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WO2025184571A1 - Inhibiteurs de pcna pour le traitement de cancers associés à la famille des gènes myc - Google Patents

Inhibiteurs de pcna pour le traitement de cancers associés à la famille des gènes myc

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Publication number
WO2025184571A1
WO2025184571A1 PCT/US2025/017943 US2025017943W WO2025184571A1 WO 2025184571 A1 WO2025184571 A1 WO 2025184571A1 US 2025017943 W US2025017943 W US 2025017943W WO 2025184571 A1 WO2025184571 A1 WO 2025184571A1
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substituted
unsubstituted
membered
independently
alkyl
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Robert J. Hickey
Linda H. Malkas
Robert G. LINGEMAN
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City of Hope
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City of Hope
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MYC amplification and high MYC expression have also been associated with a high metastatic phenotype.
  • a method of treating a cancer in a subject in need thereof including: (i) detecting a level of Myc family protein expression in a cancer cell sample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: [0005]
  • L 1 is -O-, -NR 7 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)2-, -OS(O) 2 O-, -S(O)
  • R 7 , R 8 , and R 9 are independently hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl.
  • Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
  • R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCHX 1 2 , -OCH2X 1 , -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , ⁇ NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO 2 R 1D , -
  • R 2 is hydrogen, halogen, -CX 2 3 , –CHX 2 2 , –CH 2 X 2 , -CN, -COOH, -CONH 2 , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is hydrogen, halogen, -CX 3 3, –CHX 3 2, –CH2X 3 , -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is hydrogen, halogen, -CX 6 3 , -CHX 6 2 , -CH 2 X 6 , -OCX 6 3 , -OCHX 6 2 , -OCH 2 X 6 , -CN, -SOn6R 6D , -SOv6NR 6A R 6B , ⁇ NR 6C NR 6A R 6B , ⁇ ONR 6A R 6B , ⁇ NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6
  • R 3 and R 6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted hetero
  • the symbol z1 is an integer from 0 to 4.
  • the symbols m1, m6, v1, and v6 are independently 1 or 2.
  • the symbols n1 and n6 are independently an integer from 0 to 4.
  • X, X 1 , X 2 , X 3 , and X 6 are independently –Cl, -Br, -I, or –F.
  • the symbol m is an integer from 0 to 5.
  • the symbol n is an integer from 0 to 10.
  • FIGS.1A-1B MYC amplified cell lines are sensitive to AOH1996.
  • FIG.1A AOH1996 was submitted to the NCI Developmental Therapeutics Program (DTP) for testing in their NCI-60 Human Tumor Cell Lines Screen.
  • DTP NCI Developmental Therapeutics Program
  • the panel of cell lines were incubated with serial dilutions of AOH1996 for 48 hours. At the conclusion of the incubation period, the cells were fixed with 10% trichloroacetic acid (TCA) and cell growth was analyzed by sulforhodamine B (SRB) assay. The IC 50 was calculated by the NCI.
  • the graph compares the sensitivity of MYC amplified cell lines in the NCI-60 to the rest of the cell lines in the panel. A student’s t-test performed on the datasets returned a p value of .0014 indicating a significant difference in sensitivity between the two groups.
  • FIG.1B A 72-hour dose response assay using AOH1996 on a set of MYC amplified cell lines (MCF7, HCT116, RKO, OVCAR8, NCI-H358, HCC827, and NCI-H1975) and two non-malignant cell lines (HSAEC and HMEC-1) was performed.
  • FIGS.2A-2D AOH1996 decreases c-Myc and n-Myc and increases p21.
  • FIG.2A Three cancer cell lines originating from different tissues (colon, breast, and ovary) were treated with 1 ⁇ M AOH1996 for 48 or 72 hours or left untreated.
  • FIG.2B Additional Western blot analysis showed reduced c-Myc levels after 24 hours of 1 ⁇ M AOH1996 treatment, while the same treatment on non- malignant HMEC1 cells showed no reduction in c-Myc levels at 24 or 48 hours.
  • FIG.2C In neuroblastoma n-Myc amplification is associated with poor prognosis and high probability of unfavorable outcomes.
  • BE2C and SK-N-BE2C Three neuroblastoma cell lines, two n-Myc amplified cell lines (BE2C and SK-N-BE2C) and one non-amplified cell line (SK-N-FI) were analyzed by Western blot analysis for n-Myc levels after treatment with 1 ⁇ M of AOH1996 for 24 and 48 hours.
  • BE2C and SK-N-BE2C cell lines showed decreased levels of n-Myc at both 24 and 48 hours, while the low n-Myc levels in the SK-N-FI cells were not altered after AOH1996 treatment in the assay tested.
  • FIG.2D Western blot analysis of chromatin fractions isolated from HCT116 cells treated for 12, 24, and 36 hours demonstrated that reduced levels c-Myc are present on the chromatin after 24 hours of treatment with 1 ⁇ M AOH1996.
  • a proximity ligation assay was used to identify instances of MYC and PCNA interactions.
  • HCT116 cells were serum starved for 36 hours before releasing into complete media with and without 1 ⁇ M of AOH1996 over a course of time. The cells were fixed and permeabilized and a proximity ligation assay using primary antibodies to MYC and PCNA was performed. The cells were counterstained with DAPI to mark the nuclei.
  • FIGS.4A-4B PCNA and MYC colocalize in early S-phase.
  • FIG.4A As previously described (Schönenberger et al., 2015, Chagin et al., 2016), PCNA localization is distinct for the different stages of interphase. HCT116 cells were serum starved for 36 hours in media + .1% FBS.
  • FIG.4B BrdU was incorporated into replicating HCT116 cells for 30 minutes. The cells were then fixed and permeabilized. A proximity ligation assay was performed between BrdU and MYC to indicate instances where replication forks encountered MYC (light grey foci). The cells were further stained with the PC10 antibody conjugated to Alexa Fluor 488 (medium grey foci). The DNA was counterstained with DAPI (blue).
  • FIG.5. AOH1996 disrupts interaction of MYC with transcription elongation factor SPT5.
  • HCT116 cells were serum starved for 36 hours before releasing into complete media with and without 1 ⁇ M of AOH1996 for 30 minutes. The cells were fixed and permeabilized and a proximity ligation assay using primary antibodies to MYC and SPT5 was performed. The cells were counterstained with DAPI (blue) to mark the nuclei.
  • FIG.6 AOH1996 suppresses metastatic processes. RNA seq analysis was performed on three MYC amplified and highly metastatic PDAC cell lines. Untreated and AOH1996 treated conditions for each of the cell lines were analyzed. Gene ontology analysis found biological processes related to angiogenesis, motility and migration, and proliferation were significantly decreased, while processes related to inflammation and apoptosis were significantly increased. A false discovery rate under .05 was considered significant. DETAILED DESCRIPTION I .
  • 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., C 1 -C 10 means one to ten carbons).
  • the alkyl is fully saturated.
  • the alkyl is monounsaturated.
  • the alkyl is polyunsaturated.
  • Alkyl is an uncyclized chain.
  • 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.
  • 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, -CH 2 CH 2 CH 2 CH 2 -.
  • 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.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
  • the alkylene is fully saturated.
  • the alkylene is monounsaturated.
  • the alkylene is polyunsaturated.
  • An alkenylene includes one or more double bonds.
  • An alkynylene includes one or more triple bonds.
  • 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
  • Heteroalkyl is an uncyclized chain.
  • 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.
  • 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.
  • the heteroalkyl is fully saturated.
  • the heteroalkyl is monounsaturated.
  • the heteroalkyl is polyunsaturated.
  • 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-.
  • 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) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -.
  • heteroalkyl groups 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 -SO 2 R'.
  • 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.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
  • heteroalkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne.
  • the heteroalkylene is fully saturated.
  • the heteroalkylene is monounsaturated.
  • the heteroalkylene is polyunsaturated.
  • a heteroalkenylene includes one or more double bonds.
  • a heteroalkynylene includes one or more triple bonds.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples 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.
  • the cycloalkyl is fully saturated.
  • the cycloalkyl is monounsaturated.
  • the cycloalkyl is polyunsaturated.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is monounsaturated.
  • the heterocycloalkyl is polyunsaturated.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • 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.
  • 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.
  • a cycloalkyl is a cycloalkenyl.
  • the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • 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.
  • heterocycloalkyl means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system.
  • 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.
  • 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.
  • halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-imid
  • arylene and heteroarylene are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • 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).
  • 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.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula: .
  • the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , -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).
  • the alkylarylene is unsubstituted.
  • 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.
  • 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.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • 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.
  • 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.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
  • 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.
  • Substituents for rings e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • 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.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'-, 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.
  • 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) 2 NR'-.
  • 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.
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si).
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • 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, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -
  • 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 C 1 -C 20 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 C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl
  • 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- C 7 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
  • 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.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 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 C 3 -C 8 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 C 6 - C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
  • 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 C 3 -C 8 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
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 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 C 3 -C 7 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 C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • 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 C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • 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 cycloalkyl, substituted
  • 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 alky
  • 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.
  • 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.
  • each size-limited substituent group is different.
  • 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
  • each lower substituent group is different.
  • 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
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • 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.
  • the first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R 1 may be substituted with one or more first substituent groups denoted by R 1.1 , R 2 may be substituted with one or more first substituent groups denoted by R 2.1 , R 3 may be substituted with one or more first substituent groups denoted by R 3.1 , R 4 may be substituted with one or more first substituent groups denoted by R 4.1 , R 5 may be substituted with one or more first substituent groups denoted by R 5.1 , and the like up to or exceeding an R 100 that may be substituted with one or more first substituent groups denoted by R 100.1 .
  • 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 .
  • L 1 may be substituted with one or more first substituent groups
  • L 2 may be substituted with one or more first substituent groups denoted by be substituted with one or more first substituent groups denoted by R L3.1
  • L 4 may be substituted with one or more first substituent groups denoted by R L4.1
  • L 5 may be substituted with one or more first substituent groups denoted by R L5.1 and the like up to or exceeding an L 100 which may be substituted with one or more first substituent groups denoted by R L100.1 .
  • 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.
  • each first substituent group (e.g., R 1.1 , R 2.1 , R 3.1 , R 4.1 , R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ... R 100A.1 ; R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ... R L100.1 ) may be ... ... represented 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 .
  • 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 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 .
  • 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.).
  • L WW is a linker recited in a claim or chemical formula description herein which is openly substituted.
  • WW represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • 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 .
  • 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.
  • 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 .
  • 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: .
  • R WW.1 is independently oxo, halogen, -CX WW.1 3 , -CHX WW.1 2 , -CH 2 X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.2 -substituted or or unsubstituted 3 membered, or 4 to 5 membered), R WW.2 -substituted or un
  • R WW.1 is independently oxo, halogen, -CX WW.1 3, -CHX WW.1 2, -CH 2 X WW.1 , -OCX WW.1 3 , -OCH 2 X WW.1 , -OCHX WW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted
  • X WW.1 is independently –F, -Cl, -Br, or –I.
  • R WW.2 is independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3, -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.3 -substituted or unsubstit
  • 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.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e
  • X WW.2 is independently –F, -Cl, -Br, or –I.
