Mpro inhibitors and uses thereof

Abstract

Described herein, inter alia, are Mpro inhibitors and uses thereof.

Description

Mpro INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 662,324 filed June 20, 2024, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048536- 796001WO_Sequence_Listing_ST26.xml; Size: 8,761 bytes; and Date of Creation: June 12, 2025) are hereby incorporated by reference in their entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under U19 AI171110 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0004] The major protease (Mpro, 3CL) of SARS CoV-2 is the target of marketed antiviral agents such as nirmatrelvir and ensitrelvir. Although these agents are effective clinically, they were rushed to market as a stopgap measure during the COVID-19 pandemic and are far from optimal agents. For example, nirmatrelvir is administered clinically in a combination with ritonavir due to its metabolism by CYP3A4 (marketed as Paxlovid). The need for ritonavir is a concern for patients taking other medications that may be cleared by CYP3A4 and moreover results in a clinical regimen that includes 30 pills taken over a 5 day course. Ensitrelvir (Xocova) is a non-peptidic Mpro inhibitor that is administered once daily and dose not require ritonavir. Ensitrelvir was developed by Shinogi and received emergence approval in 2022 from Japanese regulators. It is an investigational agent outside of Japan. This recent clinical experience with Paxlovid and Xocova highlights the limitations of the former and the potential of non-peptidic Mpro inhibitors like ensitrelvir to be developed for the major protease of coronaviruses with pandemic potential. Disclosed herein, inter alia, are solutions to these and other problems in the art.BRIEF SUMMARY

[0005] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0006] The symbolis a single bond or a double bond.

[0007] L1is a bond or unsubstituted C1-C4alkylene.

[0008] Ring A is heteroaryl. Ring B is heterocycloalkyl or heteroaryl.

[0009] R1is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or E. E is an electrophilic moiety.

[0010] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -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] R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B,-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -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 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.

[0013] R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl 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.

[0014] Each X2, X3, and X4is independently –F, -Cl, -Br, or –I. The symbols n2, n3, and n4 are independently an integer from 0 to 4. The symbols m2, m3, m4, v2, v3, and v4 are independently 1 or 2.

[0015] The symbol z3 is an integer from 0 to 6. The symbol z4 is an integer from 0 to 10.

[0016] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In an aspect is provided a method of treating a coronavirus infection in a subject in need thereof, the method including administering to the subject in need thereof atherapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0018] In an aspect is provided a method of reducing the level of activity of an Mpro protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG.1. Protein mass spectra following incubation of recombinant SARS CoV-2 Mpro protein with AVI-4516 (top) or without (bottom) demonstrating formation of a stable covalent adduct of AVI-4516 with Mpro.

[0020] FIG.2. Schematic of residues in the SARS CoV-2 Mpro active site that are in direct contact (Cys145, His163, Glu166, Gly143, and His41) or in proximity to AVI-4692 when bound.

[0021] FIG.3. Biochemical Mpro inhibition (IC50 and Ki values) and other in vitro assay data for AVI-4773 and AVI-4516.

[0022] FIG.4. Plasma exposure profile and calculated pharmacokinetic parameters for AVI-4516 following a single IV or PO dose in CD-1 mice.

[0023] FIG.5. Biochemical inhibition and selected in vitro ADME and pharmacokinetic data for AVI-4516, AVI-4773, AVI-4694, and AVI-4673.

[0024] FIG.6. Spider plots comparing in vitro ADME properties of AVI-4516 and nirmatrelvir. Cell-based antiviral data for two WA1 wt and WA1 FQF strains of SARS CoV- 2.

[0025] FIGS.7A-7C. FIG.7A: Oral administration of SARS-CoV-2 Mproinhibitors reduces virus replication. Experimental outline: Wild-type mice were intranasally infected with 103plaque-forming units of the SARS-CoV-2 Beta variant. Infected animals received oral doses (BID) of either a vehicle, nirmatrelvir (300 mpk), or AVI-4516 (100 mpk). Lung tissues were collected and processed for analysis at 2, 4, and 7 days post-infection (d.p.i.) (n=5 per group per time point). At these time points, a subset of mice from each group was euthanized for plaque assay, while the left lung lobe was collected for histology and omics studies. Viral load analysis: Graphs showing the number of mature virus particles in the lungs of infected mice at the specified time points. Data are presented as mean ± s.e.m. andwere analyzed using a two-tailed unpaired Student’s t-test. Each dot represents the infectious virus titer in individual mice. FIG.7B: Dose-response study. Another group of mice were infected with the SARS-CoV-2 Beta variant and treated with varying concentrations of AVI- 4516. Virus titers were measured at 2 d.p.i. Graphs showing the number of mature virus particles in the lungs of infected mice at the specified dose of treatment. Data are presented as mean ± s.e.m. and were analyzed using a two-tailed unpaired Student’s t-test. Each dot represents the infectious virus titer in individual mice. IC50values of AVI-4516 was calculated using dose response curve. FIG.7C: Mpro inhibitor treatment shows antiviral efficacy in K18 hACE2 mice. Experimental outline: K18 hACE2 mice were intranasally infected with 103plaque-forming units of the SARS-CoV-2 WA1 variant. Infected animals received oral doses (BID) of either a vehicle, nirmatrelvir (300 mpk), or AVI-4516 (100 mpk). The mice were monitored for disease parameters like body weight loss and hunched posture. Lung tissues were collected and processed for analysis at 7 days post-infection (d.p.i.) (n=5 per group per time point). Results: Graphs representing percent weight loss show moderate weight loss in nirmatrelvir and AVI-4516 treatment groups, whereas vehicle treated mice showed more than 20% body weight loss. The survival curve shows 40% survival in nirmatrelvir and AVI-4516 treatment groups while all animals reached to humane time points in vehicle treatment group.

[0026] FIGS.8A-8B. Biochemical inhibition of Mpro mutants for AVI-4516, AVI-4673, AVI-4773, AVI-4694, and nirmaltrelvir. Assays performed with 50 nM enzyme.

[0027] FIGS.9A-9B. MPro inhibitors have broad SARS-CoV-2 variant antiviral efficacy. Dose-response curves of selected compounds against XBB.1.16 (FIG.9A, top) and Omicron XBB.1.5 (FIG.9A, bottom) and WA.1 (FIG.9B, top) and Omicron EG.5.1 SARS-CoV-2 (FIG.9B, bottom) variants. Briefly, A549-ACE2h cells were pretreated with represented compounds for 2 hours prior infection with mNeon-encoding viruses for 2 h. Viral inoculum was then removed and fresh media with compounds at the indicated concentrations were added. Infection was measured as the mNeon virus-encoded fluorescent intensity with an IncucyteⓇsystem. Infection was normalized. Graph depicts the average results from three independent experiments, each conducted in triplicate, with error bars representing the standard deviation.

[0028] FIG.10. SARS-CoV-1 Mpro 50 nM data.

[0029] FIGS.11A-11B. FIG.11A: Compounds exhibit more potent anti-SARS-CoV-2 activity than nirmatrelvir in a replicon assay in Vero cells stably expressing ACE2 and TMPRSS2. FIG.11B: Top panel: AVI-4692, AVI-4694, and AVI-4773 have higher potency against a nirmatrelvir-resistant FQF mutant replicon in Vero cells stably expressing ACE2 and TMPRSS2, and AVI-4694 is the only compound with sub-micromolar activity. Bottom panel: Compounds exhibit higher potency against a recent SARS-CoV-2 variant BA.2.86.1 replicon, which contains MPro P132H, than nirmatrelvir in a replicon assay in Vero cells stably expressing ACE2 and TMPRSS2.

[0030] FIG.12. Dihyrouracil-based MPro inhibitors are potent inhibitors of SARS-CoV-2 replication. A549-ACE2h cells were pretreated 2 h with test compounds, which were then removed before viral infection WA1 original strain (MOI 0.1). Following a 2-hour infection period, the viral inoculum was removed and fresh compounds were added to the culture medium containing a cell death indicator dye. The infected cells were then monitored continuously for 48 hours using an automated imaging system that captured images every hour, allowing to track both viral replication and cell viability in real-time. EC50 are indicated on the graph.

[0031] FIGS.13A-13B. Only the positive enantiomers of AVI-4773 and 6179 exhibited significant antivial activity in the assay tested. The antiviral activity of AVI-4773, AVI- 6179, in their (M) and (P) enantiomeric forms was evaluated as previously described.

[0032] FIG.14. In vivo assessment of Mpro inhibitor. K18-hACE2 transgenic mice were used to evaluate the protective effect of AVI-4773 against lethal SARS-CoV-2 infection. Following intranasal inoculation with live virus, AVI-4773 was administered twice daily for five consecutive days. On day 7 post-infection, lungs and brains were harvested for plaque assay analysis. Notably, no viral plaques were detected in the brains of mice treated with either Ensitrelvir or AVI-4773. Survival was assessed using a ≥15% loss in body weight as the terminal endpoint. All mice in the vehicle-treated group succumbed to infection, whereas all mice treated with AVI-4773 survived. DETAILED DESCRIPTION I. Definitions

[0033] 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.

[0034] 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-.

[0035] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0036] 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.

[0037] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-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.

[0038] 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 bythe direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0039] 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.

[0040] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0041] 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.

[0042] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0043] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0044] 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.

[0045] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, 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 andheteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0046] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0047] The symbol “ ” denotes the point of attachment of a chemical moiety to theremainder of a molecule or chemical formula.

[0048] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0049] 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:

[0050] 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, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3,-SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0051] 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.

[0052] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0053] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R',-NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0054] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to thefloating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0055] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0056] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' 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.

[0057] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0058] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-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-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-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10aryl, C10aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2,-CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0059] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0060] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- 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 heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0061] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0062] 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 or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0063] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 memberedheteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0064] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted 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).

[0065] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substitutedheteroaryl, 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.

[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 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.

[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 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 plurality of lower substituent groups, each lower substituent group is different.

[0068] 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 aplurality 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.

[0069] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0070] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R1.1, R2may be substituted with one or more first substituent groups denoted by R2.1, R3may be substituted with one or more first substituent groups denoted by R3.1, R4may be substituted with one or more first substituent groups denoted by R4.1, R5may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A.1, R2Amay be substituted with one or more first substituent groups denoted by R2A.1, R3Amay be substituted with one or more first substituent groups denoted by R3A.1, R4Amay be substituted with one or more first substituent groups denoted by R4A.1, R5Amay be substituted with one or more first substituent groups denoted 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.1, R3A.1, R4A.1, R5A.1… R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1… RL100.1) 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.

[0071] 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, which may alternatively be represented herein as RWW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0072] Thus, as used herein, RWWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWWis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituentgroup 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:

[0073] RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-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, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1is independently –F, -Cl, -Br, or –I.

[0074] RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2is independently –F, -Cl, -Br, or –I.

[0075] RWW.3is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.33, -OCH2XWW.3, -OCHXWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3is independently –F, -Cl, -Br, or –I.

[0076] 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.3. Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100B.1, RWW.2is R100B.2, and RWW.3is R100B.3. RWW.1, RWW.2and RWW.3in this paragraph are as defined in the preceding paragraphs.

[0077] RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2,–NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1is independently –F, -Cl, -Br, or –I.

[0078] RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted 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 C5-C6), RLWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2,^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2is independently –F, -Cl, -Br, or –I.

[0079] RLWW.3is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3is independently –F, -Cl, -Br, or –I.

