WO2025175019A1

WO2025175019A1 - Phd ligands and uses thereof

Info

Publication number: WO2025175019A1
Application number: PCT/US2025/015811
Authority: WO
Inventors: Danica GALONIC FUJIMORI; R. Jeffrey Neitz; David P. BYUN; Jonathan SANDOVAL; Meng Yao ZHANG
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2024-02-14
Filing date: 2025-02-13
Publication date: 2025-08-21
Anticipated expiration: 2026-08-14

Abstract

Described herein, inter alia, are PHD ligands and uses thereof.

Description

PHD LIGANDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/553,523 filed February 14, 2024, which is incorporated herein by reference in its entirety and for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This invention was made with government support under grant no. R01 CA250459, awarded by The National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] Various hematological malignancies are characterized by the presence of fusion oncoproteins involving the nucleoporin 98 (NUP98). NUP98 fusions are present in approximately 10% of pediatric acute myeloid leukemia cases (1-4,12). Particularly concerning is the high prevalence of NUP98 oncofusions in pediatric patients resistant to chemotherapy, where NUP98 fusions are observed in approximately 50% of cases (1-4). NUP98 forms fusions with over 30 binding partners, many of which associate with chromatin (10,13-15). These include fusions with DNA-binding homeodomains and fragments of chromatin-modifying enzymes, including histone-binding domains such as plant homeodomains (PHD), PWWP domains, and SET domains. Seminal investigations have determined that NUP98 fusion oncoproteins transform hematopoietic stem cells and act as drivers of pediatric leukemias (8-10). Despite their high prevalence in hematological malignancies, direct targeting of any NUP98 fusion oncoprotein is yet to be achieved. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY [0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: [0005] Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [0006] R¹ is independently oxo, halogen, - - - - -OCH2X¹, -OCHX¹ ₂, -CN, -SO_n1R^1D, -SO v₁NR^1AR^1B, -NR^1CC(O)NR^1AR^1B, -N(O)_m1, -NR^1AR^1B, -C(O)R^1C, -C(O)OR^1C, -OC(O)R^1C, -OC(O)OR^1C, -C(O)NR^1AR^1B, -C(NR^1C)NR^1AR^1B, -OC(O)NR^1AR^1B, -OR^1D, -SR^1D, -NR^1ASO2R^1D, -NR^1AC(O)R^1C, -NR^1AC(O)OR^1C, -NR^1AOR^1C, -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 R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0007] The symbol z1 is an integer from 0 to 11. [0008] R² is 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. [0009] R³ and R⁴ are 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, -SF₅, -N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0010] R^1A, R^1B, R^1C, and R^1D are 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; R^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0011] Each X¹ is independently –F, -Cl, -Br, or –I. The symbol n1 is independently an integer from 0 to 4. The symbols m1 and v1 are independently 1 or 2. [0012] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0013] In an aspect is provided a method of treating an H3K4me3-associated disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG.1. Select chemical compounds for PHD3 finger, chromatin recruitment domain of NUP98-KDM5A fusion. Compounds Ligand-1 and Ligand-2 were identified by high throughput screening. The inhibitory potency was improved through iterative rounds of derivatization, leading to low micromolar ligands such as compounds Ligand-3 and Ligand- 4. Piperidine derivative Ligand-5 served as a structurally related lower affinity ligand. [0015] FIGS.2A-2E. Assessing ligand binding by ¹⁹F NMR. FIG.2A: 1084887 TFA salt, 20 µM. FIG.2B: 1084887 TFA salt, 20 µM + PHD3, 0.5 µM. FIG.2C: 1084887 TFA salt, 20 µM + PHD3, 1.0 µM. FIG.2D: 1084887 TFA salt, 20 µM + PHD3, 2.0 µM. FIG.2E: 1084887 TFA salt, 20 µM + PHD3, 4.0 µM. Normalized integrations are shown in Table 3. DETAILED DESCRIPTION I_{. Definitions} [0016] 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. [0017] 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-. [0018] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C₁-C₁₀ means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-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. [0019] 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. [0020] 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. [0021] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH₂-CH₂-S-CH₂-CH₂- and -CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds. [0022] 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. [0023] 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. [0024] 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. [0025] 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. [0026] 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. [0027] 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. [0028] 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 and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0029] 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. _{[0030] The symbol “ ” denotes the point of attachment of a chemical moiety to the} remainder of a molecule or chemical formula. [0031] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0032] 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: [0033] 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. [0034] 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. [0035] 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). [0036] 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. [0037] 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 the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0038] 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. [0039] 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. [0040] In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0041] 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, -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-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, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -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-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 (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- 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: (a) oxo, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, , 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-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, 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, -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-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). [0042] 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-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-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0043] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃- 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. [0044] 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. [0045] 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- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-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-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0046] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted 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-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0047] 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). [0048] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. [0049] 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. [0050] 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. [0051] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0052] 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. [0053] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R¹ may be substituted with one or more first substituent groups denoted by R^1.1, R² may be substituted with one or more first substituent groups denoted by R^2.1, R³ may be substituted with one or more first substituent groups denoted by R^3.1, R⁴ may be substituted with one or more first substituent groups denoted by R^4.1, R⁵ may be substituted with one or more first substituent groups denoted by R^5.1, and the like up to or exceeding an R¹⁰⁰ that may be substituted with one or more first substituent groups denoted by R^100.1. As a further example, R^1A may be substituted with one or more first substituent groups denoted by R^1A.1, R^2A may be substituted with one or more first substituent groups denoted by R^2A.1, R^3A may be substituted with one or more first substituent groups denoted by R^3A.1, R^4A may be substituted with one or more first substituent groups denoted by R^4A.1, R^5A may be substituted with one or more first substituent groups denoted by R^5A.1 and the like up to or exceeding an R^100A may be substituted with one or more first substituent groups denoted by R^100A.1. As a further example, L¹ may be substituted with one or more first substituent groups denoted by R^L1.1, L² may be substituted with one or more first substituent groups denoted by R^L2.1, L³ may be substituted with one or more first substituent groups denoted by R^L3.1, L⁴ may be substituted with one or more first substituent groups denoted by R^L4.1, L⁵ may be substituted with one or more first substituent groups denoted by R^L5.1 and the like up to or exceeding an L¹⁰⁰ which may be substituted with one or more first substituent groups denoted by R^L100.1. Thus, each numbered R group or L group (alternatively referred to herein as R^WW or L^WW wherein “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 R^WW.1 or R^LWW.1, respectively. In turn, each first substituent group (e.g., R^1.1, R^2.1, R^3.1, R^4.1, R^5.1 … R^100.1; may be one or more groups R^3.2, R^4.2, … . herein as R^WW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R^WW.2. [0054] Finally, each second substituent group (e.g., R^1.2, R^2.2, R^3.2, R^4.2, R^5.2 … R^100.2; R^1A.2, R^2A.2, R^3A.2, R^4A.2, R^5A.2 … R^100A.2; R^L1.2, R^L2.2, R^L3.2, R^L4.2, R^L5.2 … R^L100.2) may be further R^4.3, R^5.3 … R^100.3; R^1A.3, R^2A.3, R^3A.3, R^4A.3, R^5A.3 … R^100A.3; R^L1.3, R^L2.3, R^L3.3, R^L4.3, R^L5.3 … R^L100.3; represented herein as R^WW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R^WW.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. [0055] Thus, as used herein, R^WW represents 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, L^WW is 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 R^WW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3. Similarly, each L^WW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^LWW.1; each first substituent group, R^LWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^LWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^LWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if R^WW is phenyl, the said phenyl group is optionally substituted by one or more R^WW.1 groups as defined herein below, e.g., when R^WW.1 is R^WW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R^WW.2, which R^WW.2 is optionally substituted by one or more R^WW.3. By way of example when the R^WW group is phenyl substituted by R^WW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to: . [0056] -OCX^WW.13, -OCH2X^WW.1, -OCHX^WW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, ^NHC(O)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -N₃, R^WW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^WW.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), R^WW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R^WW.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), R^WW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.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, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., , unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl , unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 or 5 to 6 membered). X^WW.1 is independently –F, -Cl, -Br, or –I. [0057] R^WW.2 is independently oxo, -CX^WW.23, -CHX^WW.22, -CH2X^WW.2, - -OCHX^WW.2 ₂, - SH, (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^WW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 2 to 3 membered, or 4 to 5 membered), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R^WW.3- substituted or unsubstituted heterocycloalkyl 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.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, R^WW.2 is independently oxo, halogen, -CX^WW.2 ₃, -CHX^WW.2 ₂, -CH₂X^WW.2, -OCX^WW.2 ₃, -OCH2X^WW.2, -OCHX^WW.22, -CN, - - - - - - - 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), 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). X^WW.2 is independently –F, -Cl, -Br, [0058] R^{WW 3} is independently oxo, halogen, -CX^{WW 3} ₃, -CHX^WW'³ ₂, -CH₂X^WW'³, -OCX^{WW 3}3, -OCH₂X^{WW 3}, -OCHX^{WW 3} ₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO3H, -OSO3H, -SO₂NH₂, -NHNH2, -ONH2, -NHC(O)NHNH₂, -NHC(O)NH₂, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-C₈, Ci-C₆, C1-C4, or Ci- C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-Ce, 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, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^{WW 3} is independently -F, -Cl, -Br, or -I.

[0059] Where two different R^ww substituents 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 R^{WW 1}; each first substituent group, R^{WW 1}, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^{ww 2}; and each second substituent group, R^{WW 2}, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^ww'³; and each third substituent group, R^{WW 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 R^ww substituents joined together to form an openly substituted ring, the “WW” symbol in the R and R^{WW 3} refers to the designated number of one of the two different R^ww substituents. For example, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, _is _and Alternatively, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, is R _is and _ANd in thi paragraph are as defined in the s preceding paragraphs.

[0060] IS independently oxo, halogen, -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 or unsubstituted 6 membered, 4 to 5 membered, or 5 to 6 membered), R^LWW.2-substituted or unsubstituted aryl substituted or unsubstituted heteroaryl (e.g., 5 to or 5 to 6 membered). In embodiments, is independently oxo, -OCHX^LWW.1 ₂, -CN, - C₄, or C₁- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl C₃- C₃- C₄-C₆, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 6 4 to 5 membered, or 5 to 6 membered), unsubstituted C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, or 5 to 6 membered). X^LWW.1 is independently –F, -Cl, -Br, or –I. [0061] R^LWW.2 is independently oxo, halogen, -CX^LWW.2 ₃, -CHX^LWW.2 ₂, -CH₂X^LWW.2, - -OCHX^LWW.22, - -SH, , membered, 2 to 3 membered, or 4 to 5 , cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R^LWW.3- substituted or unsubstituted heterocycloalkyl 3 to 8 3 to 6 4 to 6 membered, 4 to 5 membered, or 5 to 6 (e.g., C6-C12, C6-C10, or phenyl), or R^LWW.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, R^LWW.2 is independently oxo, halogen, -CX^LWW.23, -CHX^LWW.22, -CH2X^LWW.2, -OCX^LWW.23, -OCH2X^LWW.2, -OCHX^LWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e. 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). X^LWW.2 is independently –F, -Cl, -Br, or –I. [0062] R^LWW.3 is independently oxo, 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 C6, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 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, or 5 to 6 membered). X^LWW.3 is independently –F, -Cl, -Br, or –I. [0063] In the event that any R group recited in a claim or chemical formula description set forth herein (R^WW substituent) is not specifically defined in this disclosure, then that R group (R^WW group) is hereby defined as independently oxo, halogen, -CX^WW3, -CHX^WW2, -CH₂X^WW, -OCX^WW ₃, -OCH₂X^WW, -OCHX^WW ₂, -CN, -OH, -NO₂, to or 4 to 5 membered), (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.1- substituted or unsubstituted heterocycloalkyl to 6 membered, 4 to 5 membered, or 5 to 6 (e.g., C6-C12, C6-C10, or phenyl), or R^WW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WW is independently –F, -Cl, -Br, or –I. “WW” represents the stated number of t_{he subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). WW.3} _{and R are} as defined above. [0064] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an L^WW substituent) is not explicitly defined, then that L group (L^WW group) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R^LWW.1-substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.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), R^LWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R^LWW.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), R^LWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or R^LWW.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.). R^LWW.1, as well as R^LWW.2 and R^LWW.3 are as defined above. [0065] 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. [0066] 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. [0067] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in isomeric forms, all such isomeric forms of the compounds being within the scope of the disclosure. [0068] 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. [0069] 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. [0070] 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. [0071] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. [0072] 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. [0073] 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. [0074] 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). [0075] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex. [0076] 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. [0077] “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. [0078] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0079] 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 R¹³ substituents are present, each R¹³ substituent may be distinguished as R^13.A, R^13.B, R^13.C, R^13.D, etc., wherein each of R^13.A, R^13.B, R^13.C, R^13.D, etc. is defined within the scope of the definition of R¹³ and 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. [0080] 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. [0081] 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. [0082] 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. [0083] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. [0084] 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. [0085] 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. [0086] 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 other _{heterologous location, e.g., in a genome of a recombinant organism, such that it is not} associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant. [0087] “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). [0088] 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. [0089] 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. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. 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. [0090] 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). [0091] “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). [0092] “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. [0093] 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. [0094] 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. [0095] 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. [0096] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component. [0097] 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. [0098] 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. [0099] 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.). [0100] 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. [0101] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human. [0102] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, liver cancer, stomach cancer, or glioblastoma). In embodiments, the disease is hepatitis B. [0103] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, _{hepatocellular carcinoma, or prostate cancer.} [0104] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [0105] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma. [0106] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma. [0107] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular _{melanoma, subungal melanoma, or superficial spreading melanoma.} [0108] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0109] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast. [0110] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin. [0111] The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs. [0112] The term “viral infection” refers to a disease or condition that can be caused by organisms such as a virus. In embodiments, the viral infection is hepatitis B. [0113] As used herein, the term “H3K4me3-associated disease” refers to any disease or condition caused by aberrant activity or signaling of enzymes depositing (e.g., KMT2A-F) or removing (e.g., KDM5A-D demethylases) H3K4 trimethylation and readers that bind to an H3K4-trimethylation (H3K4me3), such as a protein including a plant homeodomain (PHD) finger. In embodiments, the H3K4me3-associated disease is a cancer (e.g., acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, liver cancer, stomach cancer, or glioblastoma). In embodiments, the H3K4me3-associated disease is hepatitis B. [0114] 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. [0115] 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 include ¹⁸F, ³²P, ³³P, ⁴⁵Ti, ⁴⁷Sc, ⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴Tc, ⁹⁴Tc, ^99mTc, ⁹⁹Mo, ¹⁰⁵Pd, 1^54- 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. [0116] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, ¹⁸F, ³²P, ³³P, ⁴⁵Ti, ⁴⁷Sc, ⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴Tc, ⁹⁴Tc, ^99mTc, ⁹⁹Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ^154-158Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴Ir, ¹⁹⁸Au, ¹⁹⁹Au, ²¹¹At, ²¹¹Pb, ²¹²Bi, ²¹²Pb, ²¹³Bi, ²²³Ra and ²²⁵Ac. 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. [0117] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0118] 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. [0119] 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. [0120] 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, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. 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. [0121] 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. [0122] 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. [0123] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer or viral infection) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within 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. [0124] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer or viral 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. [0125] 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. [0126] 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. [0127] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density. [0128] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. [0129] 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. [0130] 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. [0131] 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. [0132] 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. [0133] 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. [0134] 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 Cys1619 of KDM5A when the selected residue occupies the same essential spatial or other structural relationship as Cys1619 of KDM5A. In some embodiments, where a selected protein is aligned for maximum homology with KDM5A, the position in the aligned selected protein aligning with Cys1619 is said to correspond to Cys1619. 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 KDM5A and the overall structures compared. In this case, an amino acid that occupies the same essential position as Cys1619 in the structural model is said to correspond to the Cys1619 residue. [0135] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome. [0136] 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. [0137] The term “plant homeodomain” or “PHD” or “PHD finger” as used herein refers to a Cys₄-His-Cys₃ zinc-finger-like motif found in nuclear proteins and is involved in chromatin remodeling and transcriptional regulation. The term “PHD3” as used herein refers to the third PHD domain of KDM5A and the PHD domain in the NUP98-KDM5A fusion oncoprotein. [0138] The term “H3K4me3” as used herein refers to a modification to the DNA packaging protein histone H3 that indicates trimethylation at the fourth lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. As used herein the term “PHD3-H3K4me3 interaction” refers to the binding interaction between PHD3 and H3K4me3. [0139] The term “histone H3” as used herein refers to one of the histone proteins (including homologs, isoforms, and functional fragments thereof) involved in the structure of chromatin in eukaryotic cells. The term includes any recombinant or naturally-occurring form of histone H3 variants thereof that maintain histone H3 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype histone H3). The term “histone H3” may refer to the nucleotide sequence or protein sequence of human histone H3 (e.g., UniProt P84243, RefSeq NP_002098.1, RefSeq NP_005315.1, RefSeq NM_002107.4, or RefSeq NM_005324.4,). [0140] The term “NUP98-KDM5A” as used herein refers to a fusion oncoprotein that contains the N-terminal segment of NUP98 and the C terminal segment of KDM5A, and includes the PHD3 domain of KDM5A that recognizes H3K4me3. [0141] The term “nuclear pore complex protein Nup98-Nup96” or “NUP98” as used herein refers to a protein (including homologs, isoforms, and functional fragments thereof) that in humans is encoded by the NUP98 gene. The term includes any recombinant or naturally- occurring form of NUP98 variants thereof that maintain NUP98 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype NUP98). The term “NUP98” may refer to the nucleotide sequence or protein sequence of human NUP98 (e.g., Entrez 4928, UniProt P52948, RefSeq NP_005378.4, RefSeq NP_057404.2, RefSeq NP_624357.1, RefSeq NP_624358.2, RefSeq NM_005387.6, RefSeq NM_016320.4, RefSeq NM_139131.4, or RefSeq NM_139132.3). [0142] The term “lysine-specific demethylase 5A” or “KDM5A” as used herein refers to a protein (including homologs, isoforms, and functional fragments thereof) that in humans is encoded by the KDM5A gene. The term includes any recombinant or naturally-occurring form of KDM5A variants thereof that maintain KDM5A activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype KDM5A). The term “KDM5A” may refer to the nucleotide sequence or protein sequence of human KDM5A (e.g., Entrez 5927, UniProt P29375, RefSeq NP_001036068.1, or RefSeq NM_001042603.2). I_{I. Compounds} [0143] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: . [0144] Ring A is cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl (e.g., C₆-C₁₀ or phenyl), or heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0145] R¹ is independently oxo, - - - - -OCH2X¹, -OCHX¹2, -CN, -SOn1R^1D, -SOv1NR^1AR^1B, -NR^1CC(O)NR^1AR^1B, -N(O)m1, -NR^1AR^1B, -C(O)R^1C, -C(O)OR^1C, -OC(O)R^1C, -OC(O)OR^1C, -C(O)NR^1AR^1B, -C(NR^1C)NR^1AR^1B, -OC(O)NR^1AR^1B, -OR^1D, -SR^1D, -NR^1ASO₂R^1D, -NR^1AC(O)R^1C, -NR^1AC(O)OR^1C, -NR^1AOR^1C, -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 R¹ substituents 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). [0146] The symbol z1 is an integer from 0 to 11. [0147] R² is 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 (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). [0148] R³ and R⁴ are 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, -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), or 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). [0149] R^1A, R^1B, R^1C, and R^1D are 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, 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); R^1A and R^1B substituents 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). [0150] Each X¹ is independently –F, -Cl, -Br, or –I. [0151] The symbol n1 is independently an integer from 0 to 4. [0152] The symbols m1 and v1 are independently 1 or 2. [0153] In embodiments, the compound has the formula: I). Ring A, R¹, z1, R³, and R⁴ are as described herein, including in embodiments. [0154] Ring B is cycloalkyl , heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), aryl (e.g., C6-C10 or phenyl), or heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0155] R⁵ is independently oxo, - - - - - - - - - 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., to 6 membered, 4 to 5 membered, or 5 to 6 membered), 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 R⁵ substituents 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 to 6 membered, 4 to 5 membered, or 5 to 6 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). [0156] The symbol z5 is an integer from 0 to 11. [0157] R^5A, R^5B, R^5C, and R^5D are independently hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, 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); R^5A and R^5B substituents 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. [0158] Each X⁵ is independently –F, -Cl, -Br, or –I. [0159] The symbol n5 is independently an integer from 0 to 4. [0160] The symbols m5 and v5 are independently 1 or 2. [0161] In embodiments, Ring A is C3-C8 cycloalkyl, 3 to 8 membered heterocycloalkyl, C6- C₁₀ aryl, or 5 to 10 membered heteroaryl. In embodiments, Ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, or 5 to 10 membered heterocycloalkyl. In embodiments, Ring A is C3- C₈ cycloalkyl. In embodiments, Ring A is 3 to 8 membered heterocycloalkyl. In embodiments, Ring A is C6-C10 aryl. In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments, Ring A is phenyl or 5 to 6 membered heteroaryl. In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments, Ring A is phenyl. In embodiments, Ring A is 5 to 6 membered heteroaryl. [0162] In embodiments, Ring A is phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, indazolyl, triazolopyridinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or pyridonyl. In embodiments, Ring A is phenyl or pyridyl. In embodiments, Ring A is phenyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyrimidinyl. In embodiments, Ring A is pyridazinyl. In embodiments, Ring A is naphthyridinyl. In embodiments, Ring A is indazolyl. In embodiments, Ring A is triazolopyridinyl. In embodiments, Ring A is piperidinyl. In embodiments, Ring A is tetrahydropyranyl. In embodiments, Ring A is morpholinyl. In embodiments, Ring A is pyridonyl. nts, In 5 5 , s 10