  • R WW.3 is independently oxo, halogen, -CX WW.3 3, -CHX WW.3 2, -CH2X WW.3 , -OCX WW.3 3 , -OCH 2 X WW.3 , -OCHX WW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C1-C8,
  • X WW.3 is independently –F, -Cl, -Br, or –I.
  • 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, 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.
  • the “WW” symbol in the R WW.1 , R WW.2 and R WW.3 refers to the designated number of one of the two different R WW substituents.
  • R WW.1 is R 100A.1
  • R WW.2 is R 100A.2
  • R WW.3 is R 100A.3 .
  • R WW.1 is R 100B.1
  • R WW.2 is R 100B.2
  • R WW.3 is R 100B.3 .
  • R WW.1 , R WW.2 and R WW.3 in this paragraph are as defined in the preceding paragraphs.
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3, -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R LWW.2 -substituted or unsubstituted alkyl (e.g., C1-
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3 , -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3, -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-
  • X LWW.1 is independently –F, -Cl, -Br, or –I.
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3, -CHX LWW.2 2, -CH2X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.3 -
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3, -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6
  • X LWW.2 is independently –F, -Cl, -Br, or –I.
  • R LWW.3 is independently oxo, halogen, -CX LWW.3 3 , -CHX LWW.3 2 , -CH 2 X LWW.3 , -OCX LWW.3 3, -OCH2X LWW.3 , -OCHX LWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g.,
  • X LWW.3 is independently –F, -Cl, -Br, or –I.
  • R group R WW group
  • R group is hereby defined as independently oxo, halogen, -CX WW 3 , -CHX WW 2 , -CH 2 X WW , -OCX WW 3 , -OCH 2 X WW , -OCHX WW 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H,
  • X WW is independently –F, -Cl, -Br, or –I.
  • WW represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • RWW.1, RWW.2, and RWW.3 are as defined above.
  • L group is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, —NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R LWW.1 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membere
  • R LWW.1 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.
  • 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.
  • 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.
  • 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.
  • the term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0077] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • 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.
  • 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 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • 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.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • 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.
  • a conjugate between a first bioconjugate reactive group e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide
  • a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
  • covalent bond or linker e.g., a first linker of second linker
  • 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).
  • 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).
  • bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group e.g., –N- hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • 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 Die
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0086]
  • the terms “a” or “an”, as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted 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 R 13 substituents are present, each R 13 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.
  • R 13 is defined within the scope of the definition of R 13 and optionally differently.
  • 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.
  • Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art.
  • a group may be substituted by one or more of a number of substituents
  • 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.
  • 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.
  • salts are 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.
  • 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.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • 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.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • compositions described herein are 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).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • 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.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.
  • 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 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.
  • 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.
  • 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.
  • control is used as a standard of comparison in evaluating experimental effects.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • inhibition refers to reduction of a disease or symptoms of disease.
  • 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).
  • 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.
  • inhibitor refers 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.
  • 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.
  • 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.
  • 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.
  • a target may be a cellular component (e.g., protein, ion
  • 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.).
  • 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.
  • to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • “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.
  • a patient is human.
  • a patient in need thereof is human.
  • a subject is human.
  • a subject in need thereof is human.
  • 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.
  • 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).
  • the disease is cancer (e.g., a Myc family protein associated cancer).
  • 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.
  • 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,
  • 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.
  • 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.
  • 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 hemo
  • 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.
  • 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
  • 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.
  • the metastatic tumor and its cells are presumed to be similar to those of the original tumor.
  • 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.
  • metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors.
  • 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.
  • 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.
  • 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).
  • a primary cancer site e.g., breast
  • 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.
  • 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).
  • a primary cancer site e.g., head and neck, liver, breast.
  • a primary cancer site e.g., head and neck, liver, breast
  • Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.
  • the term “Myc family protein associated cancer” refers to any cancer caused by aberrant activity of signaling of a Myc family protein.
  • the Myc family protein associated cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, ampullary carcinoma, basal cell carcinoma, bladder cancer, bladder urothelial carcinoma, brain lower grade glioma, breast cancer, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, colon cancer, colorectal adenocarcinoma, cutaneous squamous cell carcinoma, cutaneous T cell lymphoma, diffuse glioma, diffuse large B cell lymphoma, endometrial carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastric cancer, glioblastoma, gliobasto
  • 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.
  • 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.
  • detectable agents include 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, S
  • Radioactive substances e.g., radioisotopes
  • Radioactive substances include, but are not limited to, 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212
  • 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.
  • 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.
  • “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.
  • 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.
  • 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.
  • 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.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • 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.
  • 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.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • 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.
  • 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.
  • 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.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • 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.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient.
  • the dose administered to a patient 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.
  • a disease e.g., a protein associated disease, disease associated with a cellular component
  • the disease e.g., cancer
  • 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).
  • modulating e.g., inhibiting or activating
  • aberrant 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.
  • 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.
  • “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.
  • 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.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ - carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • that insertion will not correspond to a numbered amino acid position in the reference sequence.
  • a selected residue in a selected protein corresponds to His44 of PCNA when the selected residue occupies the same essential spatial or other structural relationship as His44 of PCNA.
  • the position in the aligned selected protein aligning with His44 is said to correspond to His44.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with PCNA and the overall structures compared. In this case, an amino acid that occupies the same essential position as His44 in the structural model is said to correspond to the His44 residue.
  • 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.
  • 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.
  • PCNA proliferating cell nuclear antigen
  • PCNA may refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, UniProt P12004, RefSeq NM_002592, or RefSeq NP_002583).
  • PCNA includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof.
  • PCNA is wild-type PCNA. In some embodiments, “PCNA” is one or more mutant forms.
  • the term “PCNA” XYZ refers to a nucleotide sequence or protein of a mutant PCNA wherein the Y numbered amino acid of PCNA that normally has an X amino acid in the wild-type, instead has a Z amino acid in the mutant.
  • a PCNA is the human PCNA.
  • the PCNA has the nucleotide sequence corresponding to reference number GI:33239449.
  • the PCNA has the nucleotide sequence corresponding to RefSeq NM_002592.2.
  • the PCNA has the protein sequence corresponding to reference number GI:4505641. In embodiments, the PCNA has the nucleotide sequence corresponding to RefSeq NP_002583.1. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the PCNA has the following amino acid sequence: MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGF DTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSD YEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFS ASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLS MSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 1).
  • the PCNA is a mutant PCNA.
  • the mutant PCNA is associated with a disease that is not associated with wild-type PCNA.
  • the PCNA includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the sequence above.
  • PCNA may be post-translationally modified. Modifications may include phosphorylation, methylation, methylesters of acidic amino acids, ribosylation, acetylation, glycosylation with a variety of sugars, lipidation with a variety of different lipids, poly(ADP) ribosylation, or other post-translational modifications known in the art.
  • a post-translational modification or plurality of post- translational modifications modify the inhibition of PCNA by a compound described herein or the binding of a compound described herein to PCNA, relative to PCNA without the post- translational modification(s).
  • cancer-associated proliferating cell nuclear antigen or “caPCNA” as used herein refer to an isoform of PCNA having an acidic isoelectric point (e.g., peptide including protonated amine and/or carboxyl groups, acidic isoelectric point compared to a non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, prevalent PCNA isoform in non-cancerous cells, or less acidic PCNA isoform in non- cancerous cells).
  • the caPCNA protein includes methylated amino acids (e.g., glutamate, aspartic acid).
  • the caPCNA protein is post-translationally modified with a methylester of an acidic amino acid.
  • the methylesterification of the acidic amino acid residues on PCNA exhibit a T 1/2 of approximately 20 minutes at pH 8.5.
  • caPCNA is post-translationally modified as described in F. Shen, et al. J Cell Biochem.2011 Mar; 112(3): 756–760, which is incorporated by reference in its entirety for all purposes.
  • non-malignant Proliferating cell nuclear antigen or “nmPCNA” as used herein refer to an isoform of PCNA having a basic isoelectric point (e.g., peptide including deprotonated amine and/or carboxyl groups, basic isoelectric point compared to a caPCNA, caPCNA in cancerous cells).
  • nmPCNA is the prevalent PCNA isoform in non-cancerous cells.
  • Myc family protein refers to one or more of the family of regulator genes and proto-oncogenes that code for transcription factors. In embodiments, the Myc family protein is c-Myc, N-Myc, or L-Myc.
  • c-Myc refers to a proto-oncogene that plays a role in cell cycle progression, apoptosis, and cellular transformation.
  • the term includes any recombinant or naturally-occurring form of MYC variants thereof that maintain MYC activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype MYC).
  • the MYC protein encoded by the MYC gene has the amino acid sequence set forth in or corresponding to Entrez 4609, UniProt P01106, RefSeq NP_002458, or RefSeq NP_001341799.
  • the MYC gene has the nucleic acid sequence set forth in RefSeq NM_002467 or RefSeq NM_001354870.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • N-Myc or “MYCN” refers to a proto-oncogene that in humans is encoded by the MYCN gene.
  • the term includes any recombinant or naturally-occurring form of N-Myc variants thereof that maintain N-Myc activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype N-Myc).
  • the N-Myc protein encoded by the MYCN gene has the amino acid sequence set forth in or corresponding to Entrez 4613, UniProt P04198, RefSeq NP_001280157, RefSeq NP_001280160, RefSeq NP_001280162, or RefSeq NP_005369.
  • the MYCN gene has the nucleic acid sequence set forth in RefSeq NM_005378, RefSeq NM_001293228, RefSeq NM_001293231, or RefSeq NM_001293233.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • L-Myc refers to a proto-oncogene that in humans is encoded by the MYCL1 gene.
  • the term includes any recombinant or naturally-occurring form of L-Myc variants thereof that maintain L-Myc activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype L-Myc).
  • the L-Myc protein encoded by the MYCL1 gene has the amino acid sequence set forth in or corresponding to Entrez 4610, UniProt P12524, RefSeq NP_001028253, RefSeq NP_001028254, or RefSeq NP_005367.
  • the MYCL1 gene has the nucleic acid sequence set forth in RefSeq NM_005376, RefSeq NM_001033081, or RefSeq NM_001033082.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. I I.
  • a method of treating a cancer in a subject in need thereof including: (i) detecting a level of Myc family protein expression in a cancer cell sample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: ).
  • R 7 , R 8 , and R 9 are independently hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
  • R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCHX 1 2 , -OCH2X 1 , -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , ⁇ NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO 2 R 1D , -
  • R 2 is hydrogen, halogen, -CX 2 3 , –CHX 2 2 , –CH 2 X 2 , -CN, -COOH, -CONH 2 , -N 3 , 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, C 4 -C 6 , or C 5 -C 6 ), 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
  • R 3 is hydrogen, halogen, -CX 3 3, –CHX 3 2, –CH2X 3 , -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 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), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , 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,
  • R 6 is hydrogen, halogen, -CX 6 3 , -CHX 6 2 , -CH 2 X 6 , -OCX 6 3 , -OCHX 6 2 , -OCH 2 X 6 , -CN, -SOn6R 6D , -SOv6NR 6A R 6B , ⁇ NR 6C NR 6A R 6B , ⁇ ONR 6A R 6B , ⁇ NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6
  • R 3 and R 6 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).