[0080] In the event that any R group recited in a claim or chemical formula description set forth herein (RWWsubstituent) is not specifically defined in this disclosure, then that R group (RWWgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). XWWis independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).RWW.1, RWW.2, and RWW.3 are as defined above.

[0081] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWWsubstituent) is not explicitly defined, then that L group (LWWgroup) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2and RLWW.3are as defined above.

[0082] 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.

[0083] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0084] 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.

[0085] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g.,sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., 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-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0091] 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, therebyresulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex.

[0092] 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.

[0093] “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.

[0094] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0095] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, 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.

[0096] A “covalent cysteine modifier moiety” as used herein refers to a subtituent that is capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g., Cys145 of the Mpro protein (e.g., human Mpro, SARS-CoV-2 Mpro protein)) to form a covalent bond. Thus, the covalent cysteine modifier moiety is typically electrophilic.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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. Theparent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0101] 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.

[0102] 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.

[0103] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, such that it is notassociated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0104] “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).

[0105] 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.

[0106] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0107] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset(or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0108] “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).

[0109] “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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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 areduction 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.

[0114] 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.

[0115] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0116] 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.).

[0117] 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.

[0118] “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 examplesinclude humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0119] “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 a coronavirus infection (e.g., a SARS-CoV- 2 infection, a SARS-CoV-1 infection, or a MERS-CoV infection).

[0120] The term “coronavirus infection” is used in accordance with its plain ordinary meaning and refers to an infection caused by a coronavirus, which is an RNA virus. 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. In embodiments, the coronavirus is SARS-CoV-2. In embodiments, the coronavirus is SARS-CoV-1. In embodiments, the coronavirus is MERS-CoV. In embodiments, the coronavirus is human CoV alpha 229E. In embodiments, the coronavirus is human CoV alpha NL63. In embodiments, the coronavirus is human CoV beta HKU1. In embodiments, the coronavirus is human CoV beta OC43. In embodiments, the coronavirus is SARS-CoV-2 Delta. In embodiments, the coronavirus is SARS-CoV-2 Delta B.1.617.2. In embodiments, the coronavirus is SARS-CoV-2 Omicron XBB. In embodiments, the coronavirus is SARS-CoV-2 Omicron XBB.1.16. In embodiments, the coronavirus is SARS-CoV-2 Omicron XBB.1.5. In embodiments, the coronavirus is SARS-CoV-2 Omicron EG.5.1. In embodiments, the coronavirus is SARS- CoV-2 Omicron BA.2. In embodiments, the coronavirus is SARS-CoV-2 Omicron B.1.1.529 BA.2. In embodiments, the coronavirus is SARS-CoV-2 Omicron BQ.1.1. In embodiments, the coronavirus is SARS-CoV-2 Omicron BA.2.86.1. In embodiments, the coronavirus is SARS-CoV-2 WA.1. In embodiments, the coronavirus is SARS-CoV-2 WA.1 MPro L50F / E166Q / L167F. In embodiments, the coronavirus is SARS-CoV-2 WA.1 MPro L50F / E166A / L167F. In embodiments, the coronavirus is SARS-CoV-2 MPro L50F. In embodiments, the coronavirus is SARS-CoV-2 MPro Q192T. In embodiments, thecoronavirus is SARS-CoV-2 MPro A173V. In embodiments, the coronavirus is SARS-CoV- 2 MPro S144A. In embodiments, the coronavirus is SARS-CoV-2 MPro E166Q. In embodiments, the coronavirus is SARS-CoV-2 MPro P168Δ. In embodiments, the coronavirus is SARS-CoV-2 MPro Q192T. In embodiments, the coronavirus is as described in Jochmans, D. et al. mBio 2023, 14:e02815-22, which is herein incorporated by reference in its entirety and for all purposes.

[0121] 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, single- stranded 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.

[0122] 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.

[0123] 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.

[0124] The term “pharmacokinetic enhancer” is used in accordance with its common meaning in the art and refers to a substance used in combination with a therapeutic agent to enhance or restore the activity of the therapeutic agent. In embodiments, the pharmacokinetic enhancer decreases the metabolism of the therapeutic agent relative to absence of the pharmacokinetic enhancer. In embodiments, the pharmacokinetic enhancer is a protease inhibitor. In embodiments, the pharmacokinetic enhancer is a CYP3A inhibitor.

[0125] 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.

[0126] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-1581Gd,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.

[0127] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by asubject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0128] 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.

[0129] 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.

[0130] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations,intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0131] 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.

[0132] 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.

[0133] 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., coronavirus 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 thepatient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0134] 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., coronavirus 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.

[0135] 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.

[0136] 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.

[0137] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0138] 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 isassociated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0139] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0140] 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.

[0141] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0142] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations,fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0143] 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.

[0144] 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 Cys145 of Mpro when the selected residue occupies the same essential spatial or other structural relationship as Cys145 of Mpro. In some embodiments, where a selected protein is aligned for maximum homology with Mpro, the position in the aligned selected protein aligning with Cys145 is said to correspond to Cys145. 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 Mpro and the overall structures compared. In this case, an amino acid that occupies the same essential position as Cys145 in the structural model is said to correspond to the Cys145 residue.

[0145] 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 complexare linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.

[0146] 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.

[0147] The term “Mpro” or “3C-like protease” or “main protease” refers to a protease found in coronaviruses (including homologs, isoforms, and functional fragments thereof). The term includes any recombinant or naturally-occurring form of Mpro variants thereof that maintain Mpro activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Mpro). In embodiments, Mpro is SARS-CoV-2 Mpro. In embodiments, Mpro is SARS-CoV-1 Mpro. In embodiments, Mpro is MERS-CoV Mpro. In embodiments, Mpro is CoV alpha 229E Mpro. In embodiments, Mpro is CoV alpha NL63 Mpro. In embodiments, Mpro is CoV beta HKU1 Mpro. In embodiments, Mpro is CoV beta OC43 Mpro. In embodiments, Mpro is SARS-CoV-2 Delta Mpro. In embodiments, Mpro is SARS-CoV-2 Delta B.1.617.2 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron XBB Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron XBB.1.16 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron XBB.1.5 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron EG.5.1 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron BA.2 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron B.1.1.529 BA.2 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron BQ.1.1 Mpro. In embodiments, Mpro is SARS-CoV-2 Omicron BA.2.86.1 Mpro. In embodiments, Mpro is SARS-CoV-2 WA.1 Mpro. In embodiments, Mpro is SARS-CoV-2 WA.1 MPro L50F / E166Q / L167F. In embodiments, Mpro is SARS- CoV-2 WA.1 MPro L50F / E166A / L167F. In embodiments, Mpro is SARS-CoV-2 MPro L50F. In embodiments, Mpro is SARS-CoV-2 MPro Q192T. In embodiments, Mpro is SARS-CoV-2 MPro A173V. In embodiments, Mpro is SARS-CoV-2 MPro S144A. In embodiments, Mpro is SARS-CoV-2 MPro E166Q. In embodiments, Mpro is SARS-CoV-2 MPro P168Δ. In embodiments, Mpro is SARS-CoV-2 MPro Q192T.

[0148] As used herein, the term “SARS-CoV-2 Mpro” refers to the Mpro protease of SARS-CoV-2. In embodiments, the amino acid sequence or nucleic acid sequence of SARS- CoV-2 Mpro is the sequence known at the time of filing of the present application. In embodiments, the amino acid sequence of SARS-CoV-2 Mpro is:

[0149] As used herein, the term “SARS-CoV-1 Mpro” refers to the Mpro protease of SARS-CoV-1. In embodiments, the amino acid sequence or nucleic acid sequence of SARS- CoV-1 Mpro is the sequence known at the time of filing of the present application. In embodiments, the amino acid sequence of SARS-CoV-1 Mpro is:

[0150] As used herein, the term “MERS-CoV Mpro” refers to the Mpro protease of MERS- CoV. In embodiments, the amino acid sequence or nucleic acid sequence of MERS-CoV Mpro is the sequence known at the time of filing of the present application. In embodiments, the amino acid sequence of MERS-CoV Mpro is:

[0151] As used herein, the term “CoV alpha 229E Mpro” refers to the Mpro protease of CoV alpha 229E. In embodiments, the amino acid sequence or nucleic acid sequence of CoV alpha 229E Mpro is the sequence known at the time of filing of the present application. In embodiments, the amino acid sequence of CoV alpha 229E Mpro is:

[0152] As used herein, the term “CoV beta OC43 Mpro” refers to the Mpro protease of CoV beta OC43. In embodiments, the amino acid sequence or nucleic acid sequence of CoV beta OC43 Mpro is the sequence known at the time of filing of the present application. In embodiments, the amino acid sequence of CoV beta OC43 Mpro is:II. Compounds

[0153] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0154] The symbols a single bond or a double bond.

[0155] L1is a bond or unsubstituted C1-C4 alkylene.

[0156] Ring A is heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0157] Ring B is 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 heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0158] R1is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), or E.

[0159] E is an electrophilic moiety.

[0160] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0161] R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0162] R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0163] R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2Aand R2Bsubstituents 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) orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3Aand R3Bsubstituents 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); R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0164] Each X2, X3, and X4is independently –F, -Cl, -Br, or –I.

[0165] The symbols n2, n3, and n4 are independently an integer from 0 to 4.

[0166] The symbols m2, m3, m4, v2, v3, and v4 are independently 1 or 2.

[0167] The symbol z3 is an integer from 0 to 6.

[0168] The symbol z4 is an integer from 0 to 10.

[0169] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: he symbolis a single bond or a double bond. L1is a bond or unsubstituted C1-C4alkylene. Ring A is heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Ring B is 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 heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R1is hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or E. E is an electrophilic moiety. R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D,-NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2Aand R2Bsubstituents 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); R3Aand R3Bsubstituents 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); R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Each X2, X3, and X4is independently –F, -Cl, -Br, or –I. The symbols n2, n3, and n4 are independently an integer from 0 to 4. The symbols m2, m3, m4, v2, v3, and v4 are independently 1 or 2. The symbol z3 is an integer from 0 to 6. The symbol z4 is an integer from 0 to 10.

[0170] In embodiments, the compound has the formula:Ring A, Ring B,1, R1, R2, R3, z3, R4, and z4 areas described herein, including in embodiments.

[0171] In embodiments, the compound has the formula: Ring A, Ring B, L1, R1, R2, R3, z3, R4, and z4 are asdescribed herein, including in embodiments.

[0172] In embodiments, the compound has the formula: Ring A, Ring B, L1, R1, R2, R3 4, z3, R , and z4 are as described herein, including in embodiments.

[0173] In embodiments, the compound has the formula: Ring A,L1, R1, R2, R3, and z3 are as describedherein, including in embodiments.

[0174] In embodiments, the compound has the formula:Ring A, L1, R1, R2, R3, and z3 are as described herein,including in embodiments.

[0175] In embodiments, the compound has the formula: Ring A, L1, R1, R2, R3, and z3 are as described herein,including in embodiments.

[0176] In embodiments, the compound has the formula: Ring B, R1, R2, R3, z3, R4, and z4 are as described herein,including in embodiments.

[0177] In embodiments, the compound has the formula: R1, R2, R3, z3, ande as described herein, including inembodiments.

[0178] In embodiments, the compound has the formula: R1, R2, R3, and z3 are as described herein, including inembodiments.

[0179] In embodiments, the compound has the formula: R1, R2, R3, and z3 are as described herein, including inembodiments.

[0180] In embodiments, the compound has the formula:R1, R2, R3, z3, andre as described herein, including in embodiments.