. . . [0165] In embodiments, Ring B is C₃ C₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C₆- C10 aryl, or 5 to 10 membered heteroaryl. In embodiments, Ring B is C3-C8 cycloalkyl. In embodiments, Ring B is 3 to 8 membered heterocycloalkyl. In embodiments, Ring B is C₆- C10 aryl. In embodiments, Ring B is 5 to 10 membered heteroaryl. In embodiments, Ring B is phenyl or 5 to 6 membered heteroaryl. In embodiments, Ring B is phenyl. In embodiments, Ring B is 5 to 6 membered heteroaryl. [0166] In embodiments, Ring B is phenyl, pyrazolyl, isoxazolyl, or pyridyl. In embodiments, Ring B is phenyl. In embodiments, Ring B is pyrazolyl. In embodiments, Ring B is isoxazolyl. In embodiments, Ring B is pyridyl. , , wherein R⁵ and z5 are as described herein, including in embodiments. In In embodiments, [0169] In embodiments, a substituted R¹ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R¹ 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 R¹ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹ is substituted, it is substituted with at least one lower substituent group. [0170] In embodiments, a substituted ring formed when two R¹ substituents 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 R¹ substituents 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 R¹ substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R¹ substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R¹ substituents are joined is substituted, it is substituted with at least one lower substituent group. [0171] In embodiments, a substituted R^1A (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 R^1A 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 R^1A is substituted, it is substituted with at least one substituent group. In embodiments, when R^1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1A is substituted, it is substituted with at least one lower substituent group. [0172] In embodiments, a substituted R^1B (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 R^1B 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 R^1B is substituted, it is substituted with at least one substituent group. In embodiments, when R^1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1B is substituted, it is substituted with at least one lower substituent group. [0173] In embodiments, a substituted ring formed when R^1A and R^1B substituents 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 R^1A and R^1B substituents 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 R^1A and R^1B substituents 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 R^1A and R^1B substituents 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 R^1A and R^1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0174] In embodiments, a substituted R^1C (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 R^1C 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 R^1C is substituted, it is substituted with at least one substituent group. In embodiments, when R^1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1C is substituted, it is substituted with at least one lower substituent group. [0175] In embodiments, a substituted R^1D (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 R^1D 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 R^1D is substituted, it is substituted with at least one substituent group. In embodiments, when R^1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1D is substituted, it is substituted with at least one lower substituent group. [0176] In embodiments, R^1A is independently hydrogen. In embodiments, R^1A is independently unsubstituted C₁-C₄ alkyl. In embodiments, R^1A is independently unsubstituted methyl. In embodiments, R^1A is independently unsubstituted ethyl. In embodiments, R^1A is independently unsubstituted propyl. In embodiments, R^1A is independently unsubstituted n-propyl. In embodiments, R^1A is independently unsubstituted isopropyl. In embodiments, R^1A is independently unsubstituted butyl. In embodiments, R^1A is independently unsubstituted n-butyl. In embodiments, R^1A is independently unsubstituted isobutyl. In embodiments, R^1A is independently unsubstituted tert-butyl. [0177] In embodiments, R^1B is independently hydrogen. In embodiments, R^1B is independently unsubstituted C1-C4 alkyl. In embodiments, R^1B is independently unsubstituted methyl. In embodiments, R^1B is independently unsubstituted ethyl. In embodiments, R^1B is independently unsubstituted propyl. In embodiments, R^1B is independently unsubstituted n-propyl. In embodiments, R^1B is independently unsubstituted isopropyl. In embodiments, R^1B is independently unsubstituted butyl. In embodiments, R^1B is independently unsubstituted n-butyl. In embodiments, R^1B is independently unsubstituted isobutyl. In embodiments, R^1B is independently unsubstituted tert-butyl. [0178] In embodiments, R^1C is independently hydrogen. In embodiments, R^1C is independently unsubstituted C₁-C₄ alkyl. In embodiments, R^1C is independently unsubstituted methyl. In embodiments, R^1C is independently unsubstituted ethyl. In embodiments, R^1C is independently unsubstituted propyl. In embodiments, R^1C is independently unsubstituted n-propyl. In embodiments, R^1C is independently unsubstituted isopropyl. In embodiments, R^1C is independently unsubstituted butyl. In embodiments, R^1C is independently unsubstituted n-butyl. In embodiments, R^1C is independently unsubstituted isobutyl. In embodiments, R^1C is independently unsubstituted tert-butyl. [0179] In embodiments, R^1D is independently hydrogen. In embodiments, R^1D is independently unsubstituted C1-C4 alkyl. In embodiments, R^1D is independently unsubstituted methyl. In embodiments, R^1D is independently unsubstituted ethyl. In embodiments, R^1D is independently unsubstituted propyl. In embodiments, R^1D is independently unsubstituted n-propyl. In embodiments, R^1D is independently unsubstituted isopropyl. In embodiments, R^1D is independently unsubstituted butyl. In embodiments, R^1D is independently unsubstituted n-butyl. In embodiments, R^1D is independently unsubstituted isobutyl. In embodiments, R^1D is independently unsubstituted tert-butyl. [0180] In embodiments, R¹ is independently halogen, -CX¹3, -CHX¹2, -CH2X¹, -OCX¹3, -OCH2X¹, -OCHX¹2, -CN, -SOn1R^1D, -SOv1NR^1AR^1B, ^NR^1CNR^1AR^1B, ^ONR^1AR^1B, -NR^1CC(O)NR^1AR^1B, -N(O)m1, -NR^1AR^1B, -C(O)R^1C, - -C(O)NR^1AR^1B, -C(NR^1C)NR^1AR^1B, -OC(O)NR^1AR^1B, -OR^1D, -SR^1D, -NR^1ASO₂R^1D, -NR^1AC(O)R^1C, -NR^1AC(O)OR^1C, -NR^1AOR^1C, -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 R¹ substituents 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). [0181] In embodiments, R¹ is 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 R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0182] In embodiments, R¹ is 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; two R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0183] In embodiments, R¹ is independently oxo. In embodiments, R¹ is independently halogen. In embodiments, R¹ is independently –F. In embodiments, R¹ is independently –Cl. In embodiments, R¹ is independently –Br. In embodiments, R¹ is independently –I. In embodiments, R¹ is independently -CCl₃. In embodiments, R¹ is independently -CBr₃. In embodiments, R¹ is independently -CF3. In embodiments, R¹ is independently -CI3. In embodiments, R¹ is independently -CH₂Cl. In embodiments, R¹ is independently -CH₂Br. In embodiments, R¹ is independently -CH2F. In embodiments, R¹ is independently -CH2I. In embodiments, R¹ is independently -CHCl₂. In embodiments, R¹ is independently -CHBr₂. In embodiments, R¹ is independently -CHF2. In embodiments, R¹ is independently -CHI2. In embodiments, R¹ is independently –CN. In embodiments, R¹ is independently –OH. In embodiments, R¹ is independently -NH2. In embodiments, R¹ is independently –COOH. In embodiments, R¹ is independently -CONH₂. In embodiments, R¹ is independently -NO₂. In embodiments, R¹ is independently –SH. In embodiments, R¹ is independently -SO3H. In embodiments, R¹ is independently -OSO₃H. In embodiments, R¹ is independently -SO₂NH₂. In embodiments, R¹ is independently ^NHNH₂. In embodiments, R¹ is independently ^ONH₂. In embodiments, R¹ is independently ^NHC(O)NH₂. In embodiments, R¹ is independently -NHSO₂H. In embodiments, R¹ is independently -NHC(O)H. In embodiments, R¹ is independently -NHC(O)OH. In embodiments, R¹ is independently –NHOH. In embodiments, R¹ is independently -OCCl₃. In embodiments, R¹ is independently -OCBr3. In embodiments, R¹ is independently -OCF3. In embodiments, R¹ is independently -OCI₃. In embodiments, R¹ is independently -OCH₂Cl. In embodiments, R¹ is independently -OCH2Br. In embodiments, R¹ is independently -OCH2F. In embodiments, R¹ is independently -OCH₂I. In embodiments, R¹ is independently -OCHCl₂. In embodiments, R¹ is independently -OCHBr2. In embodiments, R¹ is independently -OCHF2. In embodiments, R¹ is independently -OCHI₂. In embodiments, R¹ is independently -SF₅. In embodiments, R¹ is independently -N3. In embodiments, R¹ is independently unsubstituted C1-C4 alkyl. In embodiments, R¹ is independently unsubstituted methyl. In embodiments, R¹ is independently unsubstituted ethyl. In embodiments, R¹ is independently unsubstituted propyl. In embodiments, R¹ is independently unsubstituted n-propyl. In embodiments, R¹ is independently unsubstituted isopropyl. In embodiments, R¹ is independently unsubstituted butyl. In embodiments, R¹ is independently unsubstituted n-butyl. In embodiments, R¹ is independently unsubstituted isobutyl. In embodiments, R¹ is independently unsubstituted tert-butyl. In embodiments, R¹ is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R¹ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹ is independently unsubstituted methoxy. In embodiments, R¹ is independently unsubstituted ethoxy. In embodiments, R¹ is independently unsubstituted propoxy. In embodiments, R¹ is independently unsubstituted n-propoxy. In embodiments, R¹ is independently unsubstituted isopropoxy. In embodiments, R¹ is independently unsubstituted butoxy. In embodiments, R¹ is independently substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹ is independently substituted or unsubstituted piperazinyl. In embodiments, R¹ is independently substituted piperazinyl. [0184] In embodiments, R¹ is independently halogen, -CX¹ ₃, -NR^1AR^1B, -C(O)R^1C, -OR^1D, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹ is independently halogen, -CX¹3, -C(O)R^1C, -OR^1D, substituted or unsubstituted C₁-C₄ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹ is independently -CX¹3, wherein X¹ is as described herein, including in embodiments. In embodiments, R¹ is independently -NR^1AR^1B, wherein R^1A and R^1B are as described herein, including in embodiments. In embodiments, R¹ is independently -C(O)R^1C, wherein R^1C is as described herein, including in embodiments. In embodiments, R¹ is independently -OR^1D, wherein R^1D is as described herein, including in embodiments. [0185] In embodiments, R¹ is independently -F, -Cl, -Br, -CF3, -NH2, unsubstituted methyl, O , independently -F, -Cl, -Br, -CF₃, unsubstituted methyl, unsubstituted or . In embodiments, R¹ is . In embodiments, R¹ is O NH N ₂ independently . In embodiments, R¹ is In embodiments, R¹ is independently . In embodiments, R¹ is independently . [0186] In embodiments, two R¹ substituents are joined to form a 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. In embodiments, two R¹ substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, two R¹ substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two R¹ substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R¹ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. [0187] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. In embodiments, z1 is 6. In embodiments, z1 is 7. In embodiments, z1 is 8. In embodiments, z1 is 9. In embodiments, z1 is 10. In embodiments, z1 is 11. [0188] 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 R² 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 R² is substituted, it is substituted with at least one substituent group. In embodiments, when R² is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R² is substituted, it is substituted with at least one lower substituent group. [0189] In embodiments, R² is hydrogen. In embodiments, R² is halogen. In embodiments, R² is –F. In embodiments, R² is –Cl. In embodiments, R² is –Br. In embodiments, R² is –I. In embodiments, R² is -CCl₃. In embodiments, R² is -CBr₃. In embodiments, R² is -CF₃. In embodiments, R² is -CI₃. In embodiments, R² is -CH₂Cl. In embodiments, R² is -CH₂Br. In embodiments, R² is -CH2F. In embodiments, R² is -CH2I. In embodiments, R² is -CHCl2. In embodiments, R² is -CHBr₂. In embodiments, R² is -CHF₂. In embodiments, R² is -CHI₂. In embodiments, R² is –CN. In embodiments, R² is –OH. In embodiments, R² is -NH2. In embodiments, R² is –COOH. In embodiments, R² is -CONH₂. In embodiments, R² is -NO₂. In embodiments, R² is –SH. In embodiments, R² is -SO3H. In embodiments, R² is -OSO3H. In embodiments, R² is -SO2NH2. In embodiments, R² is ^NHNH2. In embodiments, R² is ^ONH2. In embodiments, R² is ^NHC(O)NH2. In embodiments, R² is -NHSO2H. In embodiments, R² is -NHC(O)H. In embodiments, R² is -NHC(O)OH. In embodiments, R² is –NHOH. In embodiments, R² is -OCCl₃. In embodiments, R² is -OCBr₃. In embodiments, R² is -OCF3. In embodiments, R² is -OCI3. In embodiments, R² is -OCH2Cl. In embodiments, R² is -OCH₂Br. In embodiments, R² is -OCH₂F. In embodiments, R² is -OCH2I. In embodiments, R² is -OCHCl2. In embodiments, R² is -OCHBr2. In embodiments, R² is -OCHF₂. In embodiments, R² is -OCHI₂. In embodiments, R² is unsubstituted C1-C4 alkyl. In embodiments, R² is unsubstituted methyl. In embodiments, R² is unsubstituted ethyl. In embodiments, R² is unsubstituted propyl. In embodiments, R² is unsubstituted n-propyl. In embodiments, R² is unsubstituted isopropyl. In embodiments, R² is unsubstituted butyl. In embodiments, R² is unsubstituted n-butyl. In embodiments, R² is unsubstituted isobutyl. In embodiments, R² is unsubstituted tert-butyl. In embodiments, R² is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R² is unsubstituted methoxy. In embodiments, R² is unsubstituted ethoxy. In embodiments, R² is unsubstituted propoxy. In embodiments, R² is unsubstituted n-propoxy. In embodiments, R² is unsubstituted isopropoxy. In embodiments, R² is unsubstituted butoxy. [0190] In embodiments, R² is substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R² is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R² is substituted or unsubstituted C6-C10 aryl. In embodiments, R² is substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R² is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R² is substituted or unsubstituted phenyl. In embodiments, R² is substituted or unsubstituted 5 to 6 membered heteroaryl. [0191] In embodiments , wherein Ring B, R⁵, and z5 are as described herein, including in embodiments. [0192] In embodiments, a substituted R³ (e.g., substituted alkyl, substituted heteroalkyl, 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 R³ 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 R³ is substituted, it is substituted with at least one substituent group. In embodiments, when R³ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R³ is substituted, it is substituted with at least one lower substituent group. [0193] In embodiments, R³ is hydrogen. In embodiments, R³ is halogen. In embodiments, R³ is –F. In embodiments, R³ is –Cl. In embodiments, R³ is –Br. In embodiments, R³ is –I. In embodiments, R³ is -CCl3. In embodiments, R³ is -CBr3. In embodiments, R³ is -CF3. In embodiments, R³ is -CI₃. In embodiments, R³ is -CH₂Cl. In embodiments, R³ is -CH₂Br. In embodiments, R³ is -CH2F. In embodiments, R³ is -CH2I. In embodiments, R³ is -CHCl2. In embodiments, R³ is -CHBr₂. In embodiments, R³ is -CHF₂. In embodiments, R³ is -CHI₂. In embodiments, R³ is –CN. In embodiments, R³ is –OH. In embodiments, R³ is -NH2. In embodiments, R³ is –COOH. In embodiments, R³ is -CONH₂. In embodiments, R³ is -NO₂. In embodiments, R³ is –SH. In embodiments, R³ is -SO3H. In embodiments, R³ is -OSO3H. In embodiments, R³ is -SO₂NH₂. In embodiments, R³ is ^NHNH₂. In embodiments, R³ is ^ONH₂. In embodiments, R³ is ^NHC(O)NH₂. In embodiments, R³ is -NHSO₂H. In embodiments, R³ is -NHC(O)H. In embodiments, R³ is -NHC(O)OH. In embodiments, R³ is –NHOH. In embodiments, R³ is -OCCl₃. In embodiments, R³ is -OCBr₃. In embodiments, R³ is -OCF3. In embodiments, R³ is -OCI3. In embodiments, R³ is -OCH2Cl. In embodiments, R³ is -OCH₂Br. In embodiments, R³ is -OCH₂F. In embodiments, R³ is -OCH2I. In embodiments, R³ is -OCHCl2. In embodiments, R³ is -OCHBr2. In embodiments, R³ is -OCHF₂. In embodiments, R³ is -OCHI₂. In embodiments, R³ is unsubstituted C1-C4 alkyl. In embodiments, R³ is unsubstituted methyl. In embodiments, R³ is unsubstituted ethyl. In embodiments, R³ is unsubstituted propyl. In embodiments, R³ is unsubstituted n-propyl. In embodiments, R³ is unsubstituted isopropyl. In embodiments, R³ is unsubstituted butyl. In embodiments, R³ is unsubstituted n-butyl. In embodiments, R³ is unsubstituted isobutyl. In embodiments, R³ is unsubstituted tert-butyl. In embodiments, R³ is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R³ is unsubstituted methoxy. In embodiments, R³ is unsubstituted ethoxy. In embodiments, R³ is unsubstituted propoxy. In embodiments, R³ is unsubstituted n-propoxy. In embodiments, R³ is unsubstituted isopropoxy. In embodiments, R³ is unsubstituted butoxy. In embodiments, R³ is unsubstituted n-butoxy. In embodiments, R³ is unsubstituted isobutoxy. In embodiments, R³ is unsubstituted tert-butoxy. [0194] In embodiments, R³ is hydrogen, -CF3, or unsubstituted C1-C4 alkyl. In embodiments, R³ is hydrogen, -CF₃, unsubstituted methyl, or unsubstituted ethyl. [0195] In embodiments, a substituted R⁴ (e.g., substituted alkyl, substituted heteroalkyl, 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 R⁴ 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 R⁴ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁴ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁴ is substituted, it is substituted with at least one lower substituent group. [0196] In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is halogen. In embodiments, R⁴ is –F. In embodiments, R⁴ is –Cl. In embodiments, R⁴ is –Br. In embodiments, R⁴ is –I. In embodiments, R⁴ is -CCl3. In embodiments, R⁴ is -CBr3. In embodiments, R⁴ is -CF3. In embodiments, R⁴ is -CI₃. In embodiments, R⁴ is -CH₂Cl. In embodiments, R⁴ is -CH₂Br. In embodiments, R⁴ is -CH2F. In embodiments, R⁴ is -CH2I. In embodiments, R⁴ is -CHCl2. In embodiments, R⁴ is -CHBr₂. In embodiments, R⁴ is -CHF₂. In embodiments, R⁴ is -CHI₂. In embodiments, R⁴ is –CN. In embodiments, R⁴ is –OH. In embodiments, R⁴ is -NH2. In embodiments, R⁴ is –COOH. In embodiments, R⁴ is -CONH₂. In embodiments, R⁴ is -NO₂. In embodiments, R⁴ is –SH. In embodiments, R⁴ is -SO3H. In embodiments, R⁴ is -OSO3H. In embodiments, R⁴ is -SO2NH2. In embodiments, R⁴ is ^NHNH2. In embodiments, R⁴ is ^ONH₂. In embodiments, R⁴ is ^NHC(O)NH₂. In embodiments, R⁴ is -NHSO₂H. In embodiments, R⁴ is -NHC(O)H. In embodiments, R⁴ is -NHC(O)OH. In embodiments, R⁴ is –NHOH. In embodiments, R⁴ is -OCCl₃. In embodiments, R⁴ is -OCBr₃. In embodiments, R⁴ is -OCF3. In embodiments, R⁴ is -OCI3. In embodiments, R⁴ is -OCH2Cl. In embodiments, R⁴ is -OCH₂Br. In embodiments, R⁴ is -OCH₂F. In embodiments, R⁴ is -OCH2I. In embodiments, R⁴ is -OCHCl2. In embodiments, R⁴ is -OCHBr2. In embodiments, R⁴ is -OCHF₂. In embodiments, R⁴ is -OCHI₂. In embodiments, R⁴ is unsubstituted C1-C4 alkyl. In embodiments, R⁴ is unsubstituted methyl. In embodiments, R⁴ is unsubstituted ethyl. In embodiments, R⁴ is unsubstituted propyl. In embodiments, R⁴ is unsubstituted n-propyl. In embodiments, R⁴ is unsubstituted isopropyl. In embodiments, R⁴ is unsubstituted butyl. In embodiments, R⁴ is unsubstituted n-butyl. In embodiments, R⁴ is unsubstituted isobutyl. In embodiments, R⁴ is unsubstituted tert-butyl. In embodiments, R⁴ is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁴ is substituted 2 to 4 membered heteroalkyl. In embodiments, R⁴ is unsubstituted methoxy. In embodiments, R⁴ is unsubstituted ethoxy. In embodiments, R⁴ is unsubstituted propoxy. In embodiments, R⁴ is unsubstituted n-propoxy. In embodiments, R⁴ is unsubstituted isopropoxy. In embodiments, R⁴ is unsubstituted butoxy. In embodiments, R⁴ is unsubstituted n-butoxy. In embodiments, R⁴ is unsubstituted isobutoxy. In embodiments, R⁴ is unsubstituted tert-butoxy. [0197] In embodiments, R⁴ is hydrogen or halogen. In embodiments, R⁴ is hydrogen or -Cl. [0198] 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 R⁵ 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 R⁵ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁵ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁵ is substituted, it is substituted with at least one lower substituent group. [0199] In embodiments, a substituted ring formed when two R⁵ substituents 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 R⁵ substituents 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 R⁵ substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R⁵ substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R⁵ substituents are joined is substituted, it is substituted with at least one lower substituent group. [0200] In embodiments, a substituted R^5A (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 R^5A 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 R^5A is substituted, it is substituted with at least one substituent group. In embodiments, when R^5A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5A is substituted, it is substituted with at least one lower substituent group. [0201] In embodiments, a substituted R^5B (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 R^5B 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 R^5B is substituted, it is substituted with at least one substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one lower substituent group. [0202] In embodiments, a substituted ring formed when R^5A and R^5B substituents 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 R^5A and R^5B substituents 