  • 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
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen, -CX3, –CHX2, –CH2X, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 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), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted or unsubstituted hetero
  • the symbol z1 is an integer from 0 to 4.
  • the symbols m1, m6, v1, and v6 are independently 1 or 2.
  • the symbols n1 and n6 are independently an integer from 0 to 4.
  • X, X 1 , X 2 , X 3 , and X 6 are independently –Cl, -Br, -I, or –F.
  • the symbol m is an integer from 0 to 5.
  • the symbol n is an integer from 0 to 10.
  • the level of Myc family protein expression is elevated relative to a standard control.
  • the standard control is a healthy subject.
  • the standard control is a subject who has cancer, but does not have a Myc family protein associated cancer.
  • a method of treating a cancer in a subject in need thereof, wherein the subject has a Myc family protein associated cancer the method including administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: I). Ring A, Ring B, L 1 , R 1 , z1, R 2 , R 3 , R 6 , m, and diments.
  • the Myc family protein is c-Myc, N-Myc, or L-Myc. In embodiments, the Myc family protein is c-Myc.
  • the Myc family protein is N-Myc. In embodiments, the Myc family protein is L-Myc.
  • the cancer is a Myc family protein associated cancer. In embodiments, the cancer is acute lymphoblastic leukemia. In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is adenoid cystic carcinoma. In embodiments, the cancer is adrenocortical carcinoma. In embodiments, the cancer is ampullary carcinoma. In embodiments, the cancer is basal cell carcinoma. In embodiments, the cancer is bladder cancer. In embodiments, the cancer is bladder urothelial carcinoma. In embodiments, the cancer is brain lower grade glioma. In embodiments, the cancer is breast cancer.
  • the cancer is breast invasive carcinoma. In embodiments, the cancer is cervical squamous cell carcinoma. In embodiments, the cancer is cholangiocarcinoma. In embodiments, the cancer is chronic lymphocytic leukemia. In embodiments, the cancer is colon cancer. In embodiments, the cancer is colorectal adenocarcinoma. In embodiments, the cancer is cutaneous squamous cell carcinoma. In embodiments, the cancer is cutaneous T cell lymphoma. In embodiments, the cancer is diffuse glioma. In embodiments, the cancer is diffuse large B cell lymphoma. In embodiments, the cancer is endometrial carcinoma. In embodiments, the cancer is esophageal adenocarcinoma.
  • the cancer is gastric adenocarcinoma. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is glioblastoma. In embodiments, the cancer is gliobastoma multiforme. In embodiments, the cancer is glioma. In embodiments, the cancer is head and neck squamous cell carcinoma. In embodiments, the cancer is hepatocellular carcinoma. In embodiments, the cancer is intrahepatic cholangiocarcinoma. In embodiments, the cancer is kidney chromophobe. In embodiments, the cancer is kidney renal clear cell carcinoma. In embodiments, the cancer is liver hepatocellular carcinoma. In embodiments, the cancer is lung adenocarcinoma.
  • the cancer is lung squamous cell carcinoma.
  • the cancer is malignant peripheral nerve sheath tumor.
  • the cancer is medulloblastoma.
  • the cancer is melanoma.
  • the cancer is mesothelioma.
  • the cancer is metastatic melanoma.
  • the cancer is metastatic prostate adenocarcinoma.
  • the cancer is multiple myeloma.
  • the cancer is myelodysplastic syndromes.
  • the cancer is neuroblastoma.
  • the cancer is non-small cell lung cancer.
  • the cancer is ovarian cancer.
  • the cancer is ovarian serous cystadenocarcinoma. In embodiments, the cancer is pancreatic adenocarcinoma. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is pancreatic ductal adenocarcinoma. In embodiments, the cancer is pancreatic neuroendocrine tumors. In embodiments, the cancer is pediatric acute lymphoid leukemia. In embodiments, the cancer is pediatric brain cancer. In embodiments, the cancer is pediatric Ewing sarcoma. In embodiments, the cancer is pheochromocytoma and paraganglioma. In embodiments, the cancer is pleural mesothelioma.
  • the cancer is prostate adenocarcinoma. In embodiments, the cancer is prostate cancer brain metastases. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer is metastatic osteosarcoma. In embodiments, the cancer is retinoblastoma. In embodiments, the cancer is sarcoma. In embodiments, the cancer is skin cutaneous melanoma. In embodiments, the cancer is stomach adenocarcinoma. In embodiments, the cancer is testicular germ cell tumors. In embodiments, the cancer is angiosarcoma. In embodiments, the cancer is renal cell carcinoma. In embodiments, the cancer is urothelial carcinoma. In embodiments, the cancer is uterine carcinosarcoma.
  • the cancer is uterine corpus endometrial carcinoma. In embodiments, the cancer is uveal melanoma.
  • the compound has the formula: z1, R 2 , R 3 , R 6 , m, and n [0174]
  • Ring A is phenyl or 5 to 6 membered heteroaryl.
  • Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl.
  • R 4 is independently a halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCX 4 3 , -OCHX 4 2 , -OCH2X 4 , -CN, -SOn4R 4D , -SOv4NR 4A R 4B , ⁇ NR 4C NR 4A R 4B , ⁇ ONR 4A R 4B , ⁇ NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -SR 4D , -NR 4A SO 2 R 4
  • R 5 is independently a halogen, -CX 5 3, -CHX 5 2, -CH2X 5 , -OCX 5 3, -OCHX 5 2, -OCH2X 5 , -CN, -SOn5R 5D , -SOv5NR 5A R 5B , ⁇ NR 5C NR 5A R 5B , ⁇ ONR 5A R 5B , ⁇ NHC(O)NR 5C NR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O)m5, -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A R 5B , -OR 5D , -SR 5D , -NR 5A SO2R 5D , -NR 5A C(O)
  • R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D are independently hydrogen, halogen, -CX 3 , –CHX 2 , –CH 2 X, -CN, -COOH, -CONH 2 , -N 3 , 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
  • the symbol z4 is an integer from 0 to 5.
  • the symbol z5 is an integer from 0 to 7.
  • the symbols m4, m5, v4, and v5 are independently 1 or 2.
  • the symbols n4 and n5 are independently an integer from 0 to 4.
  • X, X 4 , and X 5 are independently –Cl, -Br, -I, or -F.
  • the compound has the formula: Ring A, Ring B, R 1 , z1, R 2 , R 3 , in embodiments.
  • the compound has the formula: (IIIa).
  • the compound has the formula: (IIIb). L 1 , Ring A, Ring B, R 1 , z1, R 2 , R 3 , in embodiments. [0187] In embodiments, the compound has the formula: . L 1 , Ring A, Ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, in embodiments.
  • the compound has the formula: ; wherein Ring A is phenyl or 5 to 6 membered or isoquinolinyl; L 1 is -O- or -S-; R 1 is independently halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCHX 1 2, -OCH2X 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , ⁇ NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -OC(O
  • the compound has the formula: Ring A, Ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , embodiments.
  • the compound has the formula: Ring A, Ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , embodiments.
  • the compound has the formula: . L 1 , Ring A, Ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, in embodiments.
  • the compound has the formula: .
  • the compound has the formula: Ring A, Ring B, R 1 , z1, R 2 , R 3 , R 4 , embodiments.
  • the compound has the formula: R 3 , [0195] In embodiments, the compound has the formula: R 3 , [0196] In embodiments, the compound has the formula: Ring A, Ring B, R 1 , z1, R 2 , R 3 , [0197] In embodiments, L 1 is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O) 2 O-, -OS(O) 2 NH-, -NHS(O) 2 -, -S(O) 2 NH-, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-
  • L 1 is -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, S(O)-, -S(O) 2 -, -OS(O) 2 O-, -S(O) 2 O-, -OS(O) 2 -, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 -, or -CR 8 R 9 -; and R 8 and R 9 are independently halogen or unsubstituted methyl.
  • L 1 is -O-, -NH-, -NCH 3 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2-, -S(O)2NH-, -S(O) 2 -, -OS(O) 2 O-, -S(O) 2 O-, -OS(O) 2 -, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 -, or -CR 8 R 9 -; wherein R 8 and R 9 are as described herein, including in embodiments.
  • L 1 is -O-, -NH-, -NCH 3 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 -, or -CR 8 R 9 -; and R 8 and R 9 are independently halogen or unsubstituted methyl.
  • L 1 is -O-. In embodiments, L 1 is –NR 7 -, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -NH-. In embodiments, L 1 is -NCH3-. In embodiments, L 1 is -S-. In embodiments, L 1 is -C(O)-. In embodiments, L 1 is -C(O)O-. In embodiments, L 1 is -OC(O)-. In embodiments, L 1 is -NR 7 C(O)-, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -NHC(O)-.
  • L 1 is -C(O)NR 7 -, wherein R 7 is as described herein, including in embodiments.
  • L 1 is -C(O)NH-.
  • L 1 is -NR 7 C(O)NR 8 -.
  • L 1 is -NHC(O)NH-.
  • L 1 is -NR 7 S(O)2O-.
  • L 1 is -NHS(O) 2 O-.
  • L 1 is -OS(O) 2 NR 7 -.
  • L 1 is -OS(O) 2 NH-.
  • L 1 is -NR 7 S(O)2-.
  • L 1 is -NHS(O)2-. In embodiments, L 1 is -S(O) 2 NR 7 -. In embodiments, L 1 is -S(O) 2 NH-. In embodiments, L 1 is –S(O)-. In embodiments, L 1 is –S(O)2-. In embodiments, L 1 is -OS(O)2O-. In embodiments, L 1 is -S(O) 2 O-. In embodiments, L 1 is -OS(O) 2 -. In embodiments, L 1 is -P(O)(OR 7 )-, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -P(O)(OH)-.
  • L 1 is -OP(O)(OR 7 )O-, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -OP(O)(OH)O-. In embodiments, L 1 is -OP(O)(OR 7 )-, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -OP(O)(OH)-. In embodiments, L 1 is -P(O)(OR 7 )O-, wherein R 7 is as described herein, including in embodiments. In embodiments, L 1 is -P(O)(OH)O-.
  • L 1 is -CHR 9 -, wherein R 9 is as described herein, including in embodiments.
  • L 1 is -CR 8 R 9 -, wherein R 8 and R 9 are as described herein, including in embodiments.
  • L 1 is -CHF-.
  • L 1 is –CF2-.
  • a substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 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 1 is substituted, it is substituted with at least one substituent group.
  • R 1 when R 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when two R 1 substituents are joined e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • 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.
  • R 1A 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.
  • a substituted R 1B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1B 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.
  • R 1B 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.
  • 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
  • at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • 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.
  • 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.
  • 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.
  • R 1C 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.
  • a substituted R 1D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1D 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.
  • R 1D 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.
  • R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCHX 1 2, -OCH2X 1 , -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , ⁇ NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO 2 R 1
  • R 1 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 1 is independently halogen, -CF 3 , -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 is independently halogen, -CF 3 , –CHF 2 , –CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
  • R 1 is independently halogen, -OH, -CF 3 , –CHF 2 , –CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, unsubstituted methyl, or unsubstituted methoxy.