[0181] In embodiments, the compound has the formula: R1, R2, R3, and z3 are as described herein, including inembodiments.

[0182] In embodiments, the compound has the formula: R1, R2, R3, and z3 are as described herein, including inembodiments.

[0183] In embodiments, the compound has the formula:Ring B, R1, R2, R3, z3, R4, and z4 are as described herein, including in embodiments.

[0184] In embodiments,is a single bond. In embodiments,a double bond.

[0185] In embodiments, L1is a bond. In embodiments, L1is unsubstituted C1-C4alkylene. In embodiments, L1is unsubstituted methylene. In embodiments, L1is unsubstituted ethylene. In embodiments, L1is unsubstituted propylene. In embodiments, L1is unsubstituted n-propylene. In embodiments, L1is unsubstituted isopropylene. In embodiments, L1is unsubstituted butylene. In embodiments, L1is unsubstituted n-butylene. In embodiments, L1is unsubstituted isobutylene. In embodiments, L1is unsubstituted tert- butylene.

[0186] In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments, Ring A is isoquinolinyl. In embodiments, Ring A is pyridonyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyridazinyl. In embodiments, Ring A is benzisoxazolyl.

[0187] In embodiments,embodiments, (R In embodiments,embodiments,embodiments,In embodiments,

[0188] In embodiments,n embodiments,In embodiments,embodiments,n embodiments,In embodiments,embodiments,In embodiments,In embodiments,embodiments, In embodiments,In embodiments, n embodiments,n embodiments,. In embodiments,embodiments, In embodiments,

[0189] In embodiments, Ring B is 3 to 8 membered heterocycloalkyl or 5 to 10 membered heteroaryl. In embodiments, Ring B is 3 to 8 membered heterocycloalkyl. In embodiments, Ring B is 5 to 10 membered heteroaryl. In embodiments, Ring B is benzotriazolyl. In embodiments, Ring B is triazolyl. In embodiments, Ring B is tetrazolyl. In embodiments, Ring B is pyrazolyl. In embodiments, Ring B is pyrrolidinyl. In embodiments, Ring B is pyridyl. In embodiments, Ring B is pyrimidinyl. In embodiments, Ring B is indazolyl. In embodiments, Ring B is isoindoline-1,3-dionyl.

[0190] In embodiments,isn embodiments,In embodiments,embodiments,n embodiments,. In embodiments, . In embodiments,n embodiments,embodiments,is . In embodiments,embodiments,n embodiments,

[0191] In embodiments,n embodiments,In embodiments,embodiments,is . In embodiments,is In embodiments, n embodiments,In embodiments,is . In embodiments, n embodiments,. In embodiments,s . In embodiments,In embodiments,n embodiments,n embodiments,In embodiments,embodiments,n embodiments,s . In embodiments,n embodiments,In embodiments, In embodiments,In embodiments,In embodiments,s. In embodiments,is . In embodiments,In embodiments,embodiments,n embodiments,. n embodiments,is . In embodiments,In embodiments,In embodiments,n embodiments,In embodiments, n embodiments,In embodiments,embodiments,

[0192] In embodiments, a substituted R1(e.g., substituted alkyl, substituted cycloalkyl, and / or substituted heterocycloalkyl) 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.

[0193] In embodiments, R1is hydrogen, substituted or unsubstituted alkyl, or E.

[0194] In embodiments, R1is hydrogen. In embodiments, R1is substituted or unsubstituted C1-C4alkyl. In embodiments, R1is unsubstituted C1-C4alkyl. In embodiments, R1is unsubstituted methyl. In embodiments, R1is unsubstituted ethyl. In embodiments, R1is unsubstituted propyl. In embodiments, R1is unsubstituted n-propyl. In embodiments, R1is unsubstituted isopropyl. In embodiments, R1is unsubstituted butyl. In embodiments, R1is unsubstituted n-butyl. In embodiments, R1is unsubstituted isobutyl. In embodiments, R1is unsubstituted tert-butyl. In embodiments, R1is unsubstituted C2-C4 alkynyl. In embodiments, R1is unsubstituted ethynyl. In embodiments, R1is unsubstituted propynyl. In embodiments, R1is unsubstituted butynyl. In embodiments, R1isembodiments, R1is In embodiments, R1is n embodiments, R1is. In embodiments, R1is

[0195] In embodiments, R1is substituted C1-C4alkyl. In embodiments, R1is C1-C4alkyl substituted with –CN. In embodiments, R1isn embodiments, R1is In embodiments, R1is1n embodiments, R isembodiments, R1isIn embodiments, R1is C1-C4 alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1is C1-C4 alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted thienyl. In embodiments, R1isn embodiments, R1is n embodimen1ts, R is. embodiments, R1is. In embodiments, R1isembodiments, R1is1n embodiments, R isn embodiments, R1is1In embodiments, R is

[0196] In embodiments, R1is substituted or unsubstituted C3-C8cycloalkyl. In embodiments, R1is substituted C3-C8cycloalkyl. In embodiments, R1is nembodiments, R1isIn embodiments, R1is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R1is substituted 3 to 8 membered heterocycloalkyl. In embodiments, R1is n embodiments, R1is

[0197] In embodiments, R1is E, wherein E is an electrophilic moiety. In embodiments, E is a covalent cysteine modifier moiety.

[0198] In embodiments, E is:In embodiments, E is:

[0199] R5, R6, R7, and R8are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0200] X5is –F, -Cl, -Br, or –I.

[0201] In embodiments, E isn embodiments, E isembodiments, E isIn embodiments, E isembodiments, E isIn embodiments, E is. In embodiments, E isIn embodiments, E is

[0202] 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.

[0203] In embodiments, R5is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl(e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0204] In embodiments, R5is hydrogen. In embodiments, R5is halogen. In embodiments, R5is –F. In embodiments, R5is –Cl. In embodiments, R5is –Br. In embodiments, R5is –I. In embodiments, R5is -CCl3. In embodiments, R5is -CBr3. In embodiments, R5is -CF3. In embodiments, R5is -CI3. In embodiments, R5is -CH2Cl. In embodiments, R5is -CH2Br. In embodiments, R5is -CH2F. In embodiments, R5is -CH2I. In embodiments, R5is -CHCl2. In embodiments, R5is -CHBr2. In embodiments, R5is -CHF2. In embodiments, R5is -CHI2. In embodiments, R5is –CN. In embodiments, R5is –OH. In embodiments, R5is -NH2. In embodiments, R5is –COOH. In embodiments, R5is -CONH2. In embodiments, R5is -NO2. In embodiments, R5is –SH. In embodiments, R5is -SO3H. In embodiments, R5is -OSO3H. In embodiments, R5is -SO2NH2. In embodiments, R5is ^NHNH2. In embodiments, R5is ^ONH2. In embodiments, R5is ^NHC(O)NH2. In embodiments, R5is -NHSO2H. In embodiments, R5is -NHC(O)H. In embodiments, R5is -NHC(O)OH. In embodiments, R5is –NHOH. In embodiments, R5is -OCCl3. In embodiments, R5is -OCBr3. In embodiments, R5is -OCF3. In embodiments, R5is -OCI3. In embodiments, R5is -OCH2Cl. In embodiments, R5is -OCH2Br. In embodiments, R5is -OCH2F. In embodiments, R5is -OCH2I. In embodiments, R5is -OCHCl2. In embodiments, R5is -OCHBr2. In embodiments, R5is -OCHF2. In embodiments, R5is -OCHI2. In embodiments, R5is unsubstituted C1-C4 alkyl. In embodiments, R5is unsubstituted methyl. In embodiments, R5is unsubstituted ethyl. In embodiments, R5is unsubstituted propyl. In embodiments, R5is unsubstituted n-propyl. In embodiments, R5is unsubstituted isopropyl. In embodiments, R5is unsubstituted butyl. In embodiments, R5is unsubstituted n-butyl. In embodiments, R5is unsubstituted isobutyl. In embodiments, R5is unsubstituted tert-butyl.

[0205] 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, orlower 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.

[0206] In embodiments, R6is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0207] In embodiments, R6is hydrogen. In embodiments, R6is halogen. In embodiments, R6is –F. In embodiments, R6is –Cl. In embodiments, R6is –Br. In embodiments, R6is –I. In embodiments, R6is -CCl3. In embodiments, R6is -CBr3. In embodiments, R6is -CF3. In embodiments, R6is -CI3. In embodiments, R6is -CH2Cl. In embodiments, R6is -CH2Br. In embodiments, R6is -CH2F. In embodiments, R6is -CH2I. In embodiments, R6is -CHCl2. In embodiments, R6is -CHBr2. In embodiments, R6is -CHF2. In embodiments, R6is -CHI2. In embodiments, R6is –CN. In embodiments, R6is –OH. In embodiments, R6is -NH2. In embodiments, R6is –COOH. In embodiments, R6is -CONH2. In embodiments, R6is -NO2. In embodiments, R6is –SH. In embodiments, R6is -SO3H. In embodiments, R6is -OSO3H. In embodiments, R6is -SO2NH2. In embodiments, R6is ^NHNH2. In embodiments, R6is ^ONH2. In embodiments, R6is ^NHC(O)NH2. In embodiments, R6is -NHSO2H. In embodiments, R6is -NHC(O)H. In embodiments, R6is -NHC(O)OH. In embodiments, R6is –NHOH. In embodiments, R6is -OCCl3. In embodiments, R6is -OCBr3. In embodiments,R6is -OCF3. In embodiments, R6is -OCI3. In embodiments, R6is -OCH2Cl. In embodiments, R6is -OCH2Br. In embodiments, R6is -OCH2F. In embodiments, R6is -OCH2I. In embodiments, R6is -OCHCl2. In embodiments, R6is -OCHBr2. In embodiments, R6is -OCHF2. In embodiments, R6is -OCHI2. In embodiments, R6is unsubstituted C1-C4alkyl. 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.

[0208] In embodiments, a substituted R7(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 R7is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0209] In embodiments, R7is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0210] 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 -CCl3. In embodiments, R7is -CBr3. In embodiments, R7is -CF3. In embodiments, R7is -CI3. In embodiments, R7is -CH2Cl. In embodiments, R7is -CH2Br. In embodiments, R7is -CH2F. In embodiments, R7is -CH2I. In embodiments, R7is -CHCl2. In embodiments, R7is -CHBr2. In embodiments, R7is -CHF2. In embodiments, R7is -CHI2. In embodiments, R7is –CN. In embodiments, R7is –OH. In embodiments, R7is -NH2. In embodiments, R7is –COOH. In embodiments, R7is -CONH2. In embodiments, R7is -NO2. In embodiments, R7is –SH. In embodiments, R7is -SO3H. In embodiments, R7is -OSO3H. In embodiments, R7is -SO2NH2. In embodiments, R7is ^NHNH2. In embodiments, R7is ^ONH2. In embodiments, R7is ^NHC(O)NH2. In embodiments, R7is -NHSO2H. In embodiments, R7is -NHC(O)H. In embodiments, R7is -NHC(O)OH. In embodiments, R7is –NHOH. In embodiments, R7is -OCCl3. In embodiments, R7is -OCBr3. In embodiments, R7is -OCF3. In embodiments, R7is -OCI3. In embodiments, R7is -OCH2Cl. In embodiments, R7is -OCH2Br. In embodiments, R7is -OCH2F. In embodiments, R7is -OCH2I. In embodiments, R7is -OCHCl2. In embodiments, R7is -OCHBr2. In embodiments, R7is -OCHF2. In embodiments, R7is -OCHI2. In embodiments, R7is unsubstituted C1-C4alkyl. 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.