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 R^5A and R^5B substituents 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 R^5A and R^5B substituents 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 R^5A and R^5B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0203] In embodiments, a substituted R^5C (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 R^5C 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 R^5C is substituted, it is substituted with at least one substituent group. In embodiments, when R^5C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5C is substituted, it is substituted with at least one lower substituent group. [0204] In embodiments, a substituted R^5D (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 R^5D 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 R^5D is substituted, it is substituted with at least one substituent group. In embodiments, when R^5D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5D is substituted, it is substituted with at least one lower substituent group. [0205] In embodiments, R^5A is independently hydrogen. In embodiments, R^5A is independently unsubstituted C₁-C₄ alkyl. In embodiments, R^5A is independently unsubstituted methyl. In embodiments, R^5A is independently unsubstituted ethyl. In embodiments, R^5A is independently unsubstituted propyl. In embodiments, R^5A is independently unsubstituted n-propyl. In embodiments, R^5A is independently unsubstituted isopropyl. In embodiments, R^5A is independently unsubstituted butyl. In embodiments, R^5A is independently unsubstituted n-butyl. In embodiments, R^5A is independently unsubstituted isobutyl. In embodiments, R^5A is independently unsubstituted tert-butyl. [0206] In embodiments, R^5B is independently hydrogen. In embodiments, R^5B is independently unsubstituted C1-C4 alkyl. In embodiments, R^5B is independently unsubstituted methyl. In embodiments, R^5B is independently unsubstituted ethyl. In embodiments, R^5B is independently unsubstituted propyl. In embodiments, R^5B is independently unsubstituted n-propyl. In embodiments, R^5B is independently unsubstituted isopropyl. In embodiments, R^5B is independently unsubstituted butyl. In embodiments, R^5B is independently unsubstituted n-butyl. In embodiments, R^5B is independently unsubstituted isobutyl. In embodiments, R^5B is independently unsubstituted tert-butyl. [0207] In embodiments, R^5C is independently hydrogen. In embodiments, R^5C is independently unsubstituted C₁-C₄ alkyl. In embodiments, R^5C is independently unsubstituted methyl. In embodiments, R^5C is independently unsubstituted ethyl. In embodiments, R^5C is independently unsubstituted propyl. In embodiments, R^5C is independently unsubstituted n-propyl. In embodiments, R^5C is independently unsubstituted isopropyl. In embodiments, R^5C is independently unsubstituted butyl. In embodiments, R^5C is independently unsubstituted n-butyl. In embodiments, R^5C is independently unsubstituted isobutyl. In embodiments, R^5C is independently unsubstituted tert-butyl. [0208] In embodiments, R^5D is independently hydrogen. In embodiments, R^5D is independently unsubstituted C1-C4 alkyl. In embodiments, R^5D is independently unsubstituted methyl. In embodiments, R^5D is independently unsubstituted ethyl. In embodiments, R^5D is independently unsubstituted propyl. In embodiments, R^5D is independently unsubstituted n-propyl. In embodiments, R^5D is independently unsubstituted isopropyl. In embodiments, R^5D is independently unsubstituted butyl. In embodiments, R^5D is independently unsubstituted n-butyl. In embodiments, R^5D is independently unsubstituted isobutyl. In embodiments, R^5D is independently unsubstituted tert-butyl. [0209] In embodiments, R⁵ is independently halogen, -CX⁵3, -CHX⁵2, -CH2X⁵, -OCX⁵3, -OCH2X⁵, -OCHX⁵2, -CN, -SOn5R^5D, -SOv5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, -N(O)m5, -NR^5AR^5B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, -C(O)NR^5AR^5B, -C(NR^5C)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^5D, -SR^5D, -NR^5ASO₂R^5D, -NR^5AC(O)R^5C, -NR^5AC(O)OR^5C, -NR^5AOR^5C, -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 R⁵ substituents 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). [0210] In embodiments, R⁵ is 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 R⁵ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0211] In embodiments, R⁵ is 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; two R⁵ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0212] In embodiments, R⁵ is independently oxo. In embodiments, R⁵ is independently halogen. In embodiments, R⁵ is independently –F. In embodiments, R⁵ is independently –Cl. In embodiments, R⁵ is independently –Br. In embodiments, R⁵ is independently –I. In embodiments, R⁵ is independently -CCl₃. In embodiments, R⁵ is independently -CBr₃. In embodiments, R⁵ is independently -CF3. In embodiments, R⁵ is independently -CI3. In embodiments, R⁵ is independently -CH₂Cl. In embodiments, R⁵ is independently -CH₂Br. In embodiments, R⁵ is independently -CH2F. In embodiments, R⁵ is independently -CH2I. In embodiments, R⁵ is independently -CHCl₂. In embodiments, R⁵ is independently -CHBr₂. In embodiments, R⁵ is independently -CHF2. In embodiments, R⁵ is independently -CHI2. In embodiments, R⁵ is independently –CN. In embodiments, R⁵ is independently –OH. In embodiments, R⁵ is independently -NH2. In embodiments, R⁵ is independently –COOH. In embodiments, R⁵ is independently -CONH₂. In embodiments, R⁵ is independently -NO₂. In embodiments, R⁵ is independently –SH. In embodiments, R⁵ is independently -SO3H. In embodiments, R⁵ is independently -OSO₃H. In embodiments, R⁵ is independently -SO₂NH₂. In embodiments, R⁵ is independently ^NHNH2. In embodiments, R⁵ is independently ^ONH₂. In embodiments, R⁵ is independently ^NHC(O)NH₂. In embodiments, R⁵ is independently -NHSO₂H. In embodiments, R⁵ is independently -NHC(O)H. In embodiments, R⁵ is independently -NHC(O)OH. In embodiments, R⁵ is independently –NHOH. In embodiments, R⁵ is independently -OCCl₃. In embodiments, R⁵ is independently -OCBr3. In embodiments, R⁵ is independently -OCF3. In embodiments, R⁵ is independently -OCI₃. In embodiments, R⁵ is independently -OCH₂Cl. In embodiments, R⁵ is independently -OCH2Br. In embodiments, R⁵ is independently -OCH2F. In embodiments, R⁵ is independently -OCH₂I. In embodiments, R⁵ is independently -OCHCl₂. In embodiments, R⁵ is independently -OCHBr₂. In embodiments, R⁵ is independently -OCHF₂. In embodiments, R⁵ is independently -OCHI2. In embodiments, R⁵ is independently -SF5. In embodiments, R⁵ is independently -N₃. In embodiments, R⁵ is independently unsubstituted C1-C4 alkyl. In embodiments, R⁵ is independently unsubstituted methyl. In embodiments, R⁵ is independently unsubstituted ethyl. In embodiments, R⁵ is independently unsubstituted propyl. In embodiments, R⁵ is independently unsubstituted n-propyl. In embodiments, R⁵ is independently unsubstituted isopropyl. In embodiments, R⁵ is independently unsubstituted butyl. In embodiments, R⁵ is independently unsubstituted n-butyl. In embodiments, R⁵ is independently unsubstituted isobutyl. In embodiments, R⁵ is independently unsubstituted tert-butyl. In embodiments, R⁵ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁵ is independently unsubstituted methoxy. In embodiments, R⁵ is independently unsubstituted ethoxy. In embodiments, R⁵ is independently unsubstituted propoxy. In embodiments, R⁵ is independently unsubstituted n-propoxy. In embodiments, R⁵ is independently unsubstituted isopropoxy. In embodiments, R⁵ is independently unsubstituted butoxy. [0213] In embodiments, R⁵ is independently halogen, -CF₃, -NR^5AR^5B, or unsubstituted C₁- C4 alkyl. In embodiments, R⁵ is independently -NR^5AR^5B, wherein R^5A and R^5B are as described herein, including in embodiments. In embodiments, R⁵ is independently halogen, -CF3, or unsubstituted C1-C4 alkyl. In embodiments, R⁵ is independently -F, -Cl, -CF₃, -N(CH₃)₂, or unsubstituted methyl. In embodiments, R⁵ is independently -F, -Cl, -CF3, or unsubstituted methyl. [0214] In embodiments, two R⁵ substituents are joined to form a 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. In embodiments, two R⁵ substituents are joined to form a substituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, two R⁵ substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two R⁵ substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R⁵ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. [0215] In embodiments, two R⁵ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, two R⁵ substituents are joined to form an unsubstituted dioxolanyl. In embodiments, two R⁵ substituents are joined to . [0216] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6. In embodiments, z5 is 7. In embodiments, z5 is 8. In embodiments, z5 is 9. In embodiments, z5 is 10. In embodiments, z5 is 11. [0217] In embodiments, when R¹ is substituted, R¹ is substituted with one or more first substituent groups denoted by R^1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.1 substituent group is substituted, the R^1.1 substituent group is substituted with one or more second substituent groups denoted by R^1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.2 substituent group is substituted, the R^1.2 substituent group is substituted with one or more third substituent groups denoted by R^1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹, R^1.1, R^1.2, and R^1.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R¹, R^1.1, R^1.2, and R^1.3, respectively. [0218] In embodiments, when two R¹ substituents 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 R^1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.1 substituent group is substituted, the R^1.1 substituent group is substituted with one or more second substituent groups denoted by R^1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.2 substituent group is substituted, the R^1.2 substituent group is substituted with one or more third substituent groups denoted by R^1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹, R^1.1, R^1.2, and R^1.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R¹, R^1.1, R^1.2, and R^1.3, respectively. [0219] In embodiments, when R^1A is substituted, R^1A is substituted with one or more first substituent groups denoted by R^1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.1 substituent group is substituted, the R^1A.1 substituent group is substituted with one or more second substituent groups denoted by R^1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.2 substituent group is substituted, the R^1A.2 substituent group is substituted with one or more third substituent groups denoted by R^1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1A, R^1A.1, R^1A.2, and R^1A.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R^1A, R^1A.1, R^1A.2, and R^1A.3, respectively. [0220] In embodiments, when R^1B is substituted, R^1B is substituted with one or more first substituent groups denoted by R^1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.1 substituent group is substituted, the R^1B.1 substituent group is substituted with one or more second substituent groups denoted by R^1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.2 substituent group is substituted, the R^1B.2 substituent group is substituted with one or more third substituent groups denoted by R^1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1B, R^1B.1, R^1B.2, and R^1B.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R^1B, R^1B.1, R^1B.2, and R^1B.3, respectively. [0221] In embodiments, when R^1A and R^1B substituents 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 R^1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.1 substituent group is substituted, the R^1A.1 substituent group is substituted with one or more second substituent groups denoted by R^1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.2 substituent group is substituted, the R^1A.2 substituent group is substituted with one or more third substituent groups denoted by R^1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1A.1, R^1A.2, and R^1A.3 have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3 correspond to R^1A.1, R^1A.2, and R^1A.3, respectively. [0222] In embodiments, when R^1A and R^1B substituents 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 R^1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.1 substituent group is substituted, the R^1B.1 substituent group is substituted with one or more second substituent groups denoted by R^1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.2 substituent group is substituted, the R^1B.2 substituent group is substituted with one or more third substituent groups denoted by R^1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1B.1, R^1B.2, and R^1B.3 have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3 correspond to R^1B.1, R^1B.2, and R^1B.3, respectively. [0223] In embodiments, when R^1C is substituted, R^1C is substituted with one or more first substituent groups denoted by R^1C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1C.1 substituent group is substituted, the R^1C.1 substituent group is substituted with one or more second substituent groups denoted by R^1C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1C.2 substituent group is substituted, the R^1C.2 substituent group is substituted with one or more third substituent groups denoted by R^1C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1C, R^1C.1, R^1C.2, and R^1C.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, where ^.2, and R^WW.3 correspond to R^1C, R^1C.1, R^1C.2, and R^1C.3, respectively. [0224] In embodiments, when R^1D is substituted, R^1D is substituted with one or more first substituent groups denoted by R^1D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1D.1 substituent group is substituted, the R^1D.1 substituent group is substituted with one or more second substituent groups denoted by R^1D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1D.2 substituent group is substituted, the R^1D.2 substituent group is substituted with one or more third substituent groups denoted by R^1D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1D, R^1D.1, R^1D.2, and R^1D.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein and R^WW.3 correspond to R^1D, R^1D.1, R^1D.2, and R^1D.3, respectively. [0225] In embodiments, when R² is substituted, R² is substituted with one or more first substituent groups denoted by R^2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1 substituent group is substituted, the R^2.1 substituent group is substituted with one or more second substituent groups denoted by R^2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.2 substituent group is substituted, the R^2.2 substituent group is substituted with one or more third substituent groups denoted by R^2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R², R^2.1, R^2.2, and R^2.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R², R^2.1, R^2.2, and R^2.3, respectively. [0226] In embodiments, when R³ is substituted, R³ is substituted with one or more first substituent groups denoted by R^3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1 substituent group is substituted, the R^3.1 substituent group is substituted with one or more second substituent groups denoted by R^3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2 substituent group is substituted, the R^3.2 substituent group is substituted with one or more third substituent groups denoted by R^3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R³, R^3.1, R^3.2, and R^3.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R³, R^3.1, R^3.2, and R^3.3, respectively. [0227] In embodiments, when R⁴ is substituted, R⁴ is substituted with one or more first substituent groups denoted by R^4.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1 substituent group is substituted, the R^4.1 substituent group is substituted with one or more second substituent groups denoted by R^4.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2 substituent group is substituted, the R^4.2 substituent group is substituted with one or more third substituent groups denoted by R^4.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁴, R^4.1, R^4.2, and R^4.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R⁴, R^4.1, R^4.2, and R^4.3, respectively. [0228] In embodiments, when R⁵ is substituted, R⁵ is substituted with one or more first substituent groups denoted by R^5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1 substituent group is substituted, the R^5.1 substituent group is substituted with one or more second substituent groups denoted by R^5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2 substituent group is substituted, the R^5.2 substituent group is substituted with one or more third substituent groups denoted by R^5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁵, R^5.1, R^5.2, and R^5.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R⁵, R^5.1, R^5.2, and R^5.3, respectively. [0229] In embodiments, when two R⁵ substituents 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 R^5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1 substituent group is substituted, substituent group is substituted with one or more second substituent groups denoted as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2 substituent group is substituted, the R^5.2 substituent group is substituted with one or more third substituent groups denoted by R^5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁵, R^5.1, R^5.2, and R^5.3 have values corresponding to the values R^WW.2, and respectively, as explained in the definitions section above substituent group(s)”, wherein and R^WW.3 correspond to R⁵, R^5.1, R^5.2, and R^5.3, respectively. [0230] In embodiments, when R^5A is substituted, R^5A is substituted with one or more first substituent groups denoted by R^5A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.1 substituent group is substituted, the R^5A.1 substituent group is substituted with one or more second substituent groups denoted by R^5A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.2 substituent group is substituted, the R^5A.2 substituent group is substituted with one or more third substituent groups denoted by R^5A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5A, R^5A.1, R^5A.2, and R^5A.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, explained in the definitions section above R^WW, R^WW.1, R^WW.2, and R^WW.3 R^5A.3, respectively. 5 [0231] In embodiments, when R ^B is substituted, R^5B is substituent groups denoted by R^5B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.1 substituent group is substituted, the R^5B.1 substituent group is substituted with one or more second substituent groups denoted by R^5B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.2 substituent group is substituted, the R^5B.2 substituent group is substituted with one or more third substituent groups denoted by R^5B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5B, R^5B.1, R^5B.2, and R^5B.3 have values corresponding to the values respectively, as explained in the definitions section above group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3 correspond to R^5B, R^5B.1, R^5B.2, and R^5B.3, respectively. [0232] In embodiments, when R^5A and R^5B substituents 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 R^5A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.1 substituent group is substituted, the R^5A.1 substituent group is substituted with one or more second substituent groups denoted by R^5A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5A.2 substituent group is substituted, the R^5A.2 substituent group is substituted with one or more third substituent groups denoted by R^5A.3 as explained in the definitions section above in the description of “first substituent ”. In the above embodiments, R^5A.1, R^5A.2, and R^5A.3 have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the group(s)”, wherein R^WW.1, R^WW.2, and R^WW.3 correspond to [0233] In embodiments, when R^5A and R^5B substituents 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 R^5B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.1 substituent group is substituted, the R^5B.1 substituent group is substituted with one or more second substituent groups denoted by R^5B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5B.2 substituent group is substituted, the R^5B.2 substituent group is substituted with one or more third substituent groups denoted by R^5B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5B.1, R^5B.2, and R^5B.3 have values corresponding to the values of R^WW.1, R^WW.2, and R^WW.3, as in the definitions section above in the description of “first ^{WW.1 WW.2 WW.3} R , R , and R correspond to [0234] In embodiments, when R^5C is substituted, R^5C is substituted with one or more first substituent groups denoted by R^5C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.1 substituent group is substituted, the R^5C.1 substituent group is substituted with one or more second substituent groups denoted by R^5C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5C.2 substituent group is substituted, the R^5C.2 substituent group is substituted with one or more third substituent groups denoted by R^5C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5C, R^5C.1, R^5C.2, and R^5C.3 have values corresponding to the values respectively, as explained in the definitions section above group(s)”, and R^WW.3 correspond respectively. [0235] In R^5D is substituted with one or more first substituent groups denoted by R^5D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5D.1 substituent group is substituted, the R^5D.1 substituent group is substituted with one or more second substituent groups denoted by R^5D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5D.2 substituent group is substituted, the R^5D.2 substituent group is substituted with one or more third substituent groups denoted by R^5D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5D, R^5D.1, R^5D.2, and R^5D.3 have values corresponding to the values of R^WW, R^WW.1, R^WW.2, explained in the definitions section above R^WW, R^WW.1, R^WW.2, and R^WW.3 R^5D.3, respectively.