  • R 1 is independently halogen.
  • R 1 is independently –F. In embodiments, R 1 is independently –Cl. In embodiments, R 1 is independently –Br. In embodiments, R 1 is independently –I. In embodiments, R 1 is independently -CCl 3 . In embodiments, R 1 is independently -CBr 3 . In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CI 3 . In embodiments, R 1 is independently -CH 2 Cl. In embodiments, R 1 is independently -CH 2 Br. In embodiments, R 1 is independently -CH 2 F. In embodiments, R 1 is independently -CH 2 I. In embodiments, R 1 is independently -CHCl 2 .
  • R 1 is independently -CHBr2. In embodiments, R 1 is independently -CHF2. In embodiments, R 1 is independently -CHI 2 . In embodiments, R 1 is independently –CN. In embodiments, R 1 is independently –OH. In embodiments, R 1 is independently -NH2. In embodiments, R 1 is independently –COOH. In embodiments, R 1 is independently -CONH 2 . In embodiments, R 1 is independently -NO2. In embodiments, R 1 is independently –SH. In embodiments, R 1 is independently -SO 3 H. In embodiments, R 1 is independently -OSO 3 H. In embodiments, R 1 is independently -SO2NH2. In embodiments, R 1 is independently ⁇ NHNH2.
  • R 1 is independently ⁇ ONH 2 . In embodiments, R 1 is independently ⁇ NHC(O)NHNH 2 . In embodiments, R 1 is independently ⁇ NHC(O)NH 2 . In embodiments, R 1 is independently -NHSO2H. In embodiments, R 1 is independently -NHC(O)H. In embodiments, R 1 is independently -NHC(O)OH. In embodiments, R 1 is independently –NHOH. In embodiments, R 1 is independently -OCCl3. In embodiments, R 1 is independently -OCBr 3 . In embodiments, R 1 is independently -OCF 3 . In embodiments, R 1 is independently -OCI3. In embodiments, R 1 is independently -OCH2Cl.
  • R 1 is independently -OCH 2 Br. In embodiments, R 1 is independently -OCH 2 F. In embodiments, R 1 is independently -OCH2I. In embodiments, R 1 is independently -OCHCl2. In embodiments, R 1 is independently -OCHBr 2 . In embodiments, R 1 is independently -OCHF 2 . In embodiments, R 1 is independently -OCHI2. In embodiments, R 1 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl.
  • R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n- butyl. In embodiments, R 1 is independently unsubstituted isobutyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted methoxy. In embodiments, R 1 is independently unsubstituted ethoxy.
  • R 1 is independently unsubstituted propoxy. In embodiments, R 1 is independently unsubstituted n- propoxy. In embodiments, R 1 is independently unsubstituted isopropoxy. In embodiments, R 1 is independently unsubstituted butoxy. In embodiments, R 1 is independently unsubstituted n-butoxy. In embodiments, R 1 is independently unsubstituted isobutoxy. In embodiments, R 1 is independently unsubstituted tert-butoxy. [0210] 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.
  • 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. [0211] In embodiments, R 1B is independently hydrogen.
  • R 1B is independently unsubstituted C 1 -C 4 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.
  • R 1B is independently unsubstituted tert-butyl.
  • 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.
  • R 1C is independently unsubstituted n-butyl. In embodiments, R 1C is independently unsubstituted isobutyl. In embodiments, R 1C is independently unsubstituted tert-butyl. [0213] In embodiments, R 1D is independently hydrogen. In embodiments, R 1D is independently unsubstituted C 1 -C 4 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.
  • 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. [0214] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4.
  • a substituted R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2 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 2 is substituted, it is substituted with at least one substituent group.
  • R 2 when R 2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2 is substituted, it is substituted with at least one lower substituent group.
  • R 2 is hydrogen, halogen, -CX 2 3 , –CHX 2 2 , –CH 2 X 2 , -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g.,
  • R 2 is hydrogen, –CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R 2 is hydrogen. [0218] In embodiments, R 2 is hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted C1-C4 alkyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted propyl. In embodiments, R 2 is unsubstituted n-propyl.
  • R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted butyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl.
  • a substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 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 3 is substituted, it is substituted with at least one substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is hydrogen, halogen, -CX 3 3 , –CHX 3 2 , –CH 2 X 3 , -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g.,
  • R 3 is hydrogen, –CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R 3 is hydrogen. [0222] In embodiments, R 3 is hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 3 is hydrogen. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl.
  • R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted isobutyl. In embodiments, R 3 is unsubstituted tert-butyl.
  • a substituted R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4 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 4 is substituted, it is substituted with at least one substituent group.
  • R 4 when R 4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4 is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when two R 4 substituents are joined e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted R 4A (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 4A 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 4A is substituted, it is substituted with at least one substituent group.
  • R 4A when R 4A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 4B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4B 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.
  • R 4B when R 4B is substituted, it is substituted with at least one substituent group. In embodiments, when R 4B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4B is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when R 4A and R 4B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • the substituted ring formed when R 4A and R 4B 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.
  • when the substituted ring formed when R 4A and R 4B 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 4A and R 4B 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 4A and R 4B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4C (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 4C 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 4C is substituted, it is substituted with at least one substituent group.
  • R 4C when R 4C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 4D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4D 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.
  • R 4D when R 4D is substituted, it is substituted with at least one substituent group. In embodiments, when R 4D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4D is substituted, it is substituted with at least one lower substituent group.
  • R 4 is independently a halogen, -CX 4 3, -CHX 4 2, -CH2X 4 , -OCX 4 3, -OCHX 4 2, -OCH2X 4 , -CN, -SOn4R 4D , -SOv4NR 4A R 4B , ⁇ NR 4C NR 4A R 4B , ⁇ ONR 4A R 4B , ⁇ NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O)m4, -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -SR 4D , -NR 4A SO2R 4D , -NR 4A
  • R 4 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 4 is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 4 is independently halogen, -CF 3 , –CHF 2 , –CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 - C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
  • R 4 is independently halogen, -CF 3 , –CHF 2 , –CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, unsubstituted methyl, or unsubstituted methoxy.
  • R 4 is independently halogen.
  • R 4 is independently –F. In embodiments, R 4 is independently –Cl. In embodiments, R 4 is independently –Br. In embodiments, R 4 is independently –I. In embodiments, R 4 is independently -CCl3. In embodiments, R 4 is independently -CBr 3 . In embodiments, R 4 is independently -CF 3 . In embodiments, R 4 is independently -CI3. In embodiments, R 4 is independently -CH2Cl. In embodiments, R 4 is independently -CH 2 Br. In embodiments, R 4 is independently -CH 2 F. In embodiments, R 4 is independently -CH2I. In embodiments, R 4 is independently -CHCl2. In embodiments, R 4 is independently -CHBr 2 .
  • R 4 is independently -CHF 2 . In embodiments, R 4 is independently -CHI2. In embodiments, R 4 is independently –CN. In embodiments, R 4 is independently –OH. In embodiments, R 4 is independently -NH 2 . In embodiments, R 4 is independently –COOH. In embodiments, R 4 is independently -CONH 2 . In embodiments, R 4 is independently -NO 2 . In embodiments, R 4 is independently –SH. In embodiments, R 4 is independently -SO 3 H. In embodiments, R 4 is independently -OSO 3 H. In embodiments, R 4 is independently -SO2NH2. In embodiments, R 4 is independently ⁇ NHNH2. In embodiments, R 4 is independently ⁇ ONH2.
  • R 4 is independently ⁇ NHC(O)NHNH 2 . In embodiments, R 4 is independently ⁇ NHC(O)NH 2 . In embodiments, R 4 is independently -NHSO 2 H. In embodiments, R 4 is independently -NHC(O)H. In embodiments, R 4 is independently -NHC(O)OH. In embodiments, R 4 is independently –NHOH. In embodiments, R 4 is independently -OCCl 3 . In embodiments, R 4 is independently -OCBr3. In embodiments, R 4 is independently -OCF3. In embodiments, R 4 is independently -OCI 3 . In embodiments, R 4 is independently -OCH 2 Cl. In embodiments, R 4 is independently -OCH 2 Br.
  • R 4 is independently -OCH 2 F. In embodiments, R 4 is independently -OCH2I. In embodiments, R 4 is independently -OCHCl2. In embodiments, R 4 is independently -OCHBr 2 . In embodiments, R 4 is independently -OCHF 2 . In embodiments, R 4 is independently -OCHI2. In embodiments, R 4 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted n-propyl.
  • R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted butyl. In embodiments, R 4 is independently unsubstituted n- butyl. In embodiments, R 4 is independently unsubstituted isobutyl. In embodiments, R 4 is independently unsubstituted tert-butyl. In embodiments, R 4 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted methoxy. In embodiments, R 4 is independently unsubstituted ethoxy. In embodiments, R 4 is independently unsubstituted propoxy.
  • R 4 is independently unsubstituted n- propoxy. In embodiments, R 4 is independently unsubstituted isopropoxy. In embodiments, R 4 is independently unsubstituted butoxy. In embodiments, R 4 is independently unsubstituted n-butoxy. In embodiments, R 4 is independently unsubstituted isobutoxy. In embodiments, R 4 is independently unsubstituted tert-butoxy. [0233] In embodiments, R 4 is independently –OR 4D , wherein R 4D is as described herein, including in embodiments. In embodiments, R 4D is hydrogen or substituted or unsubstituted alkyl.
  • R 4D is independently hydrogen or unsubstituted alkyl. In embodiments, R 4D is independently hydrogen or unsubstituted C 1 -C 5 alkyl. In embodiments, R 4D is independently hydrogen or unsubstituted methyl.
  • R 4A is independently hydrogen. In embodiments, R 4A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4A is independently unsubstituted methyl. In embodiments, R 4A is independently unsubstituted ethyl. In embodiments, R 4A is independently unsubstituted propyl. In embodiments, R 4A is independently unsubstituted n-propyl.
  • R 4A is independently unsubstituted isopropyl. In embodiments, R 4A is independently unsubstituted butyl. In embodiments, R 4A is independently unsubstituted n-butyl. In embodiments, R 4A is independently unsubstituted isobutyl. In embodiments, R 4A is independently unsubstituted tert-butyl. [0235] In embodiments, R 4B is independently hydrogen. In embodiments, R 4B is independently unsubstituted C1-C4 alkyl. In embodiments, R 4B is independently unsubstituted methyl. In embodiments, R 4B is independently unsubstituted ethyl.
  • R 4B is independently unsubstituted propyl. In embodiments, R 4B is independently unsubstituted n-propyl. In embodiments, R 4B is independently unsubstituted isopropyl. In embodiments, R 4B is independently unsubstituted butyl. In embodiments, R 4B is independently unsubstituted n-butyl. In embodiments, R 4B is independently unsubstituted isobutyl. In embodiments, R 4B is independently unsubstituted tert-butyl. [0236] In embodiments, R 4C is independently hydrogen. In embodiments, R 4C is independently unsubstituted C 1 -C 4 alkyl.