[0211] In embodiments, a substituted R8(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 R8is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, R8is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0213] 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 -CCl3. In embodiments, R8is -CBr3. In embodiments, R8is -CF3. In embodiments, R8is -CI3. In embodiments, R8is -CH2Cl. In embodiments, R8is -CH2Br. In embodiments, R8is -CH2F. In embodiments, R8is -CH2I. In embodiments, R8is -CHCl2. In embodiments, R8is -CHBr2. In embodiments, R8is -CHF2. In embodiments, R8is -CHI2. In embodiments, R8is –CN. In embodiments, R8is –OH. In embodiments, R8is -NH2. In embodiments, R8is –COOH. In embodiments, R8is -CONH2. In embodiments, R8is -NO2. In embodiments, R8is –SH. In embodiments, R8is -SO3H. In embodiments, R8is -OSO3H. In embodiments, R8is -SO2NH2. In embodiments, R8is ^NHNH2. In embodiments, R8is ^ONH2. In embodiments, R8is ^NHC(O)NH2. In embodiments, R8is -NHSO2H. In embodiments, R8is -NHC(O)H. In embodiments, R8is -NHC(O)OH. In embodiments, R8is –NHOH. In embodiments, R8is -OCCl3. In embodiments, R8is -OCBr3. In embodiments, R8is -OCF3. In embodiments, R8is -OCI3. In embodiments, R8is -OCH2Cl. In embodiments, R8is -OCH2Br. In embodiments, R8is -OCH2F. In embodiments, R8is -OCH2I. In embodiments, R8is -OCHCl2. In embodiments, R8is -OCHBr2. In embodiments, R8is -OCHF2. In embodiments, R8is -OCHI2. 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.

[0214] In embodiments, R5, R6, R7, and R8are hydrogen.

[0215] In embodiments, X5is –F. In embodiments, X5is -Cl. In embodiments, X5is -Br. In embodiments, X5is –I.

[0216] In embodiments, E isn embodiments, E isembodiments, E isIn embodiments, E isembodiments, E isIn embodiments, E isn embodiments, E isembodiments, E isIn embodiments, E is

[0217] 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.

[0218] In embodiments, a substituted R2A(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 R2Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowersubstituent group may optionally be different. In embodiments, when R2Ais substituted, it is substituted with at least one substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one lower substituent group.

[0219] In embodiments, a substituted R2B(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 R2Bis 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 R2Bis substituted, it is substituted with at least one substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one lower substituent group.

[0220] In embodiments, a substituted ring formed when R2Aand R2Bsubstituents 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 R2Aand R2Bsubstituents 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 R2Aand R2Bsubstituents 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 R2Aand R2Bsubstituents 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 R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0221] In embodiments, a substituted R2C(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 R2Cis substituted with a plurality ofgroups 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 R2Cis substituted, it is substituted with at least one substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one lower substituent group.

[0222] In embodiments, a substituted R2D(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 R2Dis 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 R2Dis substituted, it is substituted with at least one substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one lower substituent group.

[0223] In embodiments, R2Ais hydrogen. In embodiments, R2Ais unsubstituted C1-C4alkyl. In embodiments, R2Ais unsubstituted methyl. In embodiments, R2Ais unsubstituted ethyl. In embodiments, R2Ais unsubstituted propyl. In embodiments, R2Ais unsubstituted n- propyl. In embodiments, R2Ais unsubstituted isopropyl. In embodiments, R2Ais unsubstituted butyl. In embodiments, R2Ais unsubstituted n-butyl. In embodiments, R2Ais unsubstituted isobutyl. In embodiments, R2Ais unsubstituted tert-butyl.

[0224] In embodiments, R2Bis hydrogen. In embodiments, R2Bis unsubstituted C1-C4 alkyl. In embodiments, R2Bis unsubstituted methyl. In embodiments, R2Bis unsubstituted ethyl. In embodiments, R2Bis unsubstituted propyl. In embodiments, R2Bis unsubstituted n- propyl. In embodiments, R2Bis unsubstituted isopropyl. In embodiments, R2Bis unsubstituted butyl. In embodiments, R2Bis unsubstituted n-butyl. In embodiments, R2Bis unsubstituted isobutyl. In embodiments, R2Bis unsubstituted tert-butyl.

[0225] In embodiments, R2Cis hydrogen. In embodiments, R2Cis unsubstituted C1-C4alkyl. In embodiments, R2Cis unsubstituted methyl. In embodiments, R2Cis unsubstituted ethyl. In embodiments, R2Cis unsubstituted propyl. In embodiments, R2Cis unsubstituted n- propyl. In embodiments, R2Cis unsubstituted isopropyl. In embodiments, R2Cisunsubstituted butyl. In embodiments, R2Cis unsubstituted n-butyl. In embodiments, R2Cis unsubstituted isobutyl. In embodiments, R2Cis unsubstituted tert-butyl.

[0226] In embodiments, R2Dis hydrogen. In embodiments, R2Dis unsubstituted C1-C4 alkyl. In embodiments, R2Dis unsubstituted methyl. In embodiments, R2Dis unsubstituted ethyl. In embodiments, R2Dis unsubstituted propyl. In embodiments, R2Dis unsubstituted n- propyl. In embodiments, R2Dis unsubstituted isopropyl. In embodiments, R2Dis unsubstituted butyl. In embodiments, R2Dis unsubstituted n-butyl. In embodiments, R2Dis unsubstituted isobutyl. In embodiments, R2Dis unsubstituted tert-butyl.

[0227] In embodiments, R2is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0228] In embodiments, R2is hydrogen. In embodiments, R2is halogen. In embodiments, R2is –F. In embodiments, R2is –Cl. In embodiments, R2is –Br. In embodiments, R2is –I. In embodiments, R2is -CCl3. In embodiments, R2is -CBr3. In embodiments, R2is -CF3. In embodiments, R2is -CI3. In embodiments, R2is -CH2Cl. In embodiments, R2is -CH2Br. In embodiments, R2is -CH2F. In embodiments, R2is -CH2I. In embodiments, R2is -CHCl2. In embodiments, R2is -CHBr2. In embodiments, R2is -CHF2. In embodiments, R2is -CHI2. In embodiments, R2is –CN. In embodiments, R2is –OH. In embodiments, R2is -NH2. In embodiments, R2is –COOH. In embodiments, R2is -CONH2. In embodiments, R2is -NO2. In embodiments, R2is –SH. In embodiments, R2is -SO3H. In embodiments, R2is -OSO3H. In embodiments, R2is -SO2NH2. In embodiments, R2is ^NHNH2. In embodiments, R2is ^ONH2. In embodiments, R2is ^NHC(O)NH2. In embodiments, R2is -NHSO2H. In embodiments, R2is -NHC(O)H. In embodiments, R2is -NHC(O)OH. In embodiments, R2is –NHOH. In embodiments, R2is -OCCl3. In embodiments, R2is -OCBr3. In embodiments, R2is -OCF3. In embodiments, R2is -OCI3. In embodiments, R2is -OCH2Cl. In embodiments, R2is -OCH2Br. In embodiments, R2is -OCH2F. In embodiments, R2is -OCH2I. In embodiments, R2is -OCHCl2. In embodiments, R2is -OCHBr2. Inembodiments, R2is -OCHF2. In embodiments, R2is -OCHI2. In embodiments, R2is -SF5. In embodiments, R2is -N3. 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, R2is unsubstituted n-butyl. In embodiments, R2is unsubstituted isobutyl. In embodiments, R2is unsubstituted tert-butyl. In embodiments, R2is substituted C1-C4alkyl. In embodiments, R2is substituted methyl. In embodiments, R2is substituted ethyl. In embodiments, R2is substituted propyl. In embodiments, R2is substituted n-propyl. In embodiments, R2is substituted isopropyl. In embodiments, R2is substituted butyl. In embodiments, R2is substituted n-butyl. In embodiments, R2is substituted isobutyl. In embodiments, R2is substituted tert-butyl. In embodiments, R2isembodiments, R2is. In embodiments, R2is. In embodiments, R2isIn embodiments, R2isIn embodiments, R2isembodiments, R2isIn embodiments, R2isn embodiments, R2is In embodiments, R2is n emb2odiments, R isIn embodiments, R2isn embodiments, R2is. In embodiments, R2is n embodiments, R2isIn embodiments, R2is substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R2is2n embodiments, R isIn embodiments, R2isIn embodiments, R2isembodiments, R2is2In embodiments, R isembodiments, R2is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R2is unsubstituted C3-C8cycloalkyl. In embodiments, R2is unsubstituted cyclopropyl. In embodiments, R2is unsubstituted cyclobutyl. In embodiments, R2is unsubstituted cyclopentyl. In embodiments, R2is unsubstituted cyclohexyl. In embodiments, R2is unsubstituted cycloheptyl. In embodiments, R2is unsubstituted cyclooctyl. In embodiments, R2is substituted C3-C8cycloalkyl. In embodiments, R2is substituted cyclopropyl. In embodiments, R2is substituted cyclobutyl. In embodiments, R2is substituted cyclopentyl. In embodiments, R2is substituted cyclohexyl. In embodiments, R2is substituted cycloheptyl. In embodiments, R2is substituted cyclooctyl. In embodiments, R2isembodiments, R2is

[0229] In embodiments, R2is substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R2is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R2is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted thienyl. In embodiments, R2is substituted or unsubstituted phenyl. In embodiments, R2is substituted or unsubstituted pyridyl. In embodiments, R2is substituted or unsubstituted thienyl.

[0230] In embodiments, R2is, , n embodiments, R2is

[0231] R20is independently halogen, -CX203, -CHX202, -CH2X20, -OCX203, -OCH2X20, -OCHX202, -CN, -SOn20R20D, -SOv20NR20AR20B, ^NR20CNR20AR20B, ^ONR20AR20B, -NR20CC(O)NR20AR20B, -N(O)m20, -NR20AR20B, -C(O)R20C, -C(O)OR20C, -OC(O)R20C, -OC(O)OR20C, -C(O)NR20AR20B, -OC(O)NR20AR20B, -OR20D, -SR20D, -NR20ASO2R20D, -NR20AC(O)R20C, -NR20AC(O)OR20C, -NR20AOR20C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R20substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0232] R20A, R20B, R20C, and R20Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, orC1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R20Aand R20Bsubstituents 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).

[0233] Each X20is independently –F, -Cl, -Br, or –I.

[0234] The symbol n20 is an integer from 0 to 4.

[0235] The symbols m20 and v20 are independently 1 or 2.

[0236] The symbol z20 is an integer from 0 to 5.

[0237] In embodiments, R2isn embodiments, R2isIn embodiments, R2isembodiments, R2is In embodiments, R2is

[0238] In embodiments, a substituted R20(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 R20is 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 R20is substituted, it is substituted with at least one substituent group. In embodiments, when R20is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R20is substituted, it is substituted with at least one lower substituent group.

[0239] In embodiments, a substituted ring formed when two R20substituents 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 R20substituents 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 R20substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R20substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R20substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0240] In embodiments, a substituted R20A(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 R20Ais 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 R20Ais substituted, it is substituted with at least one substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one lower substituent group.

[0241] In embodiments, a substituted R20B(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 R20Bis 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 R20Bis substituted, it issubstituted with at least one substituent group. In embodiments, when R20Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Bis substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, a substituted ring formed when R20Aand R20Bsubstituents 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 R20Aand R20Bsubstituents 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 R20Aand R20Bsubstituents 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 R20Aand R20Bsubstituents 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 R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, a substituted R20C(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 R20Cis 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 R20Cis substituted, it is substituted with at least one substituent group. In embodiments, when R20Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Cis substituted, it is substituted with at least one lower substituent group.