[0236] In embodiments, the compound has the formul In embodiments, the compound has the . In embodiments, the compound has the In embodiments, the compound has the In embodiments, the compound has the he 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: OH . In embodiments, the compound has the formu N . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: ula: 5 5 : 5 la: . In embodiments, the compound has the formula: formula: . In embodiments, the compound has the 5 formula: embodiments, the compound has the formula In embodiments, the compound has the In embodiments, the compound has 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). [0238] 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} [0239] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0240] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. In embodiments, the compound is a compound of formula (I) or (II), including embodiments thereof. I_{V. Methods of use} [0241] In an aspect is provided a method of treating an H3K4me3-associated disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is a compound of formula (I) or (II), including embodiments thereof. [0242] In embodiments, the H3K4me3-associated disease is a cancer. In embodiments, the cancer is leukemia. In embodiments, the cancer is acute myeloid leukemia (AML). In embodiments, the cancer is acute megakaryoblastic leukemia (AMKL). In embodiments, the cancer is acute lymphoblastic leukemia (ALL). In embodiments, the cancer is chronic myeloid leukemia (CML). In embodiments, the cancer is prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ER-positive breast cancer. In embodiments, the cancer is triple-negative breast cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is liver cancer. In embodiments, the cancer is hepatocellular carcinoma. In embodiments, the cancer is stomach cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is glioblastoma. In embodiments, the cancer is melanoma. In embodiments, the cancer is esophageal cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is oral cancer. In embodiments, the cancer is Ewing sarcoma. In embodiments, the cancer is glioma. [0243] In embodiments, the H3K4me3-associated disease is a viral infection. In embodiments, the viral infection is hepatitis B. [0244] In an aspect is provided a method of inhibiting the PHD3-H3K4me3 interaction in a cell, the method including contacting the cell with a compound (e.g., an effective amount of a compound) described herein, including in embodiments. In embodiments, the compound is a compound of formula (I) or (II), including embodiments thereof. V. Embodiments [0245] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein aryl, or heteroaryl; R¹ is independently oxo, halogen, -CX¹ ₃, -CHX¹ ₂, -CH₂X¹, -OCX¹ ₃, -OCH₂X¹, or unsubstituted heteroaryl; two R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 11; R² is hydrogen, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ and R⁴ are independently hydrogen, haloge I₃, - - - - - - - - - or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X¹ is independently –F, -Cl, -Br, or –I; n1 is independently an integer from 0 to 4; and m1 and v1 are independently 1 or 2. [0246] Embodiment P2. The compound of embodiment P1, having the formula: R⁵ is independently oxo, halogen, -CX⁵3, -CHX⁵2, -CH2X⁵, -OCX⁵3, -OCH2X⁵, -OCHX⁵2, -CN, -SO_n5R^5D, -SO_v5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R⁵ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 11; R^5A, R^5B, R^5C, and R^5D are 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; R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X⁵ is independently –F, -Cl, -Br, or –I; n5 is independently an integer from 0 to 4; and m5 and v5 are independently 1 or 2. [0247] Embodiment P3. The compound of embodiment P2, wherein Ring B is phenyl or 5 to 6 membered heteroaryl. [0248] Embodiment P4. The compound of embodiment P2, wherein Ring B is phenyl, pyrazolyl, isoxazolyl, or pyridyl. [0249] Embodiment P5. The compound of embodiment P2, wherein Ring B is phenyl. [0250] Embodiment P6. The compound of embodiment P2, is . [0251] Embodiment P7. The compound of one of embodiments P2 to P6, wherein R⁵ is independently halogen, -CF3, or unsubstituted C1-C4 alkyl. [0252] Embodiment P8. The compound of one of embodiments P2 to P6, wherein R⁵ is independently -F, -Cl, -CF₃, or unsubstituted methyl. [0253] Embodiment P9. The compound of one of embodiments P2 to P8, wherein z5 is 1. [0254] Embodiment P10. The compound of one of embodiments P2 to P6, wherein z5 is 0. [0255] Embodiment P11. The compound of one of embodiments P2 to P6, wherein two R⁵ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. [0256] Embodiment P12. The compound of one of embodiments P2 to P6, wherein two R⁵ substituents are joined to form an unsubstituted dioxolanyl. is A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, or 5 to 10 membered heterocycloalkyl. [0259] Embodiment P15. The compound of one of embodiments P1 to P13, wherein Ring A is phenyl or 5 to 6 membered heteroaryl. [0260] Embodiment P16. The compound of one of embodiments P1 to P13, wherein Ring A is phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, indazolyl, triazolopyridinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or pyridonyl. [0261] Embodiment P17. The compound of one of embodiments P1 to P13, wherein Ring A is phenyl or pyridyl. [0262] Embodiment P18. The compound of one of embodiments P1 to P13, wherein , is independently halogen, -CX¹3, -C(O)R^1C, -OR^1D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0264] Embodiment P20. The compound of one of embodiments P1 to P18, wherein R¹ is independently -F, -Cl, -Br, -CF3, unsubstituted methyl, unsubstituted or . P21. The compound of one of embodiments P1 to P20, wherein z1 is [0266] Embodiment P22. The compound of one of embodiments P1 to P18, wherein z1 is 0. [0267] Embodiment P23. The compound of one of embodiments P1 to P13, wherein , . is hydrogen, -CF₃, or unsubstituted C₁-C₄ alkyl. [0269] Embodiment P25. The compound of one of embodiments P1 to P23, wherein R³ is hydrogen, -CF3, unsubstituted methyl, or unsubstituted ethyl. [0270] Embodiment P26. The compound of one of embodiments P1 to P23, wherein R³ is unsubstituted methyl. [0271] Embodiment P27. The compound of one of embodiments P1 to P26, wherein R⁴ is hydrogen or halogen. [0272] Embodiment P28. The compound of one of embodiments P1 to P26, wherein R⁴ is hydrogen or -Cl. [0273] Embodiment P29. The compound of one of embodiments P1 to P26, wherein R⁴ is hydrogen. [0274] Embodiment P30. The compound of embodiment P1 or embodiment P2, having the formula: one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0276] Embodiment P32. A method of treating an H3K4me3-associated disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0277] Embodiment P33. The method of embodiment P32, wherein the H3K4me3- associated disease is a cancer. [0278] Embodiment P34. The method of embodiment P33, wherein the cancer is leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, liver cancer, stomach cancer, or glioblastoma. [0279] Embodiment P35. The method of embodiment P33, wherein the cancer is acute myeloid leukemia. [0280] Embodiment P36. The method of embodiment P33, wherein the cancer is acute megakaryoblastic leukemia. [0281] Embodiment P37. The method of embodiment P32, wherein the H3K4me3- associated disease is a viral infection. [0282] Embodiment P38. The method of embodiment P37, wherein the viral infection is hepatitis B. VI. Additional embodiments [0283] Embodiment 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein aryl, or heteroaryl; R¹ is independently oxo, halogen, -CX¹3, -CHX¹2, -CH2X¹, -OCX¹3, -OCH2X¹, -OCHX¹ ₂, -CN, -SO_n1R^1D, - -NR^1CC(O)NR^1AR^1B, -N(O)_m1, -NR^1AR^1B, -C(O)R^1C, -C(O)OR^1C, -OC(O)R^1C, -OC(O)OR^1C, -C(O)NR^1AR^1B, -C(NR^1C)NR^1AR^1B, -OC(O)NR^1AR^1B, -OR^1D, -SR^1D, -NR^1ASO2R^1D, -NR^1AC(O)R^1C, -NR^1AC(O)OR^1C, -NR^1AOR^1C, -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 R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 11; R² is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH₂I, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, substituted or unsubstituted alkyl, cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ and R⁴ are independently hydrogen, - - - - or cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R^1A, R^1B, R^1C, and R^1D are independently hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -COOH, or or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X¹ is independently –F, -Cl, -Br, or –I; n1 is independently an integer from 0 to 4; and m1 and v1 are independently 1 or 2. [0284] Embodiment 2. The compound of embodiment 1, having the formula: Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R⁵ is independently oxo, halogen, -CX⁵ ₃, -CHX⁵ ₂, -CH₂X⁵, -OCX⁵ ₃, -OCH₂X⁵, -OCHX⁵2, -CN, -SOn5R^5D, -SOv5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, -N(O)_m5, -NR^5AR^5B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, -C(O)NR^5AR^5B, -C(NR^5C)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^5D, -SR^5D, -NR^5ASO2R^5D, -NR^5AC(O)R^5C, -NR^5AC(O)OR^5C, -NR^5AOR^5C, -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 R⁵ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 11; R^5A, R^5B, R^5C, and R^5D are 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; R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X⁵ is independently –F, -Cl, -Br, or –I; n5 is independently an integer from 0 to 4; and m5 and v5 are independently 1 or 2. [0285] Embodiment 3. The compound of embodiment 2, wherein Ring B is phenyl or 5 to 6 membered heteroaryl. [0286] Embodiment 4. The compound of embodiment 2, wherein Ring B is phenyl, pyrazolyl, isoxazolyl, or pyridyl. [0287] Embodiment 5. The compound of embodiment 2, wherein Ring B is phenyl. [0288] Embodiment 6. The compound of embodiment 2, where is . [0289] Embodiment 7. The compound of one of embodiments 2 to 6, wherein R⁵ is independently halogen, -CF3, -NR^5AR^5B, or unsubstituted C1-C4 alkyl. [0290] Embodiment 8. The compound of one of embodiments 2 to 6, wherein R⁵ is independently -F, -Cl, -CF₃, -N(CH₃)₂, or unsubstituted methyl. [0291] Embodiment 9. The compound of one of embodiments 2 to 8, wherein z5 is 1. [0292] Embodiment 10. The compound of one of embodiments 2 to 6, wherein z5 is 0. [0293] Embodiment 11. The compound of one of embodiments 2 to 6, wherein two R⁵ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. [0294] Embodiment 12. The compound of one of embodiments 2 to 6, wherein two R⁵ substituents are joined to form an unsubstituted dioxolanyl. [0295] Embodiment 13. The compound of embodiment 2, is , . Ring A [0297] Embodiment 15. The compound of one of embodiments 1 to 13, wherein Ring A is phenyl or 5 to 6 membered heteroaryl. [0298] Embodiment 16. The compound of one of embodiments 1 to 13, wherein Ring A is phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, indazolyl, triazolopyridinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or pyridonyl. [0299] Embodiment 17. The compound of one of embodiments 1 to 13, wherein Ring A is phenyl or pyridyl. [0300] Embodiment 18. The compound of one of embodiments 1 to 13, wherein , independently halogen, -CX¹3, -NR^1AR^1B, -C(O)R^1C, -OR^1D, substituted or unsubstituted C1- C₄ alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0302] Embodiment 20. The compound of one of embodiments 1 to 18, wherein R¹ is independently -F, -Cl, -Br, -CF3, unsubstituted methyl, unsubstituted , . [0303] Embodiment 21. The compound of one of embodiments 1 to 20, wherein z1 is 1 or 2. [0304] Embodiment 22. The compound of one of embodiments 1 to 18, wherein z1 is 0. [0305] Embodiment 23. The compound of one of embodiments 1 to 13, wherein , ,