  • R 4C is independently unsubstituted methyl. In embodiments, R 4C is independently unsubstituted ethyl. In embodiments, R 4C is independently unsubstituted propyl. In embodiments, R 4C is independently unsubstituted n-propyl. In embodiments, R 4C is independently unsubstituted isopropyl. In embodiments, R 4C is independently unsubstituted butyl. In embodiments, R 4C is independently unsubstituted n-butyl. In embodiments, R 4C is independently unsubstituted isobutyl. In embodiments, R 4C is independently unsubstituted tert-butyl.
  • R 4D is independently hydrogen. In embodiments, R 4D is independently unsubstituted C1-C4 alkyl. In embodiments, R 4D is independently unsubstituted methyl. In embodiments, R 4D is independently unsubstituted ethyl. In embodiments, R 4D is independently unsubstituted propyl. In embodiments, R 4D is independently unsubstituted n-propyl. In embodiments, R 4D is independently unsubstituted isopropyl. In embodiments, R 4D is independently unsubstituted butyl. In embodiments, R 4D is independently unsubstituted n-butyl.
  • R 4D is independently unsubstituted isobutyl. In embodiments, R 4D is independently unsubstituted tert-butyl. [0238] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5.
  • a substituted R 4.1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4.1 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.
  • R 4.1 when R 4.1 is substituted, it is substituted with at least one substituent group.
  • R 4.1 when R 4.1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4.1 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4.2 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 4.2 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4.2 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.
  • R 4.2 when R 4.2 is substituted, it is substituted with at least one substituent group. In embodiments, when R 4.2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4.2 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4.3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4.3 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.
  • R 4.3 when R 4.3 is substituted, it is substituted with at least one substituent group.
  • R 4.3 when R 4.3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4.3 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 4.4 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 4.4 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4.4 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.
  • R 4.4 when R 4.4 is substituted, it is substituted with at least one substituent group. In embodiments, when R 4.4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4.4 is substituted, it is substituted with at least one lower substituent group.
  • R 4.1 , R 4.2 , R 4.3 , and R 4.4 are independently a halogen, -CCl3, -CBr3, -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 ,
  • R 4.1 is halogen. In embodiments, R 4.1 is –F. In embodiments, R 4.1 is –Cl. In embodiments, R 4.1 is –Br. In embodiments, R 4.1 is –I. In embodiments, R 4.1 is -CCl3. In embodiments, R 4.1 is -CBr3. In embodiments, R 4.1 is -CF3. In embodiments, R 4.1 is -CI 3 . In embodiments, R 4.1 is -CH 2 Cl. In embodiments, R 4.1 is -CH 2 Br. In embodiments, R 4.1 is -CH2F. In embodiments, R 4.1 is -CH2I. In embodiments, R 4.1 is -CHCl2.
  • R 4.1 is -CHBr 2 . In embodiments, R 4.1 is -CHF 2 . In embodiments, R 4.1 is -CHI2. In embodiments, R 4.1 is –CN. In embodiments, R 4.1 is –OH. In embodiments, R 4.1 is -NH 2 . In embodiments, R 4.1 is –COOH. In embodiments, R 4.1 is -CONH 2 . In embodiments, R 4.1 is -NO2. In embodiments, R 4.1 is –SH. In embodiments, R 4.1 is -SO3H. In embodiments, R 4.1 is -OSO 3 H. In embodiments, R 4.1 is -SO 2 NH 2 . In embodiments, R 4.1 is ⁇ NHNH2.
  • R 4.1 is ⁇ ONH2. In embodiments, R 4.1 is ⁇ NHC(O)NHNH2. In embodiments, R 4.1 is ⁇ NHC(O)NH 2 . In embodiments, R 4.1 is -NHSO 2 H. In embodiments, R 4.1 is -NHC(O)H. In embodiments, R 4.1 is -NHC(O)OH. In embodiments, R 4.1 is –NHOH. In embodiments, R 4.1 is -OCCl3. In embodiments, R 4.1 is -OCBr3. In embodiments, R 4.1 is -OCF 3 . In embodiments, R 4.1 is -OCI 3 . In embodiments, R 4.1 is -OCH 2 Cl.
  • R 4.1 is -OCH2Br. In embodiments, R 4.1 is -OCH2F. In embodiments, R 4.1 is -OCH 2 I. In embodiments, R 4.1 is -OCHCl 2 . In embodiments, R 4.1 is -OCHBr 2 . In embodiments, R 4.1 is -OCHF2. In embodiments, R 4.1 is -OCHI2. In embodiments, R 4.1 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 4.1 is unsubstituted methyl. In embodiments, R 4.1 is unsubstituted ethyl. In embodiments, R 4.1 is independently unsubstituted propyl.
  • R 4.1 is unsubstituted n-propyl. In embodiments, R 4.1 is unsubstituted isopropyl. In embodiments, R 4.1 is unsubstituted butyl. In embodiments, R 4.1 is unsubstituted n-butyl. In embodiments, R 4.1 is unsubstituted isobutyl. In embodiments, R 4.1 is unsubstituted tert- butyl. In embodiments, R 4.1 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4.1 is unsubstituted methoxy. In embodiments, R 4.1 is unsubstituted ethoxy.
  • R 4.1 is unsubstituted propoxy. In embodiments, R 4.1 is unsubstituted n- propoxy. In embodiments, R 4.1 is unsubstituted isopropoxy. In embodiments, R 4.1 is unsubstituted butoxy. In embodiments, R 4.1 is unsubstituted n-butoxy. In embodiments, R 4.1 is unsubstituted isobutoxy. In embodiments, R 4.1 is unsubstituted tert-butoxy. [0245] In embodiments, R 4.2 is halogen. In embodiments, R 4.2 is –F. In embodiments, R 4.2 is –Cl. In embodiments, R 4.2 is –Br.
  • R 4.2 is –I. In embodiments, R 4.2 is -CCl 3 . In embodiments, R 4.2 is -CBr 3 . In embodiments, R 4.2 is -CF 3 . In embodiments, R 4.2 is -CI3. In embodiments, R 4.2 is -CH2Cl. In embodiments, R 4.2 is -CH2Br. In embodiments, R 4.2 is -CH 2 F. In embodiments, R 4.2 is -CH 2 I. In embodiments, R 4.2 is -CHCl 2 . In embodiments, R 4.2 is -CHBr2. In embodiments, R 4.2 is -CHF2. In embodiments, R 4.2 is -CHI 2 .
  • R 4.2 is –CN. In embodiments, R 4.2 is –OH. In embodiments, R 4.2 is -NH2. In embodiments, R 4.2 is –COOH. In embodiments, R 4.2 is -CONH2. In embodiments, R 4.2 is -NO 2 . In embodiments, R 4.2 is –SH. In embodiments, R 4.2 is -SO 3 H. In embodiments, R 4.2 is -OSO3H. In embodiments, R 4.2 is -SO2NH2. In embodiments, R 4.2 is ⁇ NHNH2. In embodiments, R 4.2 is ⁇ ONH2. In embodiments, R 4.2 is ⁇ NHC(O)NHNH2. In embodiments, R 4.2 is ⁇ NHC(O)NH2.
  • R 4.2 is -NHSO2H. In embodiments, R 4.2 is -NHC(O)H. In embodiments, R 4.2 is -NHC(O)OH. In embodiments, R 4.2 is –NHOH. In embodiments, R 4.2 is -OCCl3. In embodiments, R 4.2 is -OCBr3. In embodiments, R 4.2 is -OCF3. In embodiments, R 4.2 is -OCI3. In embodiments, R 4.2 is -OCH2Cl. In embodiments, R 4.2 is -OCH2Br. In embodiments, R 4.2 is -OCH2F. In embodiments, R 4.2 is -OCH2I. In embodiments, R 4.2 is -OCHCl2.
  • R 4.2 is -OCHBr2. In embodiments, R 4.2 is -OCHF2. In embodiments, R 4.2 is -OCHI2. In embodiments, R 4.2 is unsubstituted C1-C4 alkyl. In embodiments, R 4.2 is unsubstituted methyl. In embodiments, R 4.2 is unsubstituted ethyl. In embodiments, R 4.2 is independently unsubstituted propyl. In embodiments, R 4.2 is unsubstituted n-propyl. In embodiments, R 4.2 is unsubstituted isopropyl. In embodiments, R 4.2 is unsubstituted butyl.
  • R 4.2 is unsubstituted n-butyl. In embodiments, R 4.2 is unsubstituted isobutyl. In embodiments, R 4.2 is unsubstituted tert- butyl. In embodiments, R 4.2 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4.2 is unsubstituted methoxy. In embodiments, R 4.2 is unsubstituted ethoxy. In embodiments, R 4.2 is unsubstituted propoxy. In embodiments, R 4.2 is unsubstituted n- propoxy. In embodiments, R 4.2 is unsubstituted isopropoxy.
  • R 4.2 is unsubstituted butoxy. In embodiments, R 4.2 is unsubstituted n-butoxy. In embodiments, R 4.2 is unsubstituted isobutoxy. In embodiments, R 4.2 is unsubstituted tert-butoxy.
  • R 4.3 is halogen. In embodiments, R 4.3 is –F. In embodiments, R 4.3 is –Cl. In embodiments, R 4.3 is –Br. In embodiments, R 4.3 is –I. In embodiments, R 4.3 is -CCl 3 . In embodiments, R 4.3 is -CBr 3 . In embodiments, R 4.3 is -CF 3 .
  • R 4.3 is -CI3. In embodiments, R 4.3 is -CH2Cl. In embodiments, R 4.3 is -CH2Br. In embodiments, R 4.3 is -CH 2 F. In embodiments, R 4.3 is -CH 2 I. In embodiments, R 4.3 is -CHCl 2 . In embodiments, R 4.3 is -CHBr2. In embodiments, R 4.3 is -CHF2. In embodiments, R 4.3 is -CHI 2 . In embodiments, R 4.3 is –CN. In embodiments, R 4.3 is –OH. In embodiments, R 4.3 is -NH2. In embodiments, R 4.3 is –COOH. In embodiments, R 4.3 is -CONH2.
  • R 4.3 is -NO 2 . In embodiments, R 4.3 is –SH. In embodiments, R 4.3 is -SO 3 H. In embodiments, R 4.3 is -OSO3H. In embodiments, R 4.3 is -SO2NH2. In embodiments, R 4.3 is ⁇ NHNH2. In embodiments, R 4.3 is ⁇ ONH2. In embodiments, R 4.3 is ⁇ NHC(O)NHNH2. In embodiments, R 4.3 is ⁇ NHC(O)NH2. In embodiments, R 4.3 is -NHSO2H. In embodiments, R 4.3 is -NHC(O)H. In embodiments, R 4.3 is -NHC(O)OH. In embodiments, R 4.3 is –NHOH.
  • R 4.3 is -OCCl 3 . In embodiments, R 4.3 is -OCBr 3 . In embodiments, R 4.3 is -OCF3. In embodiments, R 4.3 is -OCI3. In embodiments, R 4.3 is -OCH2Cl. In embodiments, R 4.3 is -OCH 2 Br. In embodiments, R 4.3 is -OCH 2 F. In embodiments, R 4.3 is -OCH2I. In embodiments, R 4.3 is -OCHCl2. In embodiments, R 4.3 is -OCHBr2. In embodiments, R 4.3 is -OCHF2. In embodiments, R 4.3 is -OCHI2.