[0244] In embodiments, a substituted R20D(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 R20Dis substituted with a plurality ofgroups 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 R20Dis substituted, it is substituted with at least one substituent group. In embodiments, when R20Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Dis substituted, it is substituted with at least one lower substituent group.

[0245] In embodiments, R20Ais independently hydrogen. In embodiments, R20Ais independently unsubstituted C1-C4alkyl. In embodiments, R20Ais independently unsubstituted methyl. In embodiments, R20Ais independently unsubstituted ethyl. In embodiments, R20Ais independently unsubstituted propyl. In embodiments, R20Ais independently unsubstituted n-propyl. In embodiments, R20Ais independently unsubstituted isopropyl. In embodiments, R20Ais independently unsubstituted butyl. In embodiments, R20Ais independently unsubstituted n-butyl. In embodiments, R20Ais independently unsubstituted isobutyl. In embodiments, R20Ais independently unsubstituted tert-butyl.

[0246] In embodiments, R20Bis independently hydrogen. In embodiments, R20Bis independently unsubstituted C1-C4 alkyl. In embodiments, R20Bis independently unsubstituted methyl. In embodiments, R20Bis independently unsubstituted ethyl. In embodiments, R20Bis independently unsubstituted propyl. In embodiments, R20Bis independently unsubstituted n-propyl. In embodiments, R20Bis independently unsubstituted isopropyl. In embodiments, R20Bis independently unsubstituted butyl. In embodiments, R20Bis independently unsubstituted n-butyl. In embodiments, R20Bis independently unsubstituted isobutyl. In embodiments, R20Bis independently unsubstituted tert-butyl.

[0247] In embodiments, R20Cis independently hydrogen. In embodiments, R20Cis independently unsubstituted C1-C4alkyl. In embodiments, R20Cis independently unsubstituted methyl. In embodiments, R20Cis independently unsubstituted ethyl. In embodiments, R20Cis independently unsubstituted propyl. In embodiments, R20Cis independently unsubstituted n-propyl. In embodiments, R20Cis independently unsubstituted isopropyl. In embodiments, R20Cis independently unsubstituted butyl. In embodiments, R20Cis independently unsubstituted n-butyl. In embodiments, R20Cis independently unsubstituted isobutyl. In embodiments, R20Cis independently unsubstituted tert-butyl.

[0248] In embodiments, R20Dis independently hydrogen. In embodiments, R20Dis independently unsubstituted C1-C4 alkyl. In embodiments, R20Dis independentlyunsubstituted methyl. In embodiments, R20Dis independently unsubstituted ethyl. In embodiments, R20Dis independently unsubstituted propyl. In embodiments, R20Dis independently unsubstituted n-propyl. In embodiments, R20Dis independently unsubstituted isopropyl. In embodiments, R20Dis independently unsubstituted butyl. In embodiments, R20Dis independently unsubstituted n-butyl. In embodiments, R20Dis independently unsubstituted isobutyl. In embodiments, R20Dis independently unsubstituted tert-butyl.

[0249] In embodiments, R20is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0250] In embodiments, R20is independently halogen. In embodiments, R20is independently –F. In embodiments, R20is independently –Cl. In embodiments, R20is independently –Br. In embodiments, R20is independently –I. In embodiments, R20is independently -CX203. In embodiments, R20is independently -CCl3. In embodiments, R20is independently -CBr3. In embodiments, R20is independently -CF3. In embodiments, R20is independently -CI3. In embodiments, R20is independently -CH2Cl. In embodiments, R20is independently -CH2Br. In embodiments, R20is independently -CH2F. In embodiments, R20is independently -CH2I. In embodiments, R20is independently -CHCl2. In embodiments, R20is independently -CHBr2. In embodiments, R20is independently -CHF2. In embodiments, R20is independently -CHI2. In embodiments, R20is independently –CN. In embodiments, R20is independently –OH. In embodiments, R20is independently -NH2. In embodiments, R20is independently –COOH. In embodiments, R20is independently -CONH2. In embodiments, R20is independently -NO2. In embodiments, R20is independently –SH. In embodiments, R20is independently -SO3H. In embodiments, R20is independently -OSO3H. In embodiments, R20is independently -SO2NH2. In embodiments, R20is independently ^NHNH2. In embodiments, R20is independently ^ONH2. In embodiments, R20is independently ^NHC(O)NH2. In embodiments, R20is independently -NHSO2H. In embodiments, R20is independently -NHC(O)H. In embodiments, R20is independently-NHC(O)OH. In embodiments, R20is independently –NHOH. In embodiments, R20is independently -OCCl3. In embodiments, R20is independently -OCBr3. In embodiments, R20is independently -OCF3. In embodiments, R20is independently -OCI3. In embodiments, R20is independently -OCH2Cl. In embodiments, R20is independently -OCH2Br. In embodiments, R20is independently -OCH2F. In embodiments, R20is independently -OCH2I. In embodiments, R20is independently -OCHCl2. In embodiments, R20is independently -OCHBr2. In embodiments, R20is independently -OCHF2. In embodiments, R20is independently -OCHI2. In embodiments, R20is independently -SF5. In embodiments, R20is independently -N3. In embodiments, R20is independently substituted or unsubstituted C1-C4alkyl. In embodiments, R20is independently unsubstituted C1-C4 alkyl. In embodiments, R20is independently unsubstituted methyl. In embodiments, R20is independently unsubstituted ethyl. In embodiments, R20is independently unsubstituted propyl. In embodiments, R20is independently unsubstituted n-propyl. In embodiments, R20is independently unsubstituted isopropyl. In embodiments, R20is independently unsubstituted butyl. In embodiments, R20is independently unsubstituted n-butyl. In embodiments, R20is independently unsubstituted isobutyl. In embodiments, R20is independently unsubstituted tert-butyl. In embodiments, R20is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R20is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R20is independently unsubstituted methoxy. In embodiments, R20is independently unsubstituted ethoxy. In embodiments, R20is independently unsubstituted propoxy. In embodiments, R20is independently unsubstituted n-propoxy. In embodiments, R20is independently unsubstituted isopropoxy. In embodiments, R20is independently unsubstituted butoxy.

[0251] In embodiments, two R20substituents are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R20substituents are joined to form a substituted or unsubstituted C5-C6cycloalkyl. In embodiments, two R20substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, two R20substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R20substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0252] In embodiments, z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 2. In embodiments, z20 is 3. In embodiments, z20 is 4. In embodiments, z20 is 5.

[0253] In embodiments, R2isn embodiments, R2isembodiments, R2is. In embodiments, R2isembodiments, R2is. In embodiments, R2is. n embodiments, R2is In embodiments, R2is n embodiments, R2is In embodiments, R2is. n embodiments, R2is In embodiments, R2isIn embodiments, R2is In embodiments, R2isn embodiments, R2is In embodiments, R2is2n embodiments, R is In embodiments, R2is

[0254] 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 groupsselected 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.

[0255] In embodiments, a substituted R3A(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 R3Ais 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 R3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one lower substituent group.

[0256] In embodiments, a substituted R3B(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 R3Bis 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 R3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one lower substituent group.

[0257] In embodiments, a substituted ring formed when R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents 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; eachsubstituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents 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 R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0258] In embodiments, a substituted R3C(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 R3Cis 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 R3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one lower substituent group.

[0259] In embodiments, a substituted R3D(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 R3Dis 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 R3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0260] In embodiments, R3Ais independently hydrogen. In embodiments, R3Ais independently unsubstituted C1-C4alkyl. In embodiments, R3Ais independently unsubstituted methyl. In embodiments, R3Ais independently unsubstituted ethyl. In embodiments, R3Ais independently unsubstituted propyl. In embodiments, R3Aisindependently unsubstituted n-propyl. In embodiments, R3Ais independently unsubstituted isopropyl. In embodiments, R3Ais independently unsubstituted butyl. In embodiments, R3Ais independently unsubstituted n-butyl. In embodiments, R3Ais independently unsubstituted isobutyl. In embodiments, R3Ais independently unsubstituted tert-butyl.

[0261] In embodiments, R3Bis independently hydrogen. In embodiments, R3Bis independently unsubstituted C1-C4alkyl. In embodiments, R3Bis independently unsubstituted methyl. In embodiments, R3Bis independently unsubstituted ethyl. In embodiments, R3Bis independently unsubstituted propyl. In embodiments, R3Bis independently unsubstituted n-propyl. In embodiments, R3Bis independently unsubstituted isopropyl. In embodiments, R3Bis independently unsubstituted butyl. In embodiments, R3Bis independently unsubstituted n-butyl. In embodiments, R3Bis independently unsubstituted isobutyl. In embodiments, R3Bis independently unsubstituted tert-butyl.

[0262] In embodiments, R3Cis independently hydrogen. In embodiments, R3Cis independently unsubstituted C1-C4 alkyl. In embodiments, R3Cis independently unsubstituted methyl. In embodiments, R3Cis independently unsubstituted ethyl. In embodiments, R3Cis independently unsubstituted propyl. In embodiments, R3Cis independently unsubstituted n-propyl. In embodiments, R3Cis independently unsubstituted isopropyl. In embodiments, R3Cis independently unsubstituted butyl. In embodiments, R3Cis independently unsubstituted n-butyl. In embodiments, R3Cis independently unsubstituted isobutyl. In embodiments, R3Cis independently unsubstituted tert-butyl.

[0263] In embodiments, R3Dis independently hydrogen. In embodiments, R3Dis independently unsubstituted C1-C4alkyl. In embodiments, R3Dis independently unsubstituted methyl. In embodiments, R3Dis independently unsubstituted ethyl. In embodiments, R3Dis independently unsubstituted propyl. In embodiments, R3Dis independently unsubstituted n-propyl. In embodiments, R3Dis independently unsubstituted isopropyl. In embodiments, R3Dis independently unsubstituted butyl. In embodiments, R3Dis independently unsubstituted n-butyl. In embodiments, R3Dis independently unsubstituted isobutyl. In embodiments, R3Dis independently unsubstituted tert-butyl.