[0306] Embodiment 24. The compound of one of embodiments 1 to 23, wherein R³ is hydrogen, -CF₃, or unsubstituted C₁-C₄ alkyl. [0307] Embodiment 25. The compound of one of embodiments 1 to 23, wherein R³ is hydrogen, -CF3, unsubstituted methyl, or unsubstituted ethyl. [0308] Embodiment 26. The compound of one of embodiments 1 to 23, wherein R³ is unsubstituted methyl. [0309] Embodiment 27. The compound of one of embodiments 1 to 26, wherein R⁴ is hydrogen or halogen. [0310] Embodiment 28. The compound of one of embodiments 1 to 26, wherein R⁴ is hydrogen or -Cl. [0311] Embodiment 29. The compound of one of embodiments 1 to 26, wherein R⁴ is hydrogen. [0312] Embodiment 30. The compound of embodiment 1 or embodiment 2, having the formula: , , 5

r f one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0314] Embodiment 32. A method of treating an H3K4me3-associated disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the compound of one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof. [0315] Embodiment 33. The method of embodiment 32, wherein the H3K4me3- associated disease is a cancer. [0316] Embodiment 34. The method of embodiment 33, wherein the cancer is leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, liver cancer, stomach cancer, or glioblastoma. [0317] Embodiment 35. The method of embodiment 33, wherein the cancer is acute myeloid leukemia. [0318] Embodiment 36. The method of embodiment 33, wherein the cancer is acute megakaryoblastic leukemia. [0319] Embodiment 37. The method of embodiment 32, wherein the H3K4me3- associated disease is a viral infection. [0320] Embodiment 38. The method of embodiment 37, wherein the viral infection is hepatitis B. [0321] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES Example 1: [0322] NUP98-KDM5A fusion. Several NUP98 fusion oncoproteins contain plant homeodomains (PHDs), which are chromatin reader domains (7,11,13). PHD domains bind to chromatin by associating with Lys residues as a function of lysine’s methylation status. NUP98-KDM5A fusion oncoprotein, present in approximately 2% of all pediatric AML patients, is associated with poor prognosis and high relapse rate (1,5,21,22). Although observed in all AML subtypes, this fusion oncoprotein is most frequent in acute megakaryoblastic leukemia. NUP98-KDM5A is causative of leukemia through the induction of expression of leukemogenic genes in hematopoietic progenitor cells (7,8). NUP98- KDM5A binds at Hox gene cluster, a locus that is otherwise compacted and repressed during differentiation, through PHD3 finger of KDM5A fusion partner. Binding sites overlap with H3K4me3-positive loci at HoxA/B genes and Meis1, promoting their expression and leukemogenic transformation. Mutational disruption of PHD finger’s ability to bind H3K4me3 marks suppresses leukemogenic transformation, validating PHD3 finger of KDM5A as a target for inhibition of leukemogenesis induced by NUP98-KDM5A fusion (7,11). [0323] Discovery of PHD3 ligands. Leukemogenesis induced by NUP98-KDM5A fusion requires the association of the fusion oncoprotein with chromatin, as mutations in the PHD3 that abrogate binding to H3K4me2/3 mark also abolish leukemic transformation (7). While these seminal findings provide genetic validation of NUP98-KDM5A oncofusion as a target in pediatric leukemias caused by this oncoprotein, the lack of chemical probes that target the PHD3 domain hinders pharmacological validation. [0324] To lay the foundation for therapeutic targeting of pediatric malignancies caused by the NUP98-KDM5A fusion, we undertook a high throughput-based strategy to identify ligands for PHD3. Our strategy relied on fluorescence polarization-based high throughput assay to identify small molecules that disrupt the interaction of a fluorophore-labeled H3K4me3 peptide and MBP-tagged PHD3 domain. In these experiments, H3K4me3 peptide was used as a positive control (72), while DMSO served as a negative control. Among the identified hits were two aryl-substituted pyrazolo[1,5-a]pyrimidin-7-ol derivatives (Ligand-1 and Ligand-2, FIG.1), which inhibited PHD3-H3K4me3 interaction with approximately 30 and 50 µM affinities. The initial SAR determined that hydroxy substituted bicyclic core with a C5-aryl group is necessary for binding. The affinity of the ligands for PHD3 was improved through iterative cycles of derivatization. These optimization efforts resulted in a series of o- substituted-3-pyridinyl derivatives at the C5 carbon of the core, which disrupted H3K4me3- PHD3 interaction with low micromolar potencies (Ligand-3 and Ligand-4, FIG.1). Importantly, the replacement of the pyridine with piperidine reduced affinity for PHD3 (Ligand-5, FIG. 1). [0325] ¹⁹F NMR was used as a secondary binding assay to validate binding to the target (Reference: DOI: 10.1016/j.ejmech.2023.116114). In these experiments, binding of the ligand 1084887 was monitored by assessing the intensity of –CF₃ group in the ligand, relative to the signal of the corresponding group in trifluoroacetic acid (TFA). A decrease in intensity of ¹⁹F signal was used as an indication of binding (FIGS.2A-2E, Table 3). NMR buffer: 20 mM Na-phosphate, 5 mM DTT, 90% H₂O/10% D₂O, at pH 7.0, 2.5% D6-DMSO. Protein (PHD3, 1609-1659), was dialyzed into the NMR buffer. [PHD3] = 0-4 ^M. [0326] We have developed low micromolar ligands that disrupt interaction of a PHD finger domain and chromatin marked by methylation of lysine 4 in histone H3 (H3K4me3). These and related molecules can be used to antagonize oncogenic transformations caused by the aberrant recruitment of PHD fingers to chromatin, including: (a) NUP98-KDM5A fusion oncoprotein, causative of AML; (b) oncogenic transformations caused by related PHD domain-containing proteins, such as NUP98-PHF23 fusion, causative of AML; and (c) oncogenesis caused by overexpression of histone demethylases KDM5A and KDM5B, common in many solid tumors, including that of prostate, breast, lung, gastric, liver, stomach and glioblastoma. Both enzymes are recruited to chromatin, in part, through their C-terminal PHD3 domains which recognize H3K4me3. Ligands that disrupt this recruitment have a potential to prevent oncogenesis. Example 2: Experimental methods [0327] General procedure for preparation of compound 3 [0328] (100 mL) and H2O (20.0 mL) was added Na2CO3 (6.02 g, 56.8 mmol, 2.00 eq), phenylboronic acid (5.20 g, 42.6 mmol, 1.50 eq) and Pd(DTBPF)Cl₂ (1.85 g, 2.84 mmol, 0.10 eq). The mixture was stirred at 100 °C for 5 h under N2 atmosphere. LC-MS showed compound 1 consumed. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was quenched by addition of H2O (200 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100/1 to 0/1). Compound 3 (1.80 g, 10.4 mmol, 36.6% yield) was obtained as brown solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.43 - 7.37 (m, 2H), 7.36 - 7.31 (m, 2H), 7.26 - 7.22 (m, 1H), 2.27 (s, 3H). [0329] General procedure for preparation of compound 4

[0330] To a solution of compound 2 (2.00 g, 14.6 mmol, 1.00 eq) in THF (20.0 mL) was added CDI (3.55 g, 21.0 mmol, 1.50 eq) and DMAP (891 mg, 7.29 mmol, 0.50 eq). The mixture was stirred at 25 ^oC for 5 h under N₂ atmosphere (R1). In another flask, (3-ethoxy-3- oxo-propanoyl) oxypotassium (3.72 g, 21.9 mmol, 1.50 eq) in THF (20.0 mL) was added MgCl₂ (1.67 g, 17.5 mmol, 781 µL, 1.20 eq) at 50 ^oC for 5 h under N₂ atmosphere (R2). R2 was subsequently added to R1 and stirred at 40 ^oC for 5 h. LC-MS showed compound 2 consumed. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was quenched by addition H2O (40.0 mL), and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100/1 to 0/1). Compound 4 (1.40 g, 6.76 mmol, 46.3% yield) was obtained as yellow oil. ¹H NMR: (400 MHz, CDCl₃) δ 9.07 (d, J = 1.90 Hz, 1H), 8.17 (dd, J = 2.30, 8.10 Hz, 1H), 7.35 - 7.30 (m, 1H), 4.26 (q, J = 7.20 Hz, 2H), 4.03 (s, 2H), 2.68 (s, 3H), 1.33 - 1.27 (m, 3H). [0331] General procedure for preparation of Target 1 [0332] To a mL) was added Cpd.4 (143 mg, . was 5 h. LC-MS showed Cpd.3 consumed, several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC ([water (FA) - ACN]; B%: 15% - 45%, 8 min). Target 1 (10.1 mg, 153 umol, 26.7% yield, 97.4% purity) was obtained as green solid. ¹H NMR: (400 MHz, CDCl₃) δ 9.17 - 9.01 (m, 1H), 8.81 (br s, 1H), 7.87 (br d, J = 7.80 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.33 (br dd, J = 8.30, 15.4 Hz, 4H), 6.03 (s, 1H), 2.62 (s, 3H), 2.41 (s, 3H). [0333] General procedure for preparation of Cpd.6 [0334] To a solution of Cpd.5 (2.00 g, 10.5 mmol, 1.00 eq) in THF (20.0 mL) was added CDI (2.55 g, 15.7 mmol, 1.50 eq) and DMAP (639 mg,5.23 mmol, 0.50 eq). The mixture was stirred at 25 ^oC for 5 h under N2 atmosphere (R1). In another flask, (3-ethoxy-3-oxo- propanoyl) oxypotassium (2.67g, 15.7 mmol, 1.50 eq) in THF (20.0 mL) was added MgCl₂ (1.20 g, 12.6 mmol, 515 uL, 1.20 eq) at 50 ^oC for 5 h under N2 atmosphere (R2). R2 was subsequently added to R1 and stirred at 40 ^oC for 5 h. TLC (Petroleum ether/Ethyl acetate = 2/1, Rf = 0.70) showed two new spots was detected. The reaction mixture was quenched by addition H₂O (40.0 mL), and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 100/1 to 0/1). Cpd.6 (1.10 g, 4.21 _{mmol, 40.2% yield) was obtained as white solid. 1H NMR: (400 MHz, CDCl3) δ 9.07 (d, J =} 1.30 Hz, 1H), 8.24 (dd, J = 1.60, 8.20 Hz, 1H), 7.76 (d, J = 8.30 Hz, 1H), 4.31 (q, J = 7.10 Hz, 2H), 1.36 (t, J = 7.20 Hz, 3H). [0335] General procedure for preparation of Target 2 [0336] To a mL) was added Cpd.3 mg, . was for 5 h. LC- MS showed Cpd.3 consumed. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was concentrated in vacuo. The crude product was triturated with MeCN (2.00 mL) at 25 ^oC for 30 min. Target 2 (20.5 mg, 467 umol, 54.0% yield, 97.9% purity) was obtained as light yellow solid. ¹H NMR: (400 MHz, DMSO-d6) δ 9.14 (br s, 1H), 8.47 (br s, 1H), 8.07 (d, J = 8.30 Hz, 1H), 7.63 - 7.43 (m, 4H), 7.41 - 7.29 (m, 1H), 6.16 (br s, 1H), 2.35 (br s, 3H). [0337] General procedure for preparation of Cpd.8 [0338] To a solution of Cpd.7 (2.22 g, 14.4 mmol, 1.00 eq) in THF (10.0 mL) was added CDI (3.52 g, 21.7 mmol, 1.50 eq) and DMAP (885 mg, 7.25 mmol, 0.50 eq). The mixture was stirred at 25 ^oC for 5 h under N2 atmosphere (R1). In another flask, to a solution of (3- ethoxy-3-oxo-propanoyl)oxypotassium (3.70 g, 21.7 mmol, 1.50 eq) in THF (10.0 mL) was added MgCl2 (1.66 g, 17.39 mmol, 713 μL, 1.20 eq). The mixture was stirred at 50 °C for 5 _{h under N2 atmosphere (R2). R2 was added dropwise to R1 and stirred at 40 °C for 5 h.} TLC (petroleum ether/ethyl acetate = 2/1, Rf = 0.67) indicated Cpd.7 was consumed _{completely and two new spots formed. The reaction was clean according to TLC. The} _{reaction mixture was quenched by addition H2O (50.0 mL) at 25 oC and then diluted with} H₂O (20.0 mL) and extracted with ethyl acetate (40.0 mL x 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/1 to 2/1). Cpd.8 (2.11 g, 8.69 mmol, 59.9% yield, 92.0% purity) was obtained as colourless oil. ¹H NMR: (400 MHz, CDCl₃) δ 8.71 (d, J =2.38 Hz, 1H), 8.07 (dd, J =8.76, 2.50 Hz, 1H), 6.74 (d, J =8.88 Hz, 1H), 4.17 - 4.12 (m, 2H), 3.94 (s, 3H), 3.89 (s, 2H), 1.20 (t, J =7.19 Hz, 3H). [0339] General procedure for preparation of Target 3 [0340] To a solution of Cpd.3 (100 mg, 577 μmol, 1.00 eq) in AcOH (1.00 mL) was added Cpd.8 (167 mg, 750 μmol, 1.30 eq). The mixture was stirred at 120 ^oC for 8 h. LC-MS showed Reactant 1 was consumed completely. Several new peaks were shown on LC-MS and 58.0% of desired compound was detected. Concentrated the reaction mixture under reduced pressure. The residue was purified by prep-HPLC ([water(FA)-ACN]; B%: 40%- 70%, 8 min). Target 3 (10.7 mg, 291 μmol, 50.55% yield, 97.0% purity) was obtained as white solid. ¹H NMR: (400 MHz, CDCl₃) δ 9.26 (br d, J =1.88 Hz, 1H), 8.44 (s, 1H), 7.84 (br d, J =5.63 Hz, 1H), 7.32 (br d, J =6.75 Hz, 2H), 7.26 (br d, J =6.25 Hz, 2H), 7.24 - 7.20 (m, 1H), 6.79 (br d, J =7.50 Hz, 1H), 5.87 (s, 1H), 3.98 - 3.87 (m, 3 H), 2.27 (s, 3 H). [0341] General procedure for preparation of Target 4 [0342] To a solution of Cpd.3 (76.3 mg, 441 μmol, 1.20 eq) in AcOH (1.00 mL) was added Cpd.10 (100 mg, 367 μmol, 1.00 eq). The mixture was stirred at 120 °C for 6 h. TLC (petroleum ether/ethyl acetate = 1/1, Rf = 0.40) indicated Reactant 1 was consumed completely and one major new spot formed. Concentrated under reduced pressure. The residue was purified by prep-HPLC ([water(NH3H2O+NH4HCO3)-ACN];B%: 20%-50%, 8 min). Compound Target 4 (20.0mg, 201 μmol, 54.8% yield, 96.0% purity) was obtained as white solid. ¹H NMR: (400 MHz, MeOD) δ 9.07 (d, J =1.50 Hz, 1H), 8.66 (d, J =2.13 Hz, 1H), 8.55 (s, 1H), 7.74 (d, J =7.50 Hz, 2H), 7.44 (t, J =7.63 Hz, 2H), 7.27 - 7.21 (m, 1H), 6.20 (s, 1H), 2.51 (s, 3H). [0343] General procedure for preparation of Cpd.17