  • R 4.3 is unsubstituted C1-C4 alkyl. In embodiments, R 4.3 is unsubstituted methyl. In embodiments, R 4.3 is unsubstituted ethyl. In embodiments, R 4.3 is independently unsubstituted propyl. In embodiments, R 4.3 is unsubstituted n-propyl. In embodiments, R 4.3 is unsubstituted isopropyl. In embodiments, R 4.3 is unsubstituted butyl. In embodiments, R 4.3 is unsubstituted n-butyl. In embodiments, R 4.3 is unsubstituted isobutyl.
  • R 4.3 is unsubstituted tert- butyl. In embodiments, R 4.3 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4.3 is unsubstituted methoxy. In embodiments, R 4.3 is unsubstituted ethoxy. In embodiments, R 4.3 is unsubstituted propoxy. In embodiments, R 4.3 is unsubstituted n- propoxy. In embodiments, R 4.3 is unsubstituted isopropoxy. In embodiments, R 4.3 is unsubstituted butoxy. In embodiments, R 4.3 is unsubstituted n-butoxy.
  • R 4.3 is unsubstituted isobutoxy. In embodiments, R 4.3 is unsubstituted tert-butoxy.
  • R 4.4 is halogen. In embodiments, R 4.4 is –F. In embodiments, R 4.4 is –Cl. In embodiments, R 4.4 is –Br. In embodiments, R 4.4 is –I. In embodiments, R 4.4 is -CCl 3 . In embodiments, R 4.4 is -CBr 3 . In embodiments, R 4.4 is -CF 3 . In embodiments, R 4.4 is -CI3. In embodiments, R 4.4 is -CH2Cl.
  • R 4.4 is -CH2Br. In embodiments, R 4.4 is -CH 2 F. In embodiments, R 4.4 is -CH 2 I. In embodiments, R 4.4 is -CHCl 2 . In embodiments, R 4.4 is -CHBr2. In embodiments, R 4.4 is -CHF2. In embodiments, R 4.4 is -CHI 2 . In embodiments, R 4.4 is –CN. In embodiments, R 4.4 is –OH. In embodiments, R 4.4 is -NH2. In embodiments, R 4.4 is –COOH. In embodiments, R 4.4 is -CONH2. In embodiments, R 4.4 is -NO 2 . In embodiments, R 4.4 is –SH.
  • R 4.4 is -SO 3 H. In embodiments, R 4.4 is -OSO3H. In embodiments, R 4.4 is -SO2NH2. In embodiments, R 4.4 is ⁇ NHNH2. In embodiments, R 4.4 is ⁇ ONH2. In embodiments, R 4.4 is ⁇ NHC(O)NHNH2. In embodiments, R 4.4 is -NHSO2H. In embodiments, R 4.4 is -NHC(O)H. In embodiments, R 4.4 is -NHC(O)OH. In embodiments, R 4.4 is –NHOH. In embodiments, R 4.4 is -OCCl 3 .
  • R 4.4 is -OCBr 3 . In embodiments, R 4.4 is -OCF3. In embodiments, R 4.4 is -OCI3. In embodiments, R 4.4 is -OCH2Cl. In embodiments, R 4.4 is -OCH 2 Br. In embodiments, R 4.4 is -OCH 2 F. In embodiments, R 4.4 is -OCH2I. In embodiments, R 4.4 is -OCHCl2. In embodiments, R 4.4 is -OCHBr2. In embodiments, R 4.4 is -OCHF 2 . In embodiments, R 4.4 is -OCHI 2 . In embodiments, R 4.4 is unsubstituted C1-C4 alkyl.
  • R 4.4 is unsubstituted methyl. In embodiments, R 4.4 is unsubstituted ethyl. In embodiments, R 4.4 is independently unsubstituted propyl. In embodiments, R 4.4 is unsubstituted n-propyl. In embodiments, R 4.4 is unsubstituted isopropyl. In embodiments, R 4.4 is unsubstituted butyl. In embodiments, R 4.4 is unsubstituted n-butyl. In embodiments, R 4.4 is unsubstituted isobutyl. In embodiments, R 4.4 is unsubstituted tert- butyl.
  • R 4.4 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4.4 is unsubstituted methoxy. In embodiments, R 4.4 is unsubstituted ethoxy. In embodiments, R 4.4 is unsubstituted propoxy. In embodiments, R 4.4 is unsubstituted n- propoxy. In embodiments, R 4.4 is unsubstituted isopropoxy. In embodiments, R 4.4 is unsubstituted butoxy. In embodiments, R 4.4 is unsubstituted n-butoxy. In embodiments, R 4.4 is unsubstituted isobutoxy.
  • R 4.4 is unsubstituted tert-butoxy.
  • a substituted R 5 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5 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.
  • R 5 when R 5 is substituted, it is substituted with at least one substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when two R 5 substituents are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R 5 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.
  • 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.
  • R 5A 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.
  • a substituted R 5B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5B 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.
  • R 5B 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.
  • 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
  • at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • 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.
  • 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.
  • 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.
  • R 5C 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.
  • a substituted R 5D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5D 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.
  • R 5D 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.
  • R 5 is independently a halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , -OCHX 5 2, -OCH2X 5 , -CN, -SOn5R 5D , -SOv5NR 5A R 5B , ⁇ NR 5C NR 5A R 5B , ⁇ ONR 5A R 5B , ⁇ NHC(O)NR 5C NR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A R 5B , -OR 5D , -SR 5D , -NR 5A SO 2
  • R 5 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 5 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 5 is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C1- C 4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, or unsubstituted phenyl.
  • R 5 is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.
  • R 5 is independently halogen. In embodiments, R 5 is independently –F. In embodiments, R 5 is independently –Cl. In embodiments, R 5 is independently –Br. In embodiments, R 5 is independently –I. In embodiments, R 5 is independently -CCl 3 . In embodiments, R 5 is independently -CBr3. In embodiments, R 5 is independently -CF3. In embodiments, R 5 is independently -CI 3 . In embodiments, R 5 is independently -CH 2 Cl. In embodiments, R 5 is independently -CH2Br. In embodiments, R 5 is independently -CH2F. In embodiments, R 5 is independently -CH 2 I.
  • R 5 is independently -CHCl 2 . In embodiments, R 5 is independently -CHBr2. In embodiments, R 5 is independently -CHF2. In embodiments, R 5 is independently -CHI 2 . In embodiments, R 5 is independently –CN. In embodiments, R 5 is independently –OH. In embodiments, R 5 is independently -NH2. In embodiments, R 5 is independently –COOH. In embodiments, R 5 is independently -CONH 2 . In embodiments, R 5 is independently -NO 2 . In embodiments, R 5 is independently –SH. In embodiments, R 5 is independently -SO 3 H. In embodiments, R 5 is independently -OSO 3 H.
  • R 5 is independently -SO 2 NH 2 . In embodiments, R 5 is independently ⁇ NHNH 2 . In embodiments, R 5 is independently ⁇ ONH 2 . In embodiments, R 5 is independently ⁇ NHC(O)NHNH2. In embodiments, R 5 is independently ⁇ NHC(O)NH2. In embodiments, R 5 is independently -NHSO2H. In embodiments, R 5 is independently -NHC(O)H. In embodiments, R 5 is independently -NHC(O)OH. In embodiments, R 5 is independently –NHOH. In embodiments, R 5 is independently -OCCl3. In embodiments, R 5 is independently -OCBr 3 . In embodiments, R 5 is independently -OCF 3 .
  • R 5 is independently -OCI3. In embodiments, R 5 is independently -OCH2Cl. In embodiments, R 5 is independently -OCH 2 Br. In embodiments, R 5 is independently -OCH 2 F. In embodiments, R 5 is independently -OCH 2 I. In embodiments, R 5 is independently -OCHCl 2 . In embodiments, R 5 is independently -OCHBr2. In embodiments, R 5 is independently -OCHF2. In embodiments, R 5 is independently -OCHI 2 . In embodiments, R 5 is independently unsubstituted C1-C4 alkyl. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl.
  • R 5 is independently unsubstituted propyl. In embodiments, R 5 is independently unsubstituted n-propyl. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted butyl. In embodiments, R 5 is independently unsubstituted n- butyl. In embodiments, R 5 is independently unsubstituted isobutyl. In embodiments, R 5 is independently unsubstituted tert-butyl. In embodiments, R 5 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted methoxy.
  • R 5 is independently unsubstituted ethoxy. In embodiments, R 5 is independently unsubstituted propoxy. In embodiments, R 5 is independently unsubstituted n- propoxy. In embodiments, R 5 is independently unsubstituted isopropoxy. In embodiments, R 5 is independently unsubstituted butoxy. In embodiments, R 5 is independently unsubstituted n-butoxy. In embodiments, R 5 is independently unsubstituted isobutoxy. In embodiments, R 5 is independently unsubstituted tert-butoxy. In embodiments, R 5 is independently substituted or unsubstituted phenyl. In embodiments, R 5 is independently substituted phenyl.
  • R 5 is independently unsubstituted phenyl.
  • 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.
  • R 5A is independently unsubstituted n-butyl. In embodiments, R 5A is independently unsubstituted isobutyl. In embodiments, R 5A is independently unsubstituted tert-butyl.
  • R 5B is independently hydrogen. In embodiments, R 5B is independently unsubstituted C 1 -C 4 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.
  • 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. [0260] 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.
  • 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. [0261] In embodiments, R 5D is independently hydrogen. In embodiments, R 5D is independently unsubstituted C 1 -C 4 alkyl.
  • 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.
  • z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6. In embodiments, z5 is 7.
  • substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6 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.
  • R 6 when R 6 is substituted, it is substituted with at least one substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one size-limited substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 6A e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 6A is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6A 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.
  • R 6A when R 6A is substituted, it is substituted with at least one substituent group. In embodiments, when R 6A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 6B (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 6B 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 6B is substituted, it is substituted with at least one substituent group.
  • R 6B when R 6B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6B is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when R 6A and R 6B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • R 6A and R 6B substituents bonded to the same nitrogen atom are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 6A and R 6B 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.
  • when the substituted ring formed when R 6A and R 6B 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 6A and R 6B 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 6A and R 6B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 6C (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 6C 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 6C is substituted, it is substituted with at least one substituent group.
  • R 6C when R 6C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 6D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 6D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 6D 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.
  • R 6D when R 6D is substituted, it is substituted with at least one substituent group. In embodiments, when R 6D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6D is substituted, it is substituted with at least one lower substituent group.