[0264] In embodiments, R3is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br,-OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0265] In embodiments, R3is independently halogen. In embodiments, R3is independently –F. In embodiments, R3is independently –Cl. In embodiments, R3is independently –Br. In embodiments, R3is independently –I. In embodiments, R3is independently -CCl3. In embodiments, R3is independently -CBr3. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2Cl. In embodiments, R3is independently -CH2Br. In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments, R3is independently -CHCl2. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. In embodiments, R3is independently –CN. In embodiments, R3is independently –OH. In embodiments, R3is independently -NH2. In embodiments, R3is independently –COOH. In embodiments, R3is independently -CONH2. In embodiments, R3is independently -NO2. In embodiments, R3is independently –SH. In embodiments, R3is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments, R3is independently -SO2NH2. In embodiments, R3is independently ^NHNH2. In embodiments, R3is independently ^ONH2. In embodiments, R3is independently ^NHC(O)NH2. In embodiments, R3is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently –NHOH. In embodiments, R3is independently -OCCl3. In embodiments, R3is independently -OCBr3. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2Cl. In embodiments, R3is independently -OCH2Br. In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCl2. In embodiments, R3is independently -OCHBr2. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI2. In embodiments, R3is independently -SF5. In embodiments, R3is independently -N3. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments, R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3is independently unsubstitutedisopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments, R3is independently unsubstituted n-butyl. In embodiments, R3is independently unsubstituted isobutyl. In embodiments, R3is independently unsubstituted tert-butyl. In embodiments, R3is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is independently unsubstituted methoxy. In embodiments, R3is independently unsubstituted ethoxy. In embodiments, R3is independently unsubstituted propoxy. In embodiments, R3is independently unsubstituted n-propoxy. In embodiments, R3is independently unsubstituted isopropoxy. In embodiments, R3is independently unsubstituted butoxy. In embodiments, R3is independently unsubstituted C3-C8 cycloalkyl. In embodiments, R3is independently unsubstituted cyclopropyl. In embodiments, R3is independently unsubstituted cyclobutyl. In embodiments, R3is independently unsubstituted cyclopentyl. In embodiments, R3is independently unsubstituted cyclohexyl. In embodiments, R3is independently unsubstituted cycloheptyl. In embodiments, R3is independently unsubstituted cyclooctyl. In embodiments, R3is independently substituted C3-C8cycloalkyl. In embodiments, R3is independently substituted cyclopropyl. In embodiments, R3is independently substituted cyclobutyl. In embodiments, R3is independently substituted cyclopentyl. In embodiments, R3is independently substituted cyclohexyl. In embodiments, R3is independently substituted cycloheptyl. In embodiments, R3is independently substituted cyclooctyl. In embodiments, R3is independently

[0266] In embodiments, R3is independently halogen, -CX33, -OR3D, unsubstituted C1-C4 alkyl, or substituted or unsubstituted C3-C8cycloalkyl. In embodiments, R3is independently –Cl, -CF3, unsubstituted methyl, or unsubstituted methoxy, or substituted or unsubstituted cyclopropyl.

[0267] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6.

[0268] 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 groupsselected 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.

[0269] 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.

[0270] 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 is substituted 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.

[0271] 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, orlower 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.

[0272] 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.

[0273] In embodiments, a substituted R4C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent 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.

[0274] 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.

[0275] In embodiments, R4Ais independently hydrogen. In embodiments, R4Ais independently unsubstituted C1-C4alkyl. In embodiments, R4Ais independently unsubstituted methyl. In embodiments, R4Ais independently unsubstituted ethyl. In embodiments, R4Ais independently unsubstituted propyl. In embodiments, R4Ais independently unsubstituted n-propyl. In embodiments, R4Ais independently unsubstituted isopropyl. In embodiments, R4Ais independently unsubstituted butyl. In embodiments, R4Ais independently unsubstituted n-butyl. In embodiments, R4Ais independently unsubstituted isobutyl. In embodiments, R4Ais independently unsubstituted tert-butyl.

[0276] In embodiments, R4Bis independently hydrogen. In embodiments, R4Bis independently unsubstituted C1-C4 alkyl. In embodiments, R4Bis independently unsubstituted methyl. In embodiments, R4Bis independently unsubstituted ethyl. In embodiments, R4Bis independently unsubstituted propyl. In embodiments, R4Bis independently unsubstituted n-propyl. In embodiments, R4Bis independently unsubstituted isopropyl. In embodiments, R4Bis independently unsubstituted butyl. In embodiments, R4Bis independently unsubstituted n-butyl. In embodiments, R4Bis independently unsubstituted isobutyl. In embodiments, R4Bis independently unsubstituted tert-butyl.

[0277] In embodiments, R4Cis independently hydrogen. In embodiments, R4Cis independently unsubstituted C1-C4alkyl. In embodiments, R4Cis independently unsubstituted methyl. In embodiments, R4Cis independently unsubstituted ethyl. In embodiments, R4Cis independently unsubstituted propyl. In embodiments, R4Cis independently unsubstituted n-propyl. In embodiments, R4Cis independently unsubstituted isopropyl. In embodiments, R4Cis independently unsubstituted butyl. In embodiments, R4Cis independently unsubstituted n-butyl. In embodiments, R4Cis independently unsubstituted isobutyl. In embodiments, R4Cis independently unsubstituted tert-butyl.

[0278] In embodiments, R4Dis independently hydrogen. In embodiments, R4Dis independently unsubstituted C1-C4alkyl. 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.

[0279] In embodiments, R4is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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 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.

[0280] In embodiments, R4is independently oxo. In embodiments, R4is independently halogen. In embodiments, R4is independently –F. In embodiments, R4is independently –Cl. In embodiments, R4is independently –Br. In embodiments, R4is independently –I. In embodiments, R4is independently -CCl3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2Cl. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHCl2. In embodiments, R4is independently -CHBr2. In embodiments, R4is independently -CHF2. In embodiments, R4is independently -CHI2. In embodiments, R4is independently –CN. In embodiments, R4is independently –OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently –COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. Inembodiments, 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)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently –NHOH. In embodiments, R4is independently -OCCl3. In embodiments, R4is independently -OCBr3. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2Cl. In embodiments, R4is independently -OCH2Br. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCl2. In embodiments, R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently -SF5. In embodiments, R4is independently -N3. In embodiments, R4is independently substituted or unsubstituted C1-C4 alkyl. 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 substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently unsubstituted 2 to 6 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 substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R4is independently unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R4is independently unsubstituted morpholinyl. In embodiments, R4is independently

[0281] In embodiments, R4is independently oxo, halogen, -CX43, -CN, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R4is independently oxo, -F, -Cl, -Br, -CF3, -CN, unsubstituted methyl, or unsubstituted morpholinyl.

[0282] In embodiments, two R4substituents are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R4substituents are joined to form a substituted or unsubstituted C5-C6 cycloalkyl. In embodiments, two R4substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, two R4substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R4substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R4substituents are joined to form

[0283] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5. In embodiments, z4 is 6. In embodiments, z4 is 7. In embodiments, z4 is 8. In embodiments, z4 is 9. In embodiments, z4 is 10.

[0284] 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 R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0285] In embodiments, when R2is substituted, R2is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0286] In embodiments, when R2Ais substituted, R2Ais substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2A, R2A.1, R2A.2, and R2A.3, respectively.

[0287] In embodiments, when R2Bis substituted, R2Bis substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted,the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2B, R2B.1, R2B.2, and R2B.3, respectively.

[0288] In embodiments, when R2Aand R2Bsubstituents 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 R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2A.1, R2A.2, and R2A.3, respectively.

[0289] In embodiments, when R2Aand R2Bsubstituents 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 R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in thedescription of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2B.1, R2B.2, and R2B.3, respectively.

[0290] In embodiments, when R2Cis substituted, R2Cis substituted with one or more first substituent groups denoted by R2C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.1substituent group is substituted, the R2C.1substituent group is substituted with one or more second substituent groups denoted by R2C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.2substituent group is substituted, the R2C.2substituent group is substituted with one or more third substituent groups denoted by R2C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2C, R2C.1, R2C.2, and R2C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2C, R2C.1, R2C.2, and R2C.3, respectively.

[0291] In embodiments, when R2Dis substituted, R2Dis substituted with one or more first substituent groups denoted by R2D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.1substituent group is substituted, the R2D.1substituent group is substituted with one or more second substituent groups denoted by R2D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.2substituent group is substituted, the R2D.2substituent group is substituted with one or more third substituent groups denoted by R2D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2D, R2D.1, R2D.2, and R2D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2D, R2D.1, R2D.2, and R2D.3, respectively.

[0292] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted,the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0293] In embodiments, when R3Ais substituted, R3Ais substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3A, R3A.1, R3A.2, and R3A.3, respectively.

[0294] In embodiments, when R3Bis substituted, R3Bis substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.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 R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3B, R3B.1, R3B.2, and R3B.3, respectively.

[0295] In embodiments, when R3Aand R3Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkylor substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3A.1, R3A.2, and R3A.3, respectively.

[0296] In embodiments, when R3Aand R3Bsubstituents 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 R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.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 R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3B.1, R3B.2, and R3B.3, respectively.

[0297] In embodiments, when R3Cis substituted, R3Cis substituted with one or more first substituent groups denoted by R3C.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 R3C.1substituent group is substituted with one or more second substituent groups denoted by R3C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.2substituent group is substituted,the R3C.2substituent group is substituted with one or more third substituent groups denoted by R3C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3C, R3C.1, R3C.2, and R3C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3C, R3C.1, R3C.2, and R3C.3, respectively.

[0298] In embodiments, when R3Dis substituted, R3Dis substituted with one or more first substituent groups denoted by R3D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.1substituent group is substituted, the R3D.1substituent group is substituted with one or more second substituent groups denoted by R3D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.2substituent group is substituted, the R3D.2substituent group is substituted with one or more third substituent groups denoted by R3D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3D, R3D.1, R3D.2, and R3D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3D, R3D.1, R3D.2, and R3D.3, respectively.

[0299] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0300] In embodiments, when two 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 R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0301] In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4A, R4A.1, R4A.2, and R4A.3, respectively.

[0302] In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R4B, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4B.1, R4B.2, and R4B.3, respectively.

[0303] In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R4A.1, R4A.2, and R4A.3, respectively.

[0304] In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R4B.1, R4B.2, and R4B.3, respectively.

[0305] 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.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4C, R4C.1, R4C.2, and R4C.3, respectively.

[0306] In embodiments, when R4Dis substituted, R4Dis substituted with one or more first substituent groups denoted by R4D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.1substituent group is substituted, the R4D.1substituent group is substituted with one or more second substituent groups denoted by R4D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D.2substituent group is substituted, the R4D.2substituent group is substituted with one or more third substituent groups denoted by R4D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4D, R4D.1, R4D.2, and R4D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4D, R4D.1, R4D.2, and R4D.3, respectively.

[0307] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

[0308] 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 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 R6.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.2substituent group is substituted, the R6.2substituent 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, R6, R6.1, R6.2, and R6.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6, R6.1, R6.2, and R6.3, respectively.

[0309] 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)”. In embodiments, when an R7.1substituent group is substituted, the R7.1substituent group is substituted with one or more second substituent groups denoted by R7.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2substituent group is substituted, the R7.2substituent group is substituted with one or more third substituent groups denoted by R7.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7, R7.1, R7.2, and R7.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R7, R7.1, R7.2, and R7.3, respectively.

[0310] 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 the description 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 substituentgroups denoted by R8.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.2substituent group is substituted, the R8.2substituent group is substituted with one or more third substituent groups denoted by R8.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8, R8.1, R8.2, and R8.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8, R8.1, R8.2, and R8.3, respectively.

[0311] In embodiments, when R20is substituted, R20is substituted with one or more first substituent groups denoted by R20.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1substituent group is substituted, the R20.1substituent group is substituted with one or more second substituent groups denoted by R20.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2substituent group is substituted, the R20.2substituent group is substituted with one or more third substituent groups denoted by R20.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20, R20.1, R20.2, and R20.3, respectively.

[0312] In embodiments, when two R20substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R20.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1substituent group is substituted, the R20.1substituent group is substituted with one or more second substituent groups denoted by R20.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2substituent group is substituted, the R20.2substituent group is substituted with one or more third substituent groups denoted by R20.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively,as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20, R20.1, R20.2, and R20.3, respectively.

[0313] In embodiments, when R20Ais substituted, R20Ais substituted with one or more first substituent groups denoted by R20A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.1substituent group is substituted, the R20A.1substituent group is substituted with one or more second substituent groups denoted by R20A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.2substituent group is substituted, the R20A.2substituent group is substituted with one or more third substituent groups denoted by R20A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20A, R20A.1, R20A.2, and R20A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20A, R20A.1, R20A.2, and R20A.3, respectively.