[0344] To a solution of Cpd.1 (3.00 g, 17.0 mmol, 1.00 eq) in dioxane (48.0 mL) and H₂O (12.0 mL) was added Na2CO3 (3.61 g, 34.0 mmol, 2.00 eq) and 1, 3-benzodioxol-5-ylboronic acid (4.24 g, 25.5 mmol, 1.50 eq) and Pd(DTBPF)Cl₂ (1.11 g, 1.70 mmol, 0.10 eq). The mixture was stirred at 100 °C for 5 h under N2. LCMS (ET68171-1-P1A1) showed the reactions was completed. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with H2O (20.0 mL) and extracted with EtOAc _{(30.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 2), dried} over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100 / 1 to 0 / 1). Compound 17 (3.00 g, 13.8 mmol, 81.0% yield) was obtained as brown solid. LCMS: product: RT = 0.47 min, [M+H]⁺ = 218, purity = 99.1%. ¹H NMR: (400 MHz, CDCl₃) δ 6.87 - 6.79 (m, 2H), 6.76 (dd, J = 7.94, 1.44 Hz, 1H), 5.96 (s, 2H), 2.23 (s, 3H). [0345] General procedure for preparation of Cpd.11 [0346] A acid (9.78 g, 79.5 mmol, 3.50 eq), Na2CO3 (4.82 g, 45.5 mmol, 2.00 eq) and di-tert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (1.48 g, 2.27 mmol, 0.10 eq) in Dioxane (23.0 mL) and H2O (5.00 mL) was degassed and purged with Ar for 3 times, and then the mixture was stirred at 80 °C for 12 h under Ar atmosphere. TLC (DCM:MeOH=5:1, Rf=0.50) indicated 50% of compound 1 was remained, and one major new spot with larger polarity was detected. LCMS showed 31% of Reactant 1 remained. Several new peaks were shown on LCMS and 35% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, DCM/MeOH=20/1). Compound 11 (3.17 g, 18.2 mmol, 80.7% yield) was obtained as a brown oil. IPC LCMS: product: Rt = 0.25 min, [M+H]⁺ = 175.2, purity = 35.0%. [0347] General procedure for preparation of Target 5 [0348] A mixture of ethyl 3-oxo-3-(3-pyridyl)propanoate (3.87 g, 20.0 mmol, 1.10 eq) and compound 11 (3.17 g, 18.2 mmol, 1.00 eq) in AcOH (21.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 115 °C for 4 h under N2 atmosphere. LC-MS showed 0% of compound 1 remained. Several new peaks were shown on LCMS and 15% of desired compound was detected. The reaction mixture was filtered and the filter cake was concentrated. Target 5 (10.0 mg, 1.65 mmol, 9.06% yield) was obtained as a light yellow solid. IPC LCMS: product: RT = 1.55 min, [M+H]⁺ = 304, purity = 95.4%. LCMS: product: RT = 2.23 min, [M+H]⁺ = 304, purity = 100%. ¹H-NMR: (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.64 - 8.60 (m, 1H), 8.51 (d, J = 6.50 Hz, 2H), 8.45 - 8.38 (m, 3H), 7.52 - 7.47 (m, 1H), 6.28 (s, 1H), 2.60 (s, 3H). [0349] General procedure for preparation of Cpd.12 [0350] A acid (838.0 mg, 6.82 mmol, 4.00 eq), Na2CO3 (541.9 mg, 5.11 mmol, 3.00 eq), di-tert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (111.0 mg, 170.4 μmol, 0.10 eq) in dioxane (3.00 mL) and H2O (0.60 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 h under N₂ atmosphere. TLC (DCM : MeOH = 5 : 1, Rf = 0.50) indicated 20% of compound 1 was remained, and one major new spot with larger polarity was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, DCM/MeOH = 20/1 to 10/1). Compound 12 (200 mg, 1.15 mmol, 67.3% yield) was obtained as black oil. IPC LCMS: product: RT = 0.16 min, [M+H]⁺ = 175, purity = 41.9%. [0351] General procedure for preparation of Target 6 [0352] A mixture of compound 12 (60.0 mg, 344.4 μmol, 1.00 eq) and ethyl 3-oxo-3-(3- pyridyl)propanoate (199.6 mg, 1.03 mmol, 3 eq) in AcOH (0.42 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 115 °C for 4 h under N₂ atmosphere. LC-MS showed 0% of Reactant 1 remained and 92.5% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Target 5 (10.0 mg, 32.9 μmol, 9.57% yield) was obtained as yellow solid. LCMS: product: RT = 2.13 min, [M+H]⁺ = 304, purity = 92.6%. ¹H-NMR: (400 MHz, MeOD) δ 9.07 (d, J = 1.8 Hz, 1H), 8.95 (s, 1H), 8.66 - 8.63 (m, 1H), 8.49 - 8.45 (m, 1H), 8.37 - 8.33 (m, 1H), 8.22 (br d, J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 2H), 6.23 (s, 1H), 2.52 (s, 3H). [0353] General procedure for preparation of cpd 2 [0354] To phenyl] boronic acid (1.62 g, 8.52 mmol, 1.50 eq) in dioxane (20.0 mL) was added Na2CO3 (1.20 g, 11.4 mmol, 2.00 eq) and Pd (DTBPF)Cl₂ (370 mg, 568 μmol, 0.10 eq). The mixture was stirred at 100 °C for 5 h. The reaction mixture was added H2O (20.0 mL), and then extracted with DCM 60.0 mL (20.0 mL * 3). The combined organic layers were washed with brine 20.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Cpd.2 (197 mg, crude) was obtained as yellow oil. [0355] General procedure for preparation of Target 7 [0356] To a solution of Cpd.2 (197 mg, 817 μmol, 1.00 eq) and ethyl 3-oxo-3-(3-pyridyl) propanoate (158 mg, 817 μmol, 1.00 eq) in AcOH (1.97 mL). The mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18250*50mm*10um; mobile phase: [water( NH₄HCO₃)-ACN];gradient:25%-50% B over 10 min). Target 7 (10.0 mg, 256 μmol, 36.5% yield) was obtained as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95 - 8.88 (m, 1H), 8.84 - 8.78 (m, 1H), 7.99 - 7.91 (m, 1H), 7.79 - 7.74 (m, 2H), 7.57 - 7.47 (m, 3H), 6.17 - 6.10 (m, 1H), 2.54 - 2.44 (m, 3H). LCMS: RT = 1.892 min. [0357] General procedure for preparation of Cpd.2 OH HO B H_{N N} [0358] ronic acid (2 .15 g, 17.0 mmol, 1.50 eq), Pd (DTBPF)Cl2 (741 mg, 1.14 mmol, 0.10 eq), Na2CO3 (3.14 g, 22.7 mmol, 2.00 eq) in dioxane (40.0 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 5 h under N2 atmosphere. TLC (petroleum _{ether/ethyl acetate = 0/1, Rf = 0.40) indicated Cpd.1 was consumed completely. The reaction} mixture was added H2O (20.0 mL) and extracted with Ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (40.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100/1 to 0/1). Cpd.2 (120 mg, 677 μmol, 5.96% yield) was obtained as black oil. [0359] General procedure for preparation of target 8 [0360] To a mg, mL) was added ethyl 3-oxo-3-(3-pyridyl) propanoate (158 mg, 817 μmol, 1.00 eq). The reaction mixture was stirred at 120 °C for 2 h. LCMS showed the desired MS was detected. The reaction mixture was concentrated in vacuo. The crude product was triturated with MeOH (1.50 mL) at 25 ^oC for 30 min. Target 8 (20.0 mg, 65.3 μmol, 96.5% purity, 11.6% yield) was obtained as yellow solid. ¹H-NMR: (400 MHz, DMSO-d6) δ 9.18 (br s, 1H), 8.59 (br s, 1H), 8.36 (br d, J = 5.9 Hz, 1H), 8.05 (s, 1H), 7.89 (br s, 1H), 7.47 (br dd, J = 4.8, 7.4 Hz, 1H), 7.14 (br d, J = 0.8 Hz, 1H), 5.96 (s, 1H), 3.90 (s, 3H), 2.39 (s, 3H). LCMS: RT=0.893 min. [0361] General procedure for preparation of Cpd.2 [0362] A yl) boronic acid (4.63 g, 34.09 mmol, 1.50 eq), Pd (DTBPF)Cl₂ (1.48 g, 2.27 mmol, 0.10 eq), Na₂CO₃ (4.82 g, 45.45 mmol, 2.00 eq) in dioxane (40.0 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 5 h under N₂ atmosphere. TLC (petroleum _{ether/ethyl acetate = 0/1, Rf = 0.40) indicated Cpd.1 was consumed completely. The reaction} mixture was added H₂O (20.0 mL) and extracted with Ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (40.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100/1 to 0/1). Cpd.2 (220 mg, 1.17 mmol, 5.17% yield) was obtained as black oil. [0363] General procedure for preparation of target 9 [0364] To a mg, mL) was added ethyl 3-oxo-3-(3-pyridyl) propanoate (111 mg, 577 μmol, 1.00 eq). The reaction mixture was stirred at 120 °C for 2 h. LCMS showed the desired MS was detected. The reaction mixture was concentrated in vacuo. The crude product was triturated with MeOH (1.50 mL) at 25 ^oC for 30 min. Target 9 (10.0 mg, 63.2 μmol, 97.4% purity, 13.1% yield) was obtained as white solid. ¹H-NMR: (400 MHz, DMSO-d₆) δ 12.23 - 12.20 (m, 1H), 8.87 - 8.84 (m, 1H), 8.72 - 8.68 (m, 1H), 8.11 - 8.06 (m, 1H), 7.53 (dd, J = 4.2, 8.1 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.29 - 7.25 (m, 2H), 6.01 (s, 1H), 2.16 (s, 3H), 2.13 (s, 3H). LCMS: RT = 1.292 min. [0365] General procedure for preparation of Cpd.2 [0366] A 4-yl) boronic acid (4.80 g, 34.09 mmol, 1.50 eq), Pd (DTBPF)Cl2 (1.48 g, 2.27 mmol, 0.10 eq), Na₂CO₃ (4.82 g, 45.45 mmol, 2.00 eq) in dioxane (80.0 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 5 h under N2 atmosphere. TLC _{(petroleum ether/ethyl acetate = 0/1, Rf = 0.40) indicated Cpd.1 was consumed completely.} The reaction mixture was added H₂O (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 100/1 to 0/1). Cpd.2 (260 mg, 1.35 mmol, 5.95% yield) was obtained as black oil. [0367] General procedure for preparation of target 10 [0368] To a mg, mL) was added ethyl 3-oxo-3-(3-pyridyl) propanoate (111 mg, 577 μmol, 1.00 eq). The reaction mixture was stirred at 120 °C for 2 h. LCMS showed the desired MS was detected. The reaction mixture was concentrated in vacuo. The crude product was triturated with MeOH (1.50 mL) at 25 ^oC for 30 min. Target 10 (11.4 mg, 32.3 μmol, 99.5% purity, 16.4% yield) was obtained as white solid. ¹H-NMR: (400 MHz, DMSO-d6) δ 12.28 (br s, 1H), 8.95 (br s, 1H), 8.90 (s, 1H), 8.73 (br d, J = 3.6 Hz, 1H), 8.20 - 8.11 (m, 1H), 8.12 (br d, J = 8.1 Hz, 1H), 7.59 - 7.55 (m, 1H), 6.06 (s, 1H), 2.27 (s, 3H), 2.17 (s, 3H), 2.08 (s, 3H). LCMS: RT = 1.802 min. [0369] General procedure for preparation of Target 11 [0370] To (20.0 mL) was added . The mixture was stirred at 118 °C for 4 h. LCMS showed the reaction was completed. The solvent was removed by concentrated under reduced pressure to produce a residue. The crude product was triturated with DCM (3.00 mL) at 25 ^oC for 2 h. Target 11 (30.0 mg, 2.60 mmol, 0.02% yield) was obtained as yellow solid. IPC LCMS: product: RT = 1.21min, [M+H]⁺ = 347, purity = 27.8%. LCMS: product: RT = 1.82 min, [M+H]⁺ = 347, purity = 95.3%. ¹H NMR: (400 MHz, DMSO-d6) δ 12.16 (br s, 1H), 8.94 (br s, 1H), 8.72 (br d, J = 4.00 Hz, 1H), 8.16 (br d, J = 2.88 Hz, 1H), 7.55 (dd, J = 7.82, 4.82 Hz, 1H), 7.11 (br s, 1H), 7.05 – 6.90 (m, 2H), 6.12 – 5.94 (m, 3H), 2.30 (br s, 3H). [0371] General procedure for preparation of Cpd 18a [0372] To a g, was added ethyl 3-oxo-3-(3-pyridyl) propanoate (1.87 g, 9.66 mmol, 1.00 eq). The mixture was stirred at 118 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was added MTBE (10.0 mL) and stirred 30 min, and then filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (8.00 mL) at 25 ^oC for 3 h. Compound 18a (1.00 g, crude) was obtained as yellow solid. IPC LCMS: product: RT = 0.97 min, [M+H]⁺ = 305 purity = 42.1%. [0373] General procedure for preparation of Target 12 mL) and was mg, 4-yl) boronic acid (346 mg, 2.75 mmol, 2.10 eq) and Pd(DTBPF)Cl₂ (85.4 mg, 131 μmol, 0.10 eq). The mixture was stirred at 85 °C for 12 h under N2. LCMS (ET68171-41-P1JC2) showed the reaction was completed. The reaction mixture was diluted with H₂O (10.0 mL) and extracted with EtOAc (15.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.10% NH₃•H₂O). Target 12 (10.0 mg, 97.9 μmol, 0.02% yield) was obtained as yellow solid. IPC LCMS: product: RT = 3.37 min, [M+H]⁺ = 307 purity = 29.3%. LCMS: product: RT = 0.89 min, [M+H]⁺ = 307, purity = 96.1%. ¹H NMR: (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.69 (br d, J = 4.25 Hz, 1H), 8.32 – 8.22 (m, 1H), 8.03 (s, 1H), 7.77 (br s, 1H), 7.54 (dd, J = 7.69, 4.82 Hz, 1H), 6.03 (s, 1H), 3.90 (s, 3H), 2.36 (s, 3H). Example 3: Biological data [0375] Fluorescence polarization (FP) assay protocol for data shown in Table 1 [0376] All assays were run in a black 384-well plate (Corning, 3573), and all reagents were added in technical triplicate using an electronic multichannel pipette. Positive control peptide [H3K4me310-mer, ARTK(me3)QTARKS] is stored as stock solution in water, and compounds are stored as stock solutions in DMSO. Experiments were run in assay buffer consisting of 50 mM HEPES, 50 mM KCl, pH = 7.5, 0.01% Tween-20. All wells contain _{final concentrations as follows (40 μL final volume): 1 μM of His-MBP-PHD3} (KDM5A1601-1662), 10 nM of H3K4me3 FAM-peptide [ARTK(me3)QTARKSK-5FAM], and 20X compound in DMSO (5% total DMSO). Protein master mix consisting of 3.33 μM His-MBP-PHD3 and 0.033% Tween-20 was prepared in assay buffer. 200 nM (20X final concentration) H3K4me3 FAM-peptide [ARTK(me3)QTARKSK-5FAM was prepared in assay buffer. An 11-point half serial dilution series was prepared for compounds and positive control peptide (20X compound diluted in DMSO or 20X positive control peptide diluted in assay buffer). [0377] Before addition to respective wells, the following samples were prepared in PCR tubes and briefly spun down in benchtop centrifuge: ^_{Compounds: 24 μL of assay buffer, then 12 μL of protein master mix, then 2 μL of} 20X compound diluted in DMSO. Incubate for 15 min. ^_{Positive control: 22 μL of assay buffer, then 12 μL of protein master mix, then 2 μL} of DMSO, then 2 μL of 20X positive control peptide in assay buffer. Incubate for 15 min. [0378] Following each addition to assay buffer in samples containing compounds or positive control, samples were mixed using an electronic multichannel pipette (5 μL, 25 cycles). [0379] After the 15 min. pre-incubation, 2 μL of 200 nM (20X final concentration) H3K4me3 FAM-peptide prepared in assay buffer was added to all wells and mixed using an electronic multichannel pipette (5 μL, 25 cycles). [0380] Plates were incubated for 30 minutes. Fluorescence polarization was measured on a SpectraMax M5e (ex/em = 480/530 nm). [0381] Table 1. Potencies measured using a fluorescence polarization (FP) based assay.