  • R 6 is hydrogen, halogen, -CX 6 3, -CHX 6 2, -CH2X 6 , -OCX 6 3, -OCHX 6 2, -OCH2X 6 , -CN, -SOn6R 6D , -SOv6NR 6A R 6B , ⁇ NR 6C NR 6A R 6B , ⁇ ONR 6A R 6B , ⁇ NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6D , -NR
  • R 6 is hydrogen, halogen, -CF 3 , –CHF 2 , –CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 6 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 6 is hydrogen. In embodiments, R 6 is halogen. In embodiments, R 6 is –F. In embodiments, R 6 is –Cl. In embodiments, R 6 is –Br. In embodiments, R 6 is –I. In embodiments, R 6 is -CCl 3 . In embodiments, R 6 is -CBr 3 . In embodiments, R 6 is -CF 3 . In embodiments, R 6 is -CI3. In embodiments, R 6 is -CH2Cl.
  • R 6 is -CH2Br. In embodiments, R 6 is -CH 2 F. In embodiments, R 6 is -CH 2 I. In embodiments, R 6 is -CHCl 2 . In embodiments, R 6 is -CHBr2. In embodiments, R 6 is -CHF2. In embodiments, R 6 is -CHI2. In embodiments, R 6 is –CN. In embodiments, R 6 is –OH. In embodiments, R 6 is -NH 2 . In embodiments, R 6 is –COOH. In embodiments, R 6 is -CONH2. In embodiments, R 6 is -NO2. In embodiments, R 6 is –SH. In embodiments, R 6 is -SO 3 H.
  • R 6 is -OSO 3 H. In embodiments, R 6 is -SO2NH2. In embodiments, R 6 is ⁇ NHNH2. In embodiments, R 6 is ⁇ ONH2. In embodiments, R 6 is ⁇ NHC(O)NHNH2. In embodiments, R 6 is ⁇ NHC(O)NH2. In embodiments, R 6 is -NHSO 2 H. In embodiments, R 6 is -NHC(O)H. In embodiments, R 6 is -NHC(O)OH. In embodiments, R 6 is –NHOH. In embodiments, R 6 is -OCCl3. In embodiments, R 6 is -OCBr 3 . In embodiments, R 6 is -OCF 3 .
  • R 6 is -OCI 3 . In embodiments, R 6 is -OCH2Cl. In embodiments, R 6 is -OCH2Br. In embodiments, R 6 is -OCH 2 F. In embodiments, R 6 is -OCH 2 I. In embodiments, R 6 is -OCHCl 2 . In embodiments, R 6 is -OCHBr 2 . In embodiments, R 6 is -OCHF 2 . In embodiments, R 6 is -OCHI2. In embodiments, R 6 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 6 is substituted C 1 -C 4 alkyl. In embodiments, R 6 is substituted methyl.
  • R 6 is substituted ethyl. In embodiments, R 6 is substituted propyl. In embodiments, R 6 is substituted n-propyl. In embodiments, R 6 is substituted isopropyl. In embodiments, R 6 is substituted butyl. In embodiments, R 6 is substituted n-butyl. In embodiments, R 6 is substituted isobutyl. In embodiments, R 6 is substituted tert-butyl. In embodiments, R 6 is unsubstituted C1-C4 alkyl. In embodiments, R 6 is unsubstituted methyl. In embodiments, R 6 is unsubstituted ethyl.
  • R 6 is unsubstituted propyl. In embodiments, R 6 is unsubstituted n-propyl. In embodiments, R 6 is unsubstituted isopropyl. In embodiments, R 6 is unsubstituted butyl. In embodiments, R 6 is unsubstituted n-butyl. In embodiments, R 6 is unsubstituted isobutyl. In embodiments, R 6 is unsubstituted tert-butyl. In embodiments, R 6 is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 6 is substituted 2 to 4 membered heteroalkyl.
  • R 6 is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 6 is unsubstituted methoxy. In embodiments, R 6 is unsubstituted ethoxy. In embodiments, R 6 is unsubstituted propoxy. In embodiments, R 6 is unsubstituted n-propoxy. In embodiments, R 6 is unsubstituted isopropoxy. In embodiments, R 6 is unsubstituted butoxy. In embodiments, R 6 is unsubstituted n-butoxy. In embodiments, R 6 is unsubstituted isobutoxy. In embodiments, R 6 is unsubstituted tert-butoxy.
  • R 6 is an amino acid side chain. In embodiments, R 6 is a glycine side chain. In embodiments, R 6 is an alanine side chain. In embodiments, R 6 is a valine side chain. In embodiments, R 6 is a leucine side chain. In embodiments, R 6 is an isoleucine side chain. In embodiments, R 6 is a methionine side chain. In embodiments, R 6 is a serine side chain. In embodiments, R 6 is a threonine side chain. In embodiments, R 6 is a cysteine side chain. In embodiments, R 6 is an aspartic acid side chain. In embodiments, R 6 is a glutamic acid side chain.
  • R 6 is an asparagine side chain. In embodiments, R 6 is a glutamine side chain. In embodiments, R 6 is a histidine side chain. In embodiments, R 6 is a phenylalanine side chain. In embodiments, R 6 is a tyrosine side chain. In embodiments, R 6 is a tryptophan side chain. In embodiments, R 6 is an arginine side chain. In embodiments, R 6 is a lysine side chain. [0274] In embodiments, R 6 is an amino acid side chain. In embodiments, R 6 is an L- glycine side chain. In embodiments, R 6 is an L-alanine side chain. In embodiments, R 6 is an L-valine side chain.
  • R 6 is an L-leucine side chain. In embodiments, R 6 is an L-isoleucine side chain. In embodiments, R 6 is an L-methionine side chain. In embodiments, R 6 is an L-serine side chain. In embodiments, R 6 is an L-threonine side chain. In embodiments, R 6 is an L-cysteine side chain. In embodiments, R 6 is an L-aspartic acid side chain. In embodiments, R 6 is an L-glutamic acid side chain. In embodiments, R 6 is an L-asparagine side chain. In embodiments, R 6 is an L-glutamine side chain. In embodiments, R 6 is an L-histidine side chain.
  • R 6 is an L-phenylalanine side chain. In embodiments, R 6 is an L-tyrosine side chain. In embodiments, R 6 is an L-tryptophan side chain. In embodiments, R 6 is an L-arginine side chain. In embodiments, R 6 is an L-lysine side chain. [0275] In embodiments, R 6 is an amino acid side chain. In embodiments, R 6 is a D-glycine side chain. In embodiments, R 6 is a D-alanine side chain. In embodiments, R 6 is a D-valine side chain. In embodiments, R 6 is a D-leucine side chain. In embodiments, R 6 is a D- isoleucine side chain.
  • R 6 is a D-methionine side chain. In embodiments, R 6 is a D-serine side chain. In embodiments, R 6 is a D-threonine side chain. In embodiments, R 6 is a D-cysteine side chain. In embodiments, R 6 is a D-aspartic acid side chain. In embodiments, R 6 is a D-glutamic acid side chain. In embodiments, R 6 is a D-asparagine side chain. In embodiments, R 6 is a D-glutamine side chain. In embodiments, R 6 is a D-histidine side chain. In embodiments, R 6 is a D-phenylalanine side chain.
  • R 6 is a D- tyrosine side chain. In embodiments, R 6 is a D-tryptophan side chain. In embodiments, R 6 is a D-arginine side chain. In embodiments, R 6 is a D-lysine side chain. [0276] In embodiments, R 6 is hydrogen, unsubstituted methyl, unsubstituted isopropyl, , alkyl. In embodiments, R 6A is unsubstituted methyl. In embodiments, R 6A is unsubstituted ethyl. In embodiments, R 6A is unsubstituted propyl. In embodiments, R 6A is unsubstituted n- propyl.
  • R 6A is unsubstituted isopropyl. In embodiments, R 6A is unsubstituted butyl. In embodiments, R 6A is unsubstituted n-butyl. In embodiments, R 6A is unsubstituted isobutyl. In embodiments, R 6A is unsubstituted tert-butyl. [0278] In embodiments, R 6B is hydrogen. In embodiments, R 6B is unsubstituted C 1 -C 4 alkyl. In embodiments, R 6B is unsubstituted methyl. In embodiments, R 6B is unsubstituted ethyl.
  • R 6B is unsubstituted propyl. In embodiments, R 6B is unsubstituted n- propyl. In embodiments, R 6B is unsubstituted isopropyl. In embodiments, R 6B is unsubstituted butyl. In embodiments, R 6B is unsubstituted n-butyl. In embodiments, R 6B is unsubstituted isobutyl. In embodiments, R 6B is unsubstituted tert-butyl. [0279] In embodiments, R 6C is hydrogen. In embodiments, R 6C is unsubstituted C1-C4 alkyl.
  • R 6C is unsubstituted methyl. In embodiments, R 6C is unsubstituted ethyl. In embodiments, R 6C is unsubstituted propyl. In embodiments, R 6C is unsubstituted n- propyl. In embodiments, R 6C is unsubstituted isopropyl. In embodiments, R 6C is unsubstituted butyl. In embodiments, R 6C is unsubstituted n-butyl. In embodiments, R 6C is unsubstituted isobutyl. In embodiments, R 6C is unsubstituted tert-butyl. [0280] In embodiments, R 6D is hydrogen.
  • R 6D is unsubstituted C 1 -C 4 alkyl. In embodiments, R 6D is unsubstituted methyl. In embodiments, R 6D is unsubstituted ethyl. In embodiments, R 6D is unsubstituted propyl. In embodiments, R 6D is unsubstituted n- propyl. In embodiments, R 6D is unsubstituted isopropyl. In embodiments, R 6D is unsubstituted butyl. In embodiments, R 6D is unsubstituted n-butyl. In embodiments, R 6D is unsubstituted isobutyl.
  • R 6D is unsubstituted tert-butyl.
  • a substituted ring formed when R 3 and R 6 substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • R 3 and R 6 substituents bonded to the same nitrogen atom are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 3 and R 6 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.
  • R 3 and R 6 may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 3 and R 6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 3 and R 6 are joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, R 3 and R 6 are joined to form an unsubstituted pyrrolidinyl. In embodiments, R 3 and R 6 are joined to form an unsubstituted piperidinyl.
  • a substituted R 7 (e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 7 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.
  • R 7 when R 7 is substituted, it is substituted with at least one substituent group.
  • R 7 when R 7 is substituted, it is substituted with at least one size-limited substituent group.
  • R 7 when R 7 is substituted, it is substituted with at least one lower substituent group.
  • R 7 is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 7 is hydrogen, halogen, -OH, -N3, or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2).
  • R 7 is hydrogen.
  • R 7 is halogen.
  • R 7 is –F.
  • R 7 is –Cl.
  • R 7 is –Br.
  • R 7 is –I. In embodiments, R 7 is -OH. In embodiments, R 7 is -N 3 . In embodiments, R 7 is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 7 is unsubstituted C1-C4 alkyl. In embodiments, R 7 is unsubstituted methyl. In embodiments, R 7 is unsubstituted ethyl. In embodiments, R 7 is unsubstituted propyl. In embodiments, R 7 is unsubstituted n-propyl. In embodiments, R 7 is unsubstituted isopropyl. In embodiments, R 7 is unsubstituted butyl.
  • R 7 is unsubstituted n-butyl. In embodiments, R 7 is unsubstituted isobutyl. In embodiments, R 7 is unsubstituted tert-butyl.
  • a substituted R 8 e.g., substituted alkyl is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 8 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.