[0314] In embodiments, when R20Bis substituted, R20Bis substituted with one or more first substituent groups denoted by R20B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.1substituent group is substituted, the R20B.1substituent group is substituted with one or more second substituent groups denoted by R20B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.2substituent group is substituted, the R20B.2substituent group is substituted with one or more third substituent groups denoted by R20B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20B, R20B.1, R20B.2, and R20B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20B, R20B.1, R20B.2, and R20B.3, respectively.

[0315] In embodiments, when R20Aand R20Bsubstituents 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 R20A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.1substituent group is substituted, the R20A.1substituent group is substituted with one or more second substituent groups denoted byR20A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.2substituent group is substituted, the R20A.2substituent group is substituted with one or more third substituent groups denoted by R20A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20A.1, R20A.2, and R20A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R20A.1, R20A.2, and R20A.3, respectively.

[0316] In embodiments, when R20Aand R20Bsubstituents 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 R20B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.1substituent group is substituted, the R20B.1substituent group is substituted with one or more second substituent groups denoted by R20B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.2substituent group is substituted, the R20B.2substituent group is substituted with one or more third substituent groups denoted by R20B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20B.1, R20B.2, and R20B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R20B.1, R20B.2, and R20B.3, respectively.

[0317] In embodiments, when R20Cis substituted, R20Cis substituted with one or more first substituent groups denoted by R20C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20C.1substituent group is substituted, the R20C.1substituent group is substituted with one or more second substituent groups denoted by R20C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20C.2substituent group is substituted, the R20C.2substituent group is substituted with one or more third substituent groups denoted by R20C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20C, R20C.1, R20C.2, and R20C.3have values corresponding to the values of RWW, RWW.1, 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, and RWW.3correspond to R20C, R20C.1, R20C.2, and R20C.3, respectively.

[0318] In embodiments, when R20Dis substituted, R20Dis substituted with one or more first substituent groups denoted by R20D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20D.1substituent group is substituted, the R20D.1substituent group is substituted with one or more second substituent groups denoted by R20D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20D.2substituent group is substituted, the R20D.2substituent group is substituted with one or more third substituent groups denoted by R20D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20D, R20D.1, R20D.2, and R20D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20D, R20D.1, R20D.2, and R20D.3, respectively.

[0319] In embodiments, the compound has the formula:N embodiments, the compound has the formula: n embodiments,the compound has the formula:n embodiments, the compound has the formula:n embodiments, the compound has the formula:. In embodiments, the compound has the formula:n embodiments, the compound has the formula: In embodiments, the compound has the formula:In embodiments, the compound has the formula: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:n 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:n 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:. 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:. 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: 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:n embodiments, the compound has the formula: n 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: NIn embodiments, the compound has the formula:. In embodiments, the compound has the formula:In embodiments, the compound has the formula: NIn embodiments, the compound has the formula: 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: 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:n 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:.

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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:In embodiments, the compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:n embodiments, the compound has the formula:

[0321] In embodiments, the compound has the formula:In embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula:embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula: embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:

[0322] In embodiments, the compound binds to Cys145, Ser46, Met49, Asn142, Gly143, His163, His164, Met165, or Glu166 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., covalently) to Cys145 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds noncovalently to Ser46, Met49, Asn142, Gly143, His163, His164, Met165, or Glu166 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Ser46 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Met49 of Mpro (e.g., SARS-CoV- 2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Asn142 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Gly143 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to His163 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to His164 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Met165 of Mpro (e.g., SARS- CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to Glu166 of Mpro (e.g., SARS-CoV-2 Mpro). In embodiments, the compound binds (e.g., noncovalently) to His41 of Mpro (e.g., SARS-CoV-2 Mpro).

[0323] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0324] 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).III. Pharmaceutical compositions

[0325] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0326] 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.

[0327] In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IV), (IVa), (IVb), (V), (Va), or (Vb), including all embodiments thereof. In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IV), (IVa), (IVb), (V), (Va), (Vb), or (VI), including all embodiments thereof. IV. Methods of use

[0328] In an aspect is provided a method of treating a coronavirus infection in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0329] In embodiments, the coronavirus infection is a SARS-CoV-2 infection. In embodiments, the coronavirus infection is a SARS-CoV-1 infection. In embodiments, the coronavirus infection is a MERS-CoV infection. In embodiments, the coronavirus infection is a human CoV alpha 229E infection. In embodiments, the coronavirus infection is a human CoV alpha NL63 infection. In embodiments, the coronavirus infection is a human CoV beta HKU1 infection. In embodiments, the coronavirus infection is a human CoV beta OC43 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Delta infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Delta B.1.617.2 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron XBB infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron XBB.1.16 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron XBB.1.5 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron EG.5.1 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron BA.2 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron B.1.1.529 BA.2 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron BQ.1.1 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 Omicron BA.2.86.1infection. In embodiments, the coronavirus infection is a SARS-CoV-2 WA.1 infection. In embodiments, the coronavirus infection is a SARS-CoV-2 WA.1 MPro L50F / E166Q / L167F infection. In embodiments, the coronavirus infection is a SARS-CoV-2 WA.1 MPro L50F / E166A / L167F infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro L50F infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro Q192T infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro A173V infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro S144A infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro E166Q infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro P168Δ infection. In embodiments, the coronavirus infection is a SARS-CoV-2 MPro Q192T infection.

[0330] In embodiments, the subject is not administered a pharmacokinetic enhancer. In embodiments, the pharmacokinetic enhancer is a protease inhibitor. In embodiments, the pharmacokinetic enhancer is a CYP3A inhibitor. In embodiments, the pharmacokinetic enhancer is ritonavir. In embodiments, the pharmacokinetic enhancer is cobicistat. In embodiments, the pharmacokinetic enhancer is as described in Krauß, J. et al. Sci. Pharm. 2018, 86(4), E43, which is herein incorporated by reference in its entirety and for all purposes.

[0331] In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IV), (IVa), (IVb), (V), (Va), or (Vb), including all embodiments thereof. In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IV), (IVa), (IVb), (V), (Va), (Vb), or (VI), including all embodiments thereof.

[0332] In an aspect is provided a method of reducing the level of activity of an Mpro protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0333] In embodiments, the level of activity of the Mpro protein is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mproprotein is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by about 1000-fold relative to a control (e.g., absence of the compound).

[0334] In embodiments, the level of activity of the Mpro protein is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the Mpro protein is reduced by at least 1000-fold relative to a control (e.g., absence of the compound).V. Embodiments

[0335] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: hereinis a single bond or a double bond; L1is a bond or unsubstituted C1-C4alkylene; Ring A is heteroaryl; Ring B is heterocycloalkyl or heteroaryl; R1is hydrogen, substituted or unsubstituted alkyl, or E; E is an electrophilic moiety; R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -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 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; R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl 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; each X2, X3, and X4is independently –F, -Cl, -Br, or –I; n2, n3, and n4 are independently an integer from 0 to 4; m2, m3, m4, v2, v3, and v4 are independently 1 or 2; z3 is an integer from 0 to 6; and z4 is an integer from 0 to 10.

[0336] Embodiment P2. The compound of embodiment P1, having the formula:

[0337] Embodiment P3. The compound of embodiment P1, having the formula:

[0338] Embodiment P4. The compound of embodiment P1, having the formula:

[0339] Embodiment P5. The compound of embodiment P1, having the formula:

[0340] Embodiment P6. The compound of embodiment P1, having the formula:

[0341] Embodiment P7. The compound of one of embodiments P1 to P6, wherein L1is a bond or unsubstituted methylene.

[0342] Embodiment P8. The compound of one of embodiments P1 to P6, wherein L1is a bond.

[0343] Embodiment P9. The compound of one of embodiments P1 to P8, wherein Ring A is 5 to 10 membered heteroaryl.

[0344] Embodiment P10. The compound of one of embodiments P1 to P8, wherein Ring A is isoquinolinyl.

[0345] Embodiment P11. The compound of one of embodiments P1 to P8, wherein Ring A is pyridonyl.

[0346] Embodiment P12. The compound of embodiment P1, having the formula:

[0347] Embodiment P13. The compound of embodiment P1, having the formula:

[0348] Embodiment P14. The compound of embodiment P1, having the formula:

[0349] Embodiment P15. The compound of one of embodiments P1 to P14, wherein R3is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0350] Embodiment P16. The compound of one of embodiments P1 to P14, wherein z3 is 0.

[0351] Embodiment P17. The compound of one of embodiments P1 to P3, P7 to P12, P15, and P16, wherein Ring B is 3 to 8 membered heterocycloalkyl or 5 to 10 membered heteroaryl.

[0352] Embodiment P18. The compound of one of embodiments P1 to P3, P7 to P12, P15, and P16, wherein Ring B is benzotriazolyl, triazolyl, tetrazolyl, pyrazolyl, or pyrrolidinyl.

[0353] Embodiment P19. The compound of one of embodiments P1 to P3, P7 to P12, P15, and P16, wherein, , ,

[0354] Embodiment P20. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P19, wherein R4is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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 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.

[0355] Embodiment P21. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P19, wherein R4is independently oxo, halogen, -CX43, -CN, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl,substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0356] Embodiment P22. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P19, wherein R4is independently oxo, -F, -Cl, -Br, -CF3, -CN, unsubstituted methyl, or unsubstituted morpholinyl.

[0357] Embodiment P23. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P19, wherein two R4substituents are joined to form a substituted or unsubstituted C5- C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0358] Embodiment P24. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P23, wherein z4 is 0, 1, or 2.

[0359] Embodiment P25. The compound of one of embodiments P1 to P3, P7 to P12, and P15 to P19, wherein

[0360] Embodiment P26. The compound of one of embodiments P1 to P25, wherein R1is hydrogen or substituted or unsubstituted C1-C4 alkyl.

[0361] Embodiment P27. The compound of one of embodiments P1 to P25, wherein R1is hydrogen.

[0362] Embodiment P28. The compound of one of embodiments P1 to P25, wherein R1is unsubstituted C2-C4alkynyl.

[0363] Embodiment P29. The compound of one of embodiments P1 to P25, wherein R1is

[0364] Embodiment P30. The compound of one of embodiments P1 to P25, wherein R1is C1-C4alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0365] Embodiment P31. The compound of one of embodiments P1 to P25, wherein R1is C1-C4alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted thienyl.

[0366] Embodiment P32. The compound of one of embodiments P1 to P25, wherein R1is

[0367] Embodiment P33. The compound of one of embodiments P1 to P25, wherein R1is E, and E is:R5, R6, R7, and R8are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH,-CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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; and X5is –F, -Cl, -Br, or –I.

[0368] Embodiment P34. The compound of embodiment P33, wherein R5, R6, R7, and R8are hydrogen.

[0369] Embodiment P35. The compound of embodiment P33, wherein E is

[0370] Embodiment P36. The compound of one of embodiments P1 to P35, wherein R2is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2,^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0371] Embodiment P37. The compound of one of embodiments P1 to P35, wherein R2is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0372] Embodiment P38. The compound of one of embodiments P1 to P35, wherein R2is unsubstituted methyl.

[0373] Embodiment P39. The compound of one of embodiments P1 to P35, wherein R2is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted thienyl.

