4;ml, m6, vl, and v6 are independently 1 or 2;nl 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; andn is an integer from 0 to 10.

2. The method of claim 1. wherein the RNA viral infection is a SARS- CoV-2 infection.

3. The method of claim 1, wherein the RNA viral infection is an HIV infection.

4. The method of claim 1, wherein the RNA viral infection is an influenza infection.

5. The method of claim 1, wherein the RNA viral infection is a parainfluenza infection.

6. The method of claim 1. wherein the RNA viral infection is a respiratory syncytial virus infection.

7. The method of claim 1, wherein the RNA viral infection is a hantavirus.

8. The method of any one of claims 1 to 7, wherein the compound has the formula:Ring A is phenyl or 5 to 6 membered heteroaryl;Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl;R4is independently a halogen, -CX43, -CHX42, -CH2X4, -OCX'S, -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 joinedto form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R5is independently a halogen, -CX5.. -CHX52, -CH2X5, -OCX5?, -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 alkyd, 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 may optionally 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; andX4and X5are independently -Cl, -Br, -I, or -F.

9. The method of claim 8, wherein the compound has the formula:(III).

10. The method of claim 8. wherein the compound has the formula:(Illa).

11. The method of claim 8, wherein the compound has the formula:(Illb).

12. The method of claim 8, wherein the compound has the formula:

13. The method of claim 8, wherein the compound has the formula:

14. The method of claim 8, wherein the compound has the formula:(VI).

15. The method of any one of claims 1 to 7, wherein 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-; andR8and R9are independently halogen or unsubstituted methyl.

16. The method of any one of claims 1 to 7, wherein L1is -O-.

17. The method of any one of claims 1 to 7, wherein L1is -S-.

18. The method of any one of claims 1 to 7, wherein L1is -S(O)2-.

19. The method of any one of claims 1 to 7, wherein R1is independently halogen, -CF3, -CHF2. -CH2F, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-Cs cycloalkyd, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted Cd-Cio aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

20. The method of any one of claims 1 to 7, 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-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

21. The method of any one of claims 1 to 7, wherein R1is independently halogen, -CF3, -CHF2, -CH2F, -OCF?, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted Ci-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

22. The method of any one of claims 1 to 7, wherein R1is independently halogen, -OH, -CF3, -CHF2, -CH2F, -OCF?, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.

23. The method of any one of claims 1 to 7, wherein zl is 1.

24. The method of any one of claims 1 to 7, wherein zl is 0.

25. The method of any one of claims 1 to 7, wherein R2is hydrogen, -CX23, -CHX22, -CH2X2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-Ce cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

26. The method of any one of claims 1 to 7, wherein R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

27. The method of any one of claims 1 to 7, wherein R2is hydrogen.

28. The method of any one of claims 1 to 7, wherein R3is hydrogen, -CX33, -CHX32, -CH2X3, -CN. -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted Ci-Cg 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.

29. The method of any one of claims 1 to 7, wherein R3is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

30. The method of any one of claims 1 to 7, wherein R3is hydrogen.

31. The method of any one of claims 1 to 7, wherein R6is hydrogen, halogen, -CF3, -CHF2. -CH2F, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -OCF?, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyd, 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.

32. The method of any one of claims 1 to 7, wherein R6is substituted or unsubstituted Ci-Ce alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

33. The method of any one of claims 1 to 7, wherein R6is hydrogen,unsubstituted methyl, unsubstituted isopropyl.

34. The method of any one of claims 1 to 7, wherein R3and R6are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

35. The method of any one of claims 1 to 7, wherein R3and R6are joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

36. The method of any one of claims 1 to 7, wherein R3and R6are joined to form an unsubstituted pyrrolidinyl.

37. The method of any one of claims 1 to 7, wherein R3and R6are joined to form an unsubstituted piperidinyl.

38. The method of claim 8. wherein R4is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs 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.

39. The method of claim 8, 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.

40. The method of claim 8, wherein R4is independently halogen, -CF3, -CHF2, -CH2F, -OCFs, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

41. The method of claim 8. wherein R4is independently halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, or unsubstituted methoxy.

42. The method of claim 8. wherein R4is independently -OR4D.

43. The method of claim 42, wherein R4Dis hydrogen or substituted or unsubstituted alkyl.

44. The method of claim 42, wherein R4Dis hydrogen or unsubstituted alkyd.

45. The method of claim 42, wherein R4Dis hydrogen or unsubstituted Ci-C5 alkyl.

46. The method of claim 42, wherein R4Dis hydrogen or unsubstituted methyl.

47. The method of claim 42, wherein R4Dis unsubstituted methyl.

48. The method of claim 8. wherein z4 is 1 or 2.

49. The method of claim 8, wherein z4 is 0.

50. The method of claim 8, wherein R5is independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -0CF3, -OCHF2, -OCH2F, substituted or unsubstituted Ci-Cs alkyd, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyd, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

51. The method of claim 8, wherein R5is independently halogen, -CF3, -CN, -OH, -NH2. -SH, substituted or unsubstituted C1-C4 alkyd, 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.

52. The method of claim 8. wherein R5is independently halogen, -CF3, -CHF2, -CH2F, -OCFs, -OCHF2, -OCH2F, -CN, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted phenyl.

53. The method of claim 8. wherein R5is independently halogen, -CF3, -CHF2, -CH2F, -OCFs, -OCHF2, -OCH2F, -CN, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

54. The method of claim 8. wherein z5 is 1.

55. The method of claim 8, wherein z5 is 0.

56. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted phenyl.

57. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 5 to 6 membered heteroaryl.

58. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted thienyl.

59. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 2 -thienyl.

60. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 3-thienyl.

61. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted pyridyl.

62. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 2-pyridyl.

63. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 3-pyridyl.

64. The method of any one of claims 1 to 7, wherein Ring A is a substituted or unsubstituted 4-pyridyl.

65. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted phenyl.

66. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted naphthyl.

67. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 1 -naphthyl.

68. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 2 -naphthyl.

69. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted quinolinyl.

70. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 2-quinolinyl.

71. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 3-quinolinyl.

72. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 4-quinolinyl.

73. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted isoquinolinyl.

74. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 1 -isoquinolinyl.

75. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 3-isoquinolinyl.

76. The method of any one of claims 1 to 7, wherein Ring B is a substituted or unsubstituted 4-isoquinolinyl.

77. The method of claim 8. wherein the compound has the formula:

78. The method of claim 8, wherein the compound has the formula:

79. The method of claim 8, wherein the compound has the formula:

80. The method of any one of claims 1 to 7, wherein the compound has the formula:

81. The method of any one of claims 1 to 7, wherein the R9-caPeptide comprises the amino acid sequence LGIPEQEY (residues 126-133 of SEQ ID NO: 1).

82. The method of any one of claims 1 to 7, wherein the R9-caPeptide comprises an N-terminal modification.

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