E [0382] Chemical synthesis [0383] All solvents (dry) used for synthesis were purchased from commercial suppliers and used without further purification. Reactions were run in oven-dried glassware under an inert atmosphere of argon. [0384] ¹H-NMR [0385] ¹H spectra were recorded at 400 MHz for proton on a Bruker Avance III HD 400 equipped with a Bruker 5 mm BBFO Z-gradient SmartProbe. Chemical shifts (δ) are expressed in parts per million (ppm) and referenced to the relevant solvent peak used for characterization. Coupling constants are reported as Hertz (Hz). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dq, doublet of quartet; ddd, doublet of doublet of doublet, m, multiplet; br, broad. [0386] LC-MS [0387] Experiments were performed on a Waters Acquity Premier UPLC with Xevo G2- XS QTof using an Acquity Premier BEH C18 column (1.7 µm, 130Å, 2.1 mm x 50 mm). The column was run at 50 °C at a 0.6 mL/min flow rate. Solvent A was water containing 0.1% formic acid, and solvent B was acetonitrile containing 0.1% formic acid. The gradient was run as follows: starting at 1% B, maintaining 1% B for 0.50 min, then going to 95% B over 1 min, maintaining 95% B for 0.7 min, returning to 1% B over 0.1 min, then maintaining 1% B over the next 0.3 min. Total run time was 2.6 min. Chromatograms were recorded with a UV detector set at 254 nm, and the mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive mode or negative mode. [0388] Flash chromatography [0389] All normal phase flash column chromatography was performed using a Teledyne ISCO CombiFlash NextGen 300+. Disposable silica columns (comprised of 40-60 µm silica) were purchased from Teledyne ISCO and used at the recommended flow rate for its designated column size. Typical solvents used for flash chromatography were mixtures of dichloromethane/methanol, hexane/ethyl acetate, or petroleum ether/ethyl acetate. [0390] HPLC purification [0391] Unless otherwise specified, preparative HPLC was performed on a Waters 2545 Quaternary Gradient Module equipped with a Waters 2998 Photodiode Array Detector and a Waters Fraction Collector III. The column used was a Waters XSelect Peptide CSH C18 column (3.5 µm, 130Å, 4.6 mm x 100 mm). Solvent A was water containing 0.1% TFA, and solvent B was acetonitrile containing 0.1% TFA. Gradients were run from 0% to 100% B at a 10 mL/min flow rate and a total run time of 30 min with detection at 254 nm. [0392] Synthetic methods [0393] The pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold present in these inhibitors of the PHD3 domain of KDM5A is established as described in Scheme 1. [0394] Scheme 1 [0395] General Step A: Suzuki-Miyaura cross coupling [0396] Reaction was run under inert atmosphere. Solvent is sparged/degassed with inert gas prior to use. [0397] General procedure: 3-amino-4-bromo-5-methylpyrazole (1.0 eq), respective boronic acid (1.50 eq), 1,1′-bis(ditertbutylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (0.1 eq), and Na2CO3 (2.0 eq) were added to reaction vessel, then evacuated and backfilled with inert gas (3x cycles, ending with contents under inert gas). The contents were dissolved in a mixture of dioxane and H2O and stirred at 100 °C until reaction completion as indicated by LC-MS. The reaction mixture was filtered through celite, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica flash column chromatography and concentrated to obtain the desired product. [0398] Compound 1a: Suzuki coupling using 4-(trifluoromethyl)phenylboronic acid [0399] Reaction was run under inert argon atmosphere. Solvent is sparged/degassed with argon under sonication prior to use.3-amino-4-bromo-5-methylpyrazole (2.00 g, 11.4 mmol, 1.0 eq), 4-(trifluoromethyl)phenylboronic acid (4.34 g, 22.9 mmol, 2.0 eq), 1,1′- bis(ditertbutylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl₂) (745 mg, 1.14 mmol, 0.1 eq), and Na2CO3 (2.42 g, 22.9 mmol, 2.0 eq) were added to a screw-cap glass pressure tube. The contents were sealed with a septum secured with parafilm, then placed under vacuum and backfilled with argon (3x cycles, ending with contents under argon). The contents were dissolved in 4:1 dioxane/H₂O (20 mL), and the mixture was stirred at 100 °C overnight for 16 hrs. LC-MS indicated that the starting material was consumed completely, and product was formed. The reaction mixture was filtered through celite, then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (80 g silica) using DCM/MeOH gradient (0 – 10% MeOH over 15 minutes, 60 mL/min) and concentrated to isolate compound 1 as a crude brown solid. This was further purified by prep-HPLC [Solvent A: H₂O + 0.1% TFA, Solvent B: ACN + 0.1% TFA; gradient: 0 – 100% B over 25 min, then 100% B for 5 min] and lyophilized to obtain compound 1a as a light brown solid (571 mg, 21% yield). LC-MS (ESI) m/z: 242.0938 [M+H]⁺, RT = 1.14 min. ¹H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H). [0400] Compound 1b: Suzuki coupling using phenylboronic acid [0401] Reaction was run under inert N₂ atmosphere. Solvent is sparged/degassed with N₂ under sonication prior to use.3-amino-4-bromo-5-methylpyrazole (5.00 g, 28.4 mmol, 1.0 eq), phenylboronic acid (5.20 g, 42.6 mmol, 1.5 eq), 1,1′- bis(ditertbutylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2) (1.85 mg, 2.84 mmol, 0.1 eq), and Na2CO3 (6.02 g, 56.8 mmol, 2.0 eq) were added to the reaction vessel. The contents were evacuated and backfilled with N2 (3x cycles, ending with contents under N2). The contents were dissolved in 5:1 dioxane/H2O (120 mL), and the mixture was stirred at 100 °C for 5 hrs. LC-MS indicated that the starting material was consumed, several new peaks formed, and desired product was detected. The reaction mixture was quenched with water (200 mL), filtered through celite, then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography using petroleum ether/EtOAc gradient (1 – 100% EtOAc) and concentrated to isolate compound 1b as a brown solid (1.80 g, 37% yield). ¹H NMR (400 MHz, CDCl3) δ 7.43 - 7.37 (m, 2H), 7.36 - 7.31 (m, 2H), 7.26 - 7.22 (m, 1H), 2.27 (s, 3H). [0402] General Step B: Formation of β-ketoester _{[0403] General (1.2 eq), and} DMAP (0.5 eq) were ethyl potassium malonate (1.2 eq) and magnesium chloride (1.2 eq) were dissolved in anhydrous THF. All contents were stirred at room temperature for 30 min (to form activated ester and enolate respectively), then the first mixture was added to the second mixture and stirred overnight at room temperature until completion as indicated by LC-MS. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by flash column chromatography and concentrated to obtain the desired product. [0404] Compound 2a: Formation of β-ketoester using 6-bromonicotinic acid [0405] 6-bromonicotinic acid (2.00 g, 9.90 mmol, 1.0 eq), CDI (1.93 g, 11.9 mmol, 1.2 eq), and DMAP (605 mg, 4.95 mmol, 0.5 eq) were dissolved in anhydrous THF (20 mL). In a separate flask, ethyl potassium malonate (2.02 g, 11.9 mmol, 1.2 eq) and magnesium chloride (1.13 g, 11.9 mmol, 1.2 eq) were dissolved in anhydrous THF (20 mL). All contents were stirred at room temperature for 30 min (to form activated ester and enolate respectively), then the first mixture was added to the second mixture and stirred overnight at room temperature for 16 hrs. LC-MS indicated that the starting material was consumed completely, and product was present as the major species. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange residue. The residue was purified by flash column chromatography (40 g silica) using hexane/EtOAc gradient (0 – 100% EtOAc over 15 minutes, 40 mL/min) and concentrated to obtain compound 2a as a light-yellow solid (1.36 g, 51% yield, present primarily as enol species). LC-MS (ESI) m/z: 271.9934/273.9917 [M+H]⁺, RT = 1.38 min. ¹H NMR (400 MHz, Chloroform-d) δ 12.54 (s, 1H), 8.73 (dd, J = 2.6, 0.7 Hz, 1H), 7.89 (dd, J = 8.4, 2.5 Hz, 1H), 7.55 (dd, J = 8.4, 0.7 Hz, 1H), 5.67 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). [0406] Compound 2b: Formation of β-ketoester using nicotinic acid [0407] Nicotinic acid (1.00 g, 8.13 mmol, 1.0 eq), CDI (1.98 g, 12.2 mmol, 1.5 eq), and DMAP (497 mg, 4.06 mmol, 0.5 eq) were dissolved in anhydrous THF (10 mL). In a separate flask, ethyl potassium malonate (2.08 g, 12.2 mmol, 1.5 eq) and magnesium chloride (929 mg, 9.75 mmol, 1.2 eq) were dissolved in anhydrous THF (10 mL). All contents were stirred at room temperature for 30 min (to form activated ester and enolate respectively), then the first mixture was added to the second mixture and stirred overnight at room temperature for 16 hrs. LC-MS indicated that the starting material was consumed completely, and product was present as the major species. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give an orange residue. The residue was purified by flash column chromatography (40 g silica) using hexane/EtOAc gradient (0 – 100% EtOAc over 15 minutes, 40 mL/min) and concentrated to obtain compound 2b as a clear oil (910 mg, 58% yield, present as a mixture of enol and ^^- ketoester species). LC-MS (ESI) m/z: 194.0816 [M+H]⁺, RT = 1.08 min. ¹H NMR (of enol) (400 MHz, Chloroform-d) δ 12.55 (s, 1H), 8.99 (dd, J = 2.4, 0.9 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.06 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 5.70 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). [0408] General Step C [0409] in anhydrous toluene or glacial acetic acid and stirred at room temperature until completion as indicated by LC-MS. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to obtain the desired product. [0410] Compound 3a: Cyclization of compound 1a and compound 2a [0411] Note: Compound 3a has solubility issues and tends to crash out of solution at higher concentrations. [0412] Compound 1a (480 mg, 1.99 mmol, 1.0 eq) and compound 2a (593 mg, 2.19 mmol, 1.1 eq) were dissolved in anhydrous toluene (10 mL) and stirred overnight at room temperature for 16 hr. LC-MS indicated that the starting material was consumed, and product was present as the major species. The solvent was removed under reduced pressure to give a yellow-brown residue. The residue was purified by flash column chromatography (40 g silica) using DCM/MeOH gradient (0 – 20% MeOH over 15 minutes, 40 mL/min) and concentrated to obtain compound 3a as an orange-brown solid (265 mg, 29% yield). LC-MS (ESI) m/z: 449.0236/451.0201 [M+H]⁺, RT = 1.53 min. ¹H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.76 (q, J = 8.1 Hz, 5H), 6.12 (s, 1H), 2.42 (s, 3H). [0413] Compound 3b: Cyclization of compound 1a and compound 2b [0414] mg, 817 µmol, 1.00 eq) were dissolved in AcOH (1.97 mL) and stirred at 120 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC using a Waters Xbridge BEH C18 column (10 µm, 130Å, 50 mm x 250 mm; mobile phase: water + 10 mM NH₄HCO₃)-ACN; gradient: 25%-50% B over 10 min) Target 7 (10.0 mg, 36.5% yield) was obtained as white solid. LC-MS (ESI) m/z: 371.1142 [M+H]⁺, RT = 1.31 min. ¹H NMR (400 MHz, Chloroform-d) δ 8.95 - 8.88 (m, 1H) 8.84 - 8.78 (m, 1H) 7.99 - 7.91 (m, 1H) 7.79 - 7.74 (m, 2H) 7.57 - 7.47 (m, 3H) 6.17 - 6.10 (m, 1H) 2.54 - 2.44 (m, 3H) [0415] General Step D: Reductive amination of formyl-nicotinic acid ethyl esters [0416] The formyl-nicotinic acid ethyl ester (1.0 eq) and dimethylamine (1.2 eq) were dissolved in anhydrous solvent and stirred at room temperature until imine was formed, then sodium triacetoxyborohydride (1.5 eq) was added. The reaction was stirred at room temperature until completion as indicated by LC-MS, then diluted with water and extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by flash column chromatography and concentrated to obtain the desired product. [0417] Compound 4a: Reductive amination of ethyl 4-formyl-3-pyridinecarboxylate [0418] To a mmol, 1.00 eq) in THF (160 mL) was added dimethylamine (2M in THF, 163 mL, 2.00 eq) and stirred for 30 min, then sodium triacetoxyborohydride (69.3 g, 326 mmol, 2.00 eq) was added and stirred at room temperature for 6.5 hr. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound 4a was obtained as a crude yellow solid (33.2 g, 66.2% purity, 70% yield). [0419] Compound 4b: Reductive amination of ethyl 6-formyl-3-pyridinecarboxylate [0420] To a solution of ethyl 6-formyl-3-pyridinecarboxylate (27.0 g, 279 µmol, 1.0 eq) in anhydrous dichloroethane (2 mL) was added dimethylamine (2M in anhydrous MeOH, 335 µmol, 1.2 eq) and stirred for 30 min, then sodium triacetoxyborohydride (88.7 mg, 419 µmol, 1.5 eq) was added and stirred overnight at room temperature for 16 hr. LC-MS indicated that the reaction was complete. The solvent was removed using a stream of air through a blunt needle to afford a crude residue. The residue was purified by prep-HPLC [Solvent A: H2O + 0.1% TFA, Solvent B: ACN + 0.1% TFA; gradient: 0 – 10% B over 5 min, then 10 –25% B for 19 min, then 25 – 100% B for 1 min, then 100% B for 5 min] and lyophilized to obtain compound 4b as a clear oil (93.7 mg, >100% yield). LC-MS (ESI) m/z: 209.1304 [M+H]⁺, RT = 0.71 min. ¹H NMR (400 MHz, Methanol-d4) δ 9.25 (dd, J = 2.1, 0.9 Hz, 1H), 8.46 (dd, J = 8.1, 2.1 Hz, 1H), 7.61 (dq, J = 8.2, 0.7 Hz, 1H), 4.61 (s, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.99 (s, 6H), 1.43 (t, J = 7.1 Hz, 3H). [0421] General Step E: Buchwald-Hartwig cross coupling of compound 3a [0422] anhydrous and sparged/degassed with argon prior to use. All glassware is oven-dried prior to use. [0423] General procedure: Compound 3a (1.0 eq), respective amine/amide (1.50 eq), Pd(COD)(DQ) (0.1 eq), XantPhos (0.2 eq) and sodium tert-butoxide (1.5 eq) were added to reaction vessel, then evacuated and backfilled with argon (3x cycles, ending with contents under argon). The contents were dissolved in anhydrous dioxane and stirred at 100 °C until reaction completion as indicated by LC-MS. The reaction mixture was filtered through celite, and the filter was washed with ethyl acetate. The filtrate was concentrated to obtain crude product used directly for following step. [0424] Compound 5a: Buchwald coupling of compound 3a to N-boc-piperazine [0425] Reaction was run under inert atmosphere. Solvent used in reaction is strictly anhydrous and sparged/degassed with argon prior to use. All glassware is oven-dried prior to use. [0426] Compound 3a (100 mg, 223 µmol, 1.0 eq), N-boc-piperazine (62.3 mg, 335 µmol, 1.5 eq), Pd(COD)(DQ) (8.44 mg, 22.3 µmol, 0.1 eq), XantPhos (25.8 mg, 44.6 µmol, 0.2 eq) and sodium tert-butoxide (32.2 mg, 335 µmol, 1.5 eq) were added to a screw-cap glass pressure tube. The contents were seals with a septum and secured with parafilm, then placed under vacuum and backfilled with argon (3x cycles, ending with contents under argon). The contents were dissolved in anhydrous dioxane (5 mL) and stirred overnight at 100 °C for 16 hr. Starting material was completely consumed, and the product was present as the major species as indicated by LC-MS. The reaction mixture was filtered through celite, and the filter was washed with ethyl acetate. The filtrate was concentrated to obtain crude product as an orange-brown solid which was used directly for the next step (compound 5b). LC-MS (ESI) m/z: 555.2723 [M+H]⁺, RT = 1.67 min. [0427] Compound 5b: Boc deprotection of compound 5a [0428] Compound 5a (123.7 mg, 223 µmol, 1.0 eq) was dissolved in 1:1 TFA/DCM (2 mL) and stirred at room temperature for 30 min. Starting material was completely consumed, and the product was present as the major species as indicated by LC-MS. The solvent was removed using a stream of air through a blunt needle to afford a crude residue which was purified by prep-HPLC [Solvent A: H2O + 0.1% TFA, Solvent B: ACN + 0.1% TFA; gradient: 0 – 100% B over 25 min, then 100% B for 5 min] and lyophilized to obtain compound 5b (59.2 mg, 47% yield over two steps) as a light yellow solid, TFA salt. LC-MS (ESI) m/z: 455.2205 [M+H]⁺, RT = 1.13 min. [0429] Compound 5c: Acetylation of compound 5b 1.2 eq) and DIPEA (1.84 µL, 10.6 µmol, 3.0 eq) were dissolved in a solution of glacial acetic acid (0.254 mg, 3.5 µmol, 1.0 eq, added as 127 µL of a 2 mg/mL solution in DMF) in DMF and stirred for about 10 min to form the activated ester. The solution of compound 5b was added to the activated ester reaction mixture and stirred for 30 min at room temperature. LC-MS (ESI) m/z: 497.2350 [M+H]⁺, RT = 1.30 min. [0431] Compound 5d: Buchwald coupling of compound 3a to pivalamide [0432] Compound 3a (68 mg, 152 µmol, 1.0 eq), pivalamide (23.0 mg, 228 µmol, 1.5 eq), Pd(COD)(DQ) (6.65 mg, 15.2 µmol, 0.1 eq), XantPhos (17.6 mg, 30.4 µmol, 0.2 eq) and sodium tert-butoxide (21.9 mg, 228 µmol, 1.5 eq) were added to a screw-cap glass pressure tube. The contents were seals with a septum and secured with parafilm, then placed under vacuum and backfilled with argon (3x cycles, ending with contents under argon). The contents were dissolved in anhydrous dioxane (5 mL) and stirred overnight at 100 °C for 16 hr. Starting material was completely consumed, and the product was present as the major species as indicated by LC-MS. The reaction mixture was filtered through celite, and the filter was washed with ethyl acetate. The filtrate was concentrated to obtain crude product as an orange-brown solid which was used directly for the next step (compound 5d). LC-MS (ESI) m/z: 470.1836 [M+H]⁺, RT = 1.58 min. [0433] Compound 5e: Pivalamide deprotection of compound 5d [0434] pressure tube and dissolved in 5:1 EtOH/HCl (5 mL) and stirred overnight at 80˚C for 16 hr. Starting material was completely consumed, and the product was present as indicated by LC-MS. The solvent was removed using a stream of air through a blunt needle to afford a crude residue which was purified by prep-HPLC [Solvent A: H2O + 0.1% TFA, Solvent B: ACN + 0.1% TFA; gradient: 0 – 100% B over 25 min, then 100% B for 5 min] and lyophilized to obtain compound 5e (7.7 mg, 10% yield over two steps) as a light yellow solid, TFA salt. LC-MS (ESI) m/z: 386.1223 [M+H]⁺, RT = 1.05 min. ¹H NMR (400 MHz, d6-DMSO) δ 12.2 - 11.9 (m, 1H), 8.52 - 8.35 (m, 1H), 8.29 - 7.96 (m, 3H), 7.91 - 7.68 (m, 4H), 7.05 - 6.86 (m, 1H), 6.20 - 5.91 (m, 1H), 5.74 (s, 1H), 2.43 - 2.23 (m, 4H). [0435] Compound 6a: Chlorination of compound 3b using POCl3 _{[0436] To a solution of compound 3b (1.00 g, 2.70 mmol, 1.00 eq) in ACN (7.00 mL) was} added POCl₃ (828 mg, 5.40 mmol, 503 µL, 2.00 eq). The mixture was stirred at 130 °C for 3 hrs. LCMS showed the reaction was consumed completed. The reaction mixture was diluted with water (50.0 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (1.00 mL) at room temperature for 1 hr. Target 1 (900 mg, 2.13 mmol, 80% yield) was obtained as yellow solid. LC-MS (ESI) m/z: 389.1121 [M+H]⁺, RT = 1.76 min. ¹H NMR (400 MHz, Methanol-d₄) δ 9.37 (s, 1H), 8.71 - 8.61 (m, 2H), 8.06 (br d, J = 7.80 Hz, 2H), 7.95 (s, 1H), 7.81 (br d, J = 8.10 Hz, 2H), 7.66 - 7.56 (m, 1H), 2.72 (s, 3H). [0437] General Step F: SNAr of compound 6a [0438] amine of interest (>60 eq). The reaction was stirred at desired temperature until completion as indicated by LC-MS. The reaction mixture was concentrated in vacuum and purified by prep-HPLC to obtain the desired product. [0439] Compound 7a: SNAr of Compound 6a with ammonia [0440] To a solution of compound 6a (100 mg, 257 µmol, 1.00 eq) in dioxane (2.00 mL) was added NH3^.H2O (2.73 g, 21.8 mmol, 3.00 mL, 28% purity, 84.8 eq). The mixture was stirred at 40 °C for 6 hrs. LCMS showed Reactant 1 remained. Several new peaks were shown on LCMS and desired compound was detected. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC ([H₂O (0.05% NH₃H₂O + 10 mM NH4HCO3)-ACN]; gradient: 45.0%-75.0% B over 8.00 min). Compound 7a (15.9 mg, 16.7% yield) was obtained as yellow solid. LC-MS (ESI) m/z: 370.1601 [M+H]⁺, RT = 1.54 min. ¹H NMR (400 MHz, Methanol-d4) δ 9.23 (d, J = 1.60 Hz, 1H), 8.61 (dd, J = 1.30, 4.90 Hz, 1H), 8.52 (td, J = 1.90, 7.90 Hz, 1H), 8.09 (d, J = 8.20 Hz, 2H), 7.73 (d, J = 8.30 Hz, 2H), 7.56 (dd, J = 5.00, 8.00 Hz, 1H), 6.70 (s, 1H), 2.66 (s, 3H). [0441] Compound 7b: SNAr of Compound 6a with dimethylamine [0442] mL) was added Me₂NH (1.78 g, 15.79 mmol, 2 mL, 40% purity, 61.40 eq). The mixture was stirred at 20 °C for 2hrs. LCMS showed compound 6a consumed. Several new peaks were shown on LCMS and desired compound was detected. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC ([H₂O (10mM NH₄HCO₃)-ACN]; gradient: 55.0% - 85.0% B over 8.00 min). Compound 7b (20.0 mg, 19.5% yield) was obtained as _{yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 9.31 (d, J = 1.70 Hz, 1H), 8.66 - 8.53 (m,} 2H), 8.07 (d, J = 8.20 Hz, 2H), 7.75 (d, J = 8.20 Hz, 2H), 7.57 (dd, J = 5.10, 8.00 Hz, 1H), 6.71 (s, 1H), 3.47 (s, 6H), 2.65 (s, 3H). Example 5: Additional biological data [0443] Fluorescence polarization (FP) assay protocol for data shown in Table 2 [0444] All assays were run in a black 384-well plate (Corning, 3820), and all reagents were added in technical triplicate using an electronic multichannel pipette. Positive control peptide [H3K4me310-mer, ARTK(me3)QTARKS] is stored as stock solution in water, and compounds are stored as stock solutions in DMSO. Experiments were run in assay buffer consisting of 50 mM HEPES, 50 mM KCl, pH = 7.5, 0.01% Tween-20. All wells contain final concentrations as follows: 1 μM of His-MBP-PHD3 (KDM5A1601-1662), 10 nM of H3K4me3 FAM-peptide [ARTK(me3)QTARKSK-5FAM], and 20X compound in DMSO (5% total DMSO). [0445] Protein master mix consisting of 2 μM His-MBP-PHD3 and 20 nM H3K4me3 FAM-peptide was prepared in assay buffer. For blank sample, a separate blank master mix consisting of 20 nM H3K4me3 FAM-peptide was prepared in assay buffer. An 11-point half serial dilution series was prepared for compounds and positive control peptide (20X compound diluted in DMSO or 20X positive control peptide diluted in assay buffer). [0446] To respective wells, the following were added: ^_{Compounds: 18 μL of assay buffer, then 20 μL of protein master mix for compounds.} _{^ Positive control: 16 μL of assay buffer, then 20 μL of protein master mix, then 2 μL} of DMSO ^_{Blank: 18 μL of assay buffer, then 20 μL of blank master mix, then 2 μL of DMSO.} [0447] 2 μL of 20X compound in DMSO or 2 μL of 20X positive control peptide in assay buffer were added to respective wells, then mixed [20 uL, 10 cycles] and incubated for 30 min with shaking on an orbital shaker. Fluorescence polarization was measured on a SpectraMax M5e (ex/em = 480/530 nm). [0448] Table 2. Potencies measured using the fluorescence polarization (FP) based assay described above. ) Example 6: ¹⁹F NMR studies [0449] NMR conditions [0450] ¹⁹F NMR was used as a secondary binding assay to validate binding to the target. In these experiments, 1084887 was used as small molecule ligand, which is purified as TFA salt. The comparison of intensity of –CF3 group in the ligand, 1084887, relative to TFA, which is inert, was used to assess binding. Decrease in intensity of ¹⁹F signal was used as an indication of binding. [0451] NMR buffer: Buffer- 20 mM Na-phosphate, 5 mM DTT, 90% H2O/10% D2O) at pH 7.0, 2.5% D6-DMSO. [0452] Protein (PHD31609-1659), dialyzed into NMR buffer, 0-4 µM [0453] [1084887], TFA salt: 20 µM final [0454] Table 3 REFERENCES [0455] 1. Bolouri, H.; Farrar, J. E.; Triche, T.; Ries, R. E.; Lim, E. L.; Alonzo, T. A.; Ma, Y.; Moore, R.; Mungall, A. J.; Marra, M. 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Claims