[0374] Embodiment P40. The compound of one of embodiments P1 to P35, wherein R2isR20is independently halogen, -CX203, -CHX202, -CH2X20, -OCX203, -OCH2X20, -OCHX202, -CN, -SOn20R20D, -SOv20NR20AR20B, ^NR20CNR20AR20B, ^ONR20AR20B, -NR20CC(O)NR20AR20B, -N(O)m20, -NR20AR20B, -C(O)R20C, -C(O)OR20C, -OC(O)R20C, -OC(O)OR20C, -C(O)NR20AR20B, -OC(O)NR20AR20B, -OR20D, -SR20D, -NR20ASO2R20D, -NR20AC(O)R20C, -NR20AC(O)OR20C, -NR20AOR20C, -SF5, -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 R20substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R20A, R20B, R20C, and R20Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R20Aand R20Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X20is independently –F, -Cl, -Br, or –I; n20 is an integer from 0 to 4; m20 and v20 are independently 1 or 2; and z20 is an integer from 0 to 5.

[0375] Embodiment P41. The compound of embodiment P40, wherein R20is independently halogen or -CX203.

[0376] Embodiment P42. The compound of embodiment P40, wherein R20is independently -F, -Cl, or -CF3.

[0377] Embodiment P43. The compound of embodiment P40, wherein two R20substituents are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0378] Embodiment P44. The compound of one of embodiments P40 to P43, wherein z20 is 1 or 2.

[0379] Embodiment P45. The compound of one of embodiments P1 to P35, wherein R2is

[0380] Embodiment P46. The compound of embodiment P1, having the formula: N

[0381] Embodiment P47. The compound of embodiment P1, having the formula:

[0382] Embodiment P48. A pharmaceutical composition comprising a compound of one of embodiments P1 to P47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0383] Embodiment P49. A method of treating a coronavirus 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 one of embodiments P1 to P47, or a pharmaceutically acceptable salt thereof.

[0384] Embodiment P50. The method of embodiment P49, wherein the coronavirus infection is a SARS-CoV-2 infection, a SARS-CoV-1 infection, or a MERS-CoV infection.

[0385] Embodiment P51. The method of embodiment P49, wherein the coronavirus infection is a SARS-CoV-2 infection.

[0386] Embodiment P52. The method of embodiment P49, wherein the coronavirus infection is a human CoV alpha 229E infection, a human CoV alpha NL63 infection, a human CoV beta HKU1 infection, a human CoV beta OC43 infection, a SARS-CoV-2 Delta infection, a SARS-CoV-2 Omicron XBB infection, a SARS-CoV-2 Omicron XBB.1.16 infection, a SARS-CoV-2 Omicron XBB.1.5 infection, a SARS-CoV-2 Omicron EG.5.1 infection, a SARS-CoV-2 Omicron BA.2 infection, a SARS-CoV-2 Omicron BQ.1.1 infection, a SARS-CoV-2 Omicron BA.2.86.1 infection, a SARS-CoV-2 WA.1 infection, a SARS-CoV-2 WA.1 MPro L50F / E166Q / L167F infection, a SARS-CoV-2 WA.1 MPro L50F / E166A / L167F infection, a SARS-CoV-2 MPro A173V infection, a SARS-CoV-2 MProS144A infection, a SARS-CoV-2 MPro E166Q infection, a SARS-CoV-2 MPro P168Δ infection, a SARS-CoV-2 MPro Q192T infection, a SARS-CoV-1 infection, or a MERS-CoV infection.

[0387] Embodiment P53. The method of one of embodiments P49 to P52, wherein the subject is not administered a pharmacokinetic enhancer.

[0388] Embodiment P54. The method of embodiment P53, wherein the pharmacokinetic enhancer is a protease inhibitor.

[0389] Embodiment P55. The method of embodiment P53, wherein the pharmacokinetic enhancer is a CYP3A inhibitor.

[0390] Embodiment P56. The method of embodiment P53, wherein the pharmacokinetic enhancer is ritonavir or cobicistat.

[0391] Embodiment P57. A method of reducing the level of activity of an Mpro protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of embodiments P1 to P47, or a pharmaceutically acceptable salt thereof. VI. Additional embodiments

[0392] Embodiment 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: hereinis a single bond or a double bond; L1is a bond or unsubstituted C1-C4alkylene; Ring A is heteroaryl; Ring B is heterocycloalkyl or heteroaryl; R1is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or E;E is an electrophilic moiety; R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalk...

Claims

WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:whereinis a single bond or a double bond; L1is a bond or unsubstituted C1-C4alkylene; Ring A is heteroaryl; Ring B is heterocycloalkyl or heteroaryl; R1is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or E; E is an electrophilic moiety; R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, ^NR3CNR3AR3B, ^ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, ^NR4CNR4AR4B, ^ONR4AR4B,-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -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 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; R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl 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; each X2, X3, and X4is independently –F, -Cl, -Br, or –I; n2, n3, and n4 are independently an integer from 0 to 4; m2, m3, m4, v2, v3, and v4 are independently 1 or 2; z3 is an integer from 0 to 6; and z4 is an integer from 0 to 10.

2. The compound of claim 1, having the formula:

3. The compound of claim 1, having the formula:

4. The compound of claim 1, having the formula:

5. The compound of claim 1, having the formula:

6. The compound of claim 1, having the formula:

7. The compound of claim 1, wherein L1is a bond or unsubstituted methylene.

8. The compound of claim 1, wherein L1is a bond.

9. The compound of claim 1, wherein Ring A is 5 to 10 membered heteroaryl.

10. The compound of claim 1, wherein Ring A is isoquinolinyl, pyridonyl, pyridyl, pyrazinyl, pyridazinyl, or benzisoxazolyl.

11. The compound of claim 1, wherein Ring A is isoquinolinyl.

12. The compound of claim 1, wherein Ring A is pyridonyl.

13. The compound of claim 1, having the formula:

14. The compound of claim 1, having the formula:

15. The compound of claim 1, having the formula:

16. The compound of claim 1, having the formula:

17. The compound of claim 1, wherein R3is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5,-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.

18. The compound of claim 1, wherein R3is independently halogen, -CX33, -OR3D, unsubstituted C1-C4 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl.

19. The compound of claim 1, wherein R3is independently –Cl, -CF3, unsubstituted methyl, or unsubstituted methoxy, or substituted or unsubstituted cyclopropyl.

20. The compound of claim 1, wherein z3 is 1.

21. The compound of claim 1, wherein z3 is 0.

22. The compound of claim 1, wherein Ring B is 3 to 8 membered heterocycloalkyl or 5 to 10 membered heteroaryl.

23. The compound of claim 1, wherein Ring B is benzotriazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, or indazolyl.

24. The compound of claim 1, wherein25. The compound of claim 1, wherein R4is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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 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.

26. The compound of claim 1, wherein R4is independently oxo, halogen, -CX43, -CN, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

27. The compound of claim 1, wherein R4is independently oxo, -F, -Cl, -Br, -CF3, -CN, unsubstituted methyl, or unsubstituted morpholinyl.

28. The compound of claim 1, wherein two R4substituents are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

29. The compound of claim 1, wherein z4 is 1 or 2.

30. The compound of claim 1, wherein z4 is 0.

31. The compound of claim 1, wherein32. The compound of claim 1, wherein R1is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

33. The compound of claim 1, wherein R1is hydrogen.

34. The compound of claim 1, wherein R1is unsubstituted C2-C4 alkynyl.

35. The compound of claim 1, wherein R1is36. The compound of claim 1, wherein R1is37. The compound of claim 1, wherein R1is, , , , 38. The compound of claim 1, wherein R1is39. The compound of claim 1, wherein R1is C1-C4 alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

40. The compound of claim 1, wherein R1is C1-C4 alkyl substituted with a substituted or unsubstituted phenyl or substituted or unsubstituted thienyl.

41. The compound of claim 1, wherein R1is42. The compound of claim 1, wherein R1is E, and E is:R5, R6, R7, and R8are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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; and X5is –F, -Cl, -Br, or –I.

43. The compound of claim 42, wherein R5, R6, R7, and R8are hydrogen.

44. The compound of claim 42, wherein E is45. The compound of claim 1, wherein R2is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

46. The compound of claim 1, wherein R2is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

47. The compound of claim 1, wherein R2is unsubstituted methyl.

48. The compound of claim 1, wherein R2is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted thienyl.

49. The compound of claim 1, wherein R2isR20is independently halogen, -CX203, -CHX202, -CH2X20, -OCX203, -OCH2X20, -OCHX202, -CN, -SOn20R20D, -SOv20NR20AR20B, ^NR20CNR20AR20B, ^ONR20AR20B, -NR20CC(O)NR20AR20B, -N(O)m20, -NR20AR20B, -C(O)R20C, -C(O)OR20C, -OC(O)R20C, -OC(O)OR20C, -C(O)NR20AR20B, -OC(O)NR20AR20B, -OR20D, -SR20D, -NR20ASO2R20D, -NR20AC(O)R20C, -NR20AC(O)OR20C, -NR20AOR20C, -SF5, -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 R20substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R20A, R20B, R20C, and R20Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R20Aand R20Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X20is independently –F, -Cl, -Br, or –I; n20 is an integer from 0 to 4; m20 and v20 are independently 1 or 2; and z20 is an integer from 0 to 5.

50. The compound of claim 49, wherein R20is independently halogen or -CX203.

51. The compound of claim 49, wherein R20is independently -F, -Cl, or -CF3.

52. The compound of claim 49, wherein two R20substituents are joined to form a substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

53. The compound of claim 49, wherein z20 is 1 or 2.

54. The compound of claim 1, wherein R2is55. The compound of claim 1, having the formula: N56. The compound of claim 1, having the formula:

57. A pharmaceutical composition comprising the compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

58. A method of treating a coronavirus infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeuticallyeffective amount of the compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein the coronavirus infection is a SARS- CoV-2 infection, a SARS-CoV-1 infection, or a MERS-CoV infection.

60. The method of claim 58, wherein the coronavirus infection is a SARS- CoV-2 infection.

61. The method of claim 58, wherein the coronavirus infection is a human CoV alpha 229E infection, a human CoV alpha NL63 infection, a human CoV beta HKU1 infection, a human CoV beta OC43 infection, a SARS-CoV-2 Delta infection, a SARS-CoV- 2 Omicron XBB infection, a SARS-CoV-2 Omicron XBB.1.16 infection, a SARS-CoV-2 Omicron XBB.1.5 infection, a SARS-CoV-2 Omicron EG.5.1 infection, a SARS-CoV-2 Omicron BA.2 infection, a SARS-CoV-2 Omicron BQ.1.1 infection, a SARS-CoV-2 Omicron BA.2.86.1 infection, a SARS-CoV-2 WA.1 infection, a SARS-CoV-2 WA.1 MPro L50F / E166Q / L167F infection, a SARS-CoV-2 WA.1 MPro L50F / E166A / L167F infection, a SARS-CoV-2 MPro A173V infection, a SARS-CoV-2 MPro S144A infection, a SARS-CoV- 2 MPro E166Q infection, a SARS-CoV-2 MPro P168Δ infection, a SARS-CoV-2 MPro Q192T infection, a SARS-CoV-1 infection, or a MERS-CoV infection.

62. The method of claim 58, wherein the subject is not administered a pharmacokinetic enhancer.

63. The method of claim 62, wherein the pharmacokinetic enhancer is a protease inhibitor.

64. The method of claim 62, wherein the pharmacokinetic enhancer is a CYP3A inhibitor.

65. The method of claim 62, wherein the pharmacokinetic enhancer is ritonavir or cobicistat.

66. A method of reducing the level of activity of an Mpro protein in a cell, said method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof.

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