WHAT IS CLAIMED IS: 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R¹ is independently oxo, halogen, -CX¹ ₃, -CHX¹ ₂, -CH₂X¹, -OCX¹ ₃, -OCH₂X¹, -OCHX¹2, -CN, -SOn1R^1D, -SOv1NR^1AR^1B, ^NR^1CNR^1AR^1B, ^ONR^1AR^1B, or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 11; R² is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH₂I, -CHCl₂, -CHBr₂, -CHF₂, - alkyl, or aryl, or substituted or unsubstituted heteroaryl; R³ and R⁴ are 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, -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCl₂, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, -N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R^1A, R^1B, R^1C, and R^1D are 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; R^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X¹ is independently –F, -Cl, -Br, or –I; n1 is independently an integer from 0 to 4; and m1 and v1 are independently 1 or 2. 2. The compound of claim 1, having the formula: ; or heteroaryl; R⁵ is independently oxo, halogen, -CX⁵ ₃, -CHX⁵ ₂, -CH₂X⁵, -OCX⁵ ₃, -OCH₂X⁵, -OCHX⁵2, -CN, -SOn5R^5D, -SOv5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, -N(O)m5, -NR^5AR^5B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, -C(O)NR^5AR^5B, -C(NR^5C)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^5D, -SR^5D, -NR^5ASO2R^5D, -NR^5AC(O)R^5C, -NR^5AC(O)OR^5C, -NR^5AOR^5C, -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 R⁵ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 11; I₃, , Cl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X⁵ is independently –F, -Cl, -Br, or –I; n5 is independently an integer from 0 to 4; and m5 and v5 are independently 1 or 2. 3. The compound of claim 2, wherein Ring B is phenyl or 5 to 6 membered heteroaryl. 4. The compound of claim 2, wherein Ring B is phenyl, pyrazolyl, isoxazolyl, or pyridyl. 5. The compound of claim 2, wherein Ring B is phenyl. 6. The compound of claim 2, . -CF₃, 5 -NR ^AR^5B, or 8. The compound of claim 2, wherein R⁵ is independently -F, -Cl, -CF3, -N(CH₃)₂, or unsubstituted methyl. 9. The compound of claim 2, wherein z5 is 1. 10. The compound of claim 2, wherein z5 is 0.

11. The compound of claim 2, wherein two R⁵ substituents are joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. 12. The compound of claim 2, wherein two R⁵ substituents are joined to form an unsubstituted dioxolanyl. or membered heteroaryl, or 5 to 10 membered heterocycloalkyl. 15. The compound of claim 1, wherein Ring A is phenyl or 5 to 6 membered heteroaryl. 16. The compound of claim 1, wherein Ring A is phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, indazolyl, triazolopyridinyl, piperidinyl, tetrahydropyranyl, morpholinyl, or pyridonyl. 17. The compound of claim 1, wherein Ring A is phenyl or pyridyl. 18. The compound of claim 1, is

-CX¹3, -NR^1AR^1B, -C(O)R^1C, -OR^1D, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. 20. The compound of claim 1, wherein R¹ is independently -F, -Cl, -Br, -CF3, unsubstituted methyl, unsubstituted , O . 22. The compound of claim 1, wherein z1 is 0. 23. The compound of claim wherein is

unsubstituted C1-C4 alkyl.

25. The compound of claim 1, wherein R³ is hydrogen, -CF3, unsubstituted methyl, or unsubstituted ethyl. 26. The compound of claim 1, wherein R³ is unsubstituted methyl. 27. The compound of claim 1, wherein R⁴ is hydrogen or halogen. 28. The compound of claim 1, wherein R⁴ is hydrogen or -Cl. 29. The compound of claim 1, wherein R⁴ is hydrogen. 30. The compound of claim 1, having the formula: ,

.

31. A pharmaceutical composition comprising the compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 32. A method of treating an H3K4me3-associated disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the H3K4me3-associated disease is a cancer. 34. The method of claim 33, wherein the cancer is leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, liver cancer, stomach cancer, or glioblastoma. 35. The method of claim 33, wherein the cancer is acute myeloid leukemia. 36. The method of claim 33, wherein the cancer is acute megakaryoblastic leukemia. 37. The method of claim 32, wherein the H3K4me3-associated disease is a viral infection. 38. The method of claim 37, wherein the viral infection is hepatitis B.