  • R 8 when R 8 is substituted, it is substituted with at least one substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one lower substituent group.
  • R 8 is hydrogen, halogen, -OH, -N3, or substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 8 is hydrogen, halogen, -OH, -N3, or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 8 is hydrogen. In embodiments, R 8 is halogen. In embodiments, R 8 is –F. In embodiments, R 8 is –Cl. In embodiments, R 8 is –Br. In embodiments, R 8 is –I. In embodiments, R 8 is -OH. In embodiments, R 8 is -N 3 . In embodiments, R 8 is substituted or unsubstituted C1-C4 alkyl.
  • R 8 is hydrogen. In embodiments, R 8 is halogen. In embodiments, R 8 is –F. In embodiments, R 8 is –Cl. In embodiments, R 8 is –Br. In embodiments, R 8 is –I. In embodiments, R 8 is -OH. In embodiments, R 8 is -N
  • R 8 is unsubstituted C1-C4 alkyl. In embodiments, R 8 is unsubstituted methyl. In embodiments, R 8 is unsubstituted ethyl. In embodiments, R 8 is unsubstituted propyl. In embodiments, R 8 is unsubstituted n-propyl. In embodiments, R 8 is unsubstituted isopropyl. In embodiments, R 8 is unsubstituted butyl. In embodiments, R 8 is unsubstituted n-butyl. In embodiments, R 8 is unsubstituted isobutyl. In embodiments, R 8 is unsubstituted tert-butyl.
  • a substituted R 9 (e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 9 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.
  • R 9 when R 9 is substituted, it is substituted with at least one substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one size-limited substituent group.
  • R 9 when R 9 is substituted, it is substituted with at least one lower substituent group.
  • R 9 is hydrogen, halogen, -OH, -N 3 , or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 9 is hydrogen, halogen, -OH, -N 3 , or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 9 is hydrogen. In embodiments, R 9 is halogen. In embodiments, R 9 is –F. In embodiments, R 9 is –Cl.
  • R 9 is –Br. In embodiments, R 9 is –I. In embodiments, R 9 is -OH. In embodiments, R 9 is -N3. In embodiments, R 9 is substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 9 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 9 is unsubstituted methyl. In embodiments, R 9 is unsubstituted ethyl. In embodiments, R 9 is unsubstituted propyl. In embodiments, R 9 is unsubstituted n-propyl. In embodiments, R 9 is unsubstituted isopropyl.
  • R 9 is unsubstituted butyl. In embodiments, R 9 is unsubstituted n-butyl. In embodiments, R 9 is unsubstituted isobutyl. In embodiments, R 9 is unsubstituted tert-butyl.
  • a substituted Ring A (e.g., substituted phenyl and/or substituted 5 to 6 membered heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • Ring A when Ring A is substituted, it is substituted with at least one substituent group.
  • Ring A when Ring A is substituted, it is substituted with at least one size-limited substituent group.
  • Ring A when Ring A is substituted, it is substituted with at least one lower substituent group.
  • Ring A is unsubstituted phenyl or unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted phenyl. In embodiments, Ring A is an unsubstituted phenyl. In embodiments, Ring A is a substituted 5 to 6 membered heteroaryl. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted thienyl. In embodiments, Ring A is an unsubstituted thienyl.
  • Ring A is a substituted 2-thienyl. In embodiments, Ring A is an unsubstituted 2-thienyl. In embodiments, Ring A is a substituted 3-thienyl. In embodiments, Ring A is an unsubstituted 3-thienyl. In embodiments, Ring A is a substituted pyridyl. In embodiments, Ring A is an unsubstituted pyridyl. In embodiments, Ring A is a substituted 2-pyridyl. In embodiments, Ring A is an unsubstituted 2-pyridyl. In embodiments, Ring A is a substituted 3-pyridyl. In embodiments, Ring A is an unsubstituted 3-pyridyl.
  • Ring A is a substituted 4-pyridyl. In embodiments, Ring A is an unsubstituted 4-pyridyl. In embodiments, Ring A is a substituted pyrrolyl. In embodiments, Ring A is an unsubstituted pyrrolyl. In embodiments, Ring A is a substituted furanyl. In embodiments, Ring A is an unsubstituted furanyl. In embodiments, Ring A is a substituted pyrazolyl. In embodiments, Ring A is an unsubstituted pyrazolyl. In embodiments, Ring A is a substituted imidazolyl. In embodiments, Ring A is an unsubstituted imidazolyl.
  • Ring A is a substituted oxazolyl. In embodiments, Ring A is an unsubstituted oxazolyl. In embodiments, Ring A is a substituted isoxazolyl. In embodiments, Ring A is an unsubstituted isoxazolyl. In embodiments, Ring A is a substituted thiazolyl. In embodiments, Ring A is an unsubstituted thiazolyl. In embodiments, Ring A is a substituted triazolyl. In embodiments, Ring A is an unsubstituted triazolyl. [0292] In embodiments, Ring A is phenyl. In embodiments, Ring A is 5 to 6 membered heteroaryl.
  • Ring A is thienyl. In embodiments, Ring A is 2-thienyl. In embodiments, Ring A is 3-thienyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is 2-pyridyl. In embodiments, Ring A is 3-pyridyl. In embodiments, Ring A is 4- pyridyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl.
  • Ring A is triazolyl. , . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A In embodiments, R . R 4.1 , R 4.2 , R 4.3 , and R 4.4 are independently any value of R 4 as described in embodiments.
  • R 4.1 , R 4.2 , R 4.3 , and R 4.4 are independently a halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCX 4 3, -OCHX 4 2, -OCH2X 4 , -CN, -SOn4R 4D , -SOv4NR 4A R 4B , ⁇ NR 4C NR 4A R 4B , ⁇ ONR 4A R 4B , ⁇ NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -SR
  • Ring B when Ring B is substituted, it is substituted with at least one substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one size-limited substituent group.
  • Ring B when Ring B is substituted, it is substituted with at least one lower substituent group.
  • Ring B is unsubstituted phenyl, unsubstituted naphthyl, unsubstituted quinolinyl, or unsubstituted isoquinolinyl.
  • Ring B is a substituted phenyl.
  • Ring B is an unsubstituted phenyl.
  • Ring B is a substituted naphthyl.
  • Ring B is an unsubstituted naphthyl.
  • Ring B is a substituted 1-naphthyl.
  • Ring B is an unsubstituted 1-naphthyl. In embodiments, Ring B is a substituted 2-naphthyl. In embodiments, Ring B is an unsubstituted 2-naphthyl. In embodiments, Ring B is a substituted quinolinyl. In embodiments, Ring B is an unsubstituted quinolinyl. In embodiments, Ring B is a substituted 2-quinolinyl. In embodiments, Ring B is an unsubstituted 2-quinolinyl. In embodiments, Ring B is a substituted 3-quinolinyl. In embodiments, Ring B is an unsubstituted 3-quinolinyl.
  • Ring B is a substituted 4-quinolinyl. In embodiments, Ring B is an unsubstituted 4-quinolinyl. In embodiments, Ring B is a substituted 5-quinolinyl. In embodiments, Ring B is an unsubstituted 5-quinolinyl. In embodiments, Ring B is a substituted 6-quinolinyl. In embodiments, Ring B is an unsubstituted 6-quinolinyl. In embodiments, Ring B is a substituted 7-quinolinyl. In embodiments, Ring B is an unsubstituted 7-quinolinyl. In embodiments, Ring B is a substituted 8-quinolinyl.
  • Ring B is an unsubstituted 8-quinolinyl. In embodiments, Ring B is a substituted isoquinolinyl. In embodiments, Ring B is an unsubstituted isoquinolinyl. In embodiments, Ring B is a substituted 1-isoquinolinyl. In embodiments, Ring B is an unsubstituted 1-isoquinolinyl. In embodiments, Ring B is a substituted 3-isoquinolinyl. In embodiments, Ring B is an unsubstituted 3-isoquinolinyl. In embodiments, Ring B is a substituted 4-isoquinolinyl. In embodiments, Ring B is an unsubstituted 4-isoquinolinyl.
  • Ring B is a substituted 5-isoquinolinyl. In embodiments, Ring B is an unsubstituted 5-isoquinolinyl. In embodiments, Ring B is a substituted 6-isoquinolinyl. In embodiments, Ring B is an unsubstituted 6-isoquinolinyl. In embodiments, Ring B is a substituted 7-isoquinolinyl. In embodiments, Ring B is an unsubstituted 7-isoquinolinyl. In embodiments, Ring B is a substituted 8-isoquinolinyl. In embodiments, Ring B is an unsubstituted 8-isoquinolinyl. [0299] In embodiments, Ring B is phenyl.
  • Ring B is naphthyl. In embodiments, Ring B is 1-naphthyl. In embodiments, Ring B is 2-naphthyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is 2-quinolinyl. In embodiments, Ring B is 3-quinolinyl. In embodiments, Ring B is 4-quinolinyl. In embodiments, Ring B is 5-quinolinyl. In embodiments, Ring B is 6-quinolinyl. In embodiments, Ring B is 7-quinolinyl. In embodiments, Ring B is 8-quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is 1-isoquinolinyl.
  • Ring B is 3-isoquinolinyl. In embodiments, Ring B is 4-isoquinolinyl. In embodiments, Ring B is 5-isoquinolinyl. In embodiments, Ring B is 6-isoquinolinyl. In embodiments, Ring B is 7-isoquinolinyl. In embodiments, Ring B is 8-isoquinolinyl. In embodiments, embodiments, In embodiments, is embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. [0302] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. [0303] In embodiments, the compound has the formula: z1, R 2 , R 3 , R 4 , z4, and R 6 are as described herein, [0304] In embodiments, the compound has the formula: 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 are as described herein, [0305] In embodiments, the compound has the formula: in [0306] In embodiments, the compound has the formula: .
  • R 2 , R 3 , R 4 , z4, and R 6 are as described herein, including in [0307]
  • the compound has the formula: . R 4 , z4, and R 6 are as described herein, including in the compound has the formula: . R 4 , z4, and R 6 are as described herein, including in [0309]
  • the compound has the formula: are as described herein, including in [0310]
  • the compound has the formula: . R 4 , z4, and R 6 are as described herein, including in [0311]
  • the compound has the formula: described herein, including in embodiments. has the formula: as described herein, including in embodiments. pound has the formula: .
  • R 6 is as described herein, including in embodiments. the compound has the formula: herein, [0316] In embodiments, the compound has the formula: . R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 are as described herein, [0317] In embodiments, the compound has the formula: . R 4 , R 5 , z5, and R 6 are as described herein, including in [0318] In embodiments, the compound has the formula: . R 4 , R 5 , z5, and R 6 are as described herein, including in [0319] In embodiments, the compound has the formula: .
  • R 4 , R 5 , z5, and R 6 are as described herein, including in [0320]
  • the compound has the formula: . R 4 , R 5 , z5, and R 6 are as described herein, including in [0321]
  • the compound has the formula: in in in . R 5 , z5, and R 6 are as described herein, including in [0325]
  • the compound has the formula: , wherein L 1 , R 4.2 , and R 4.4 are as described herein, including in embodiments.
  • the compound has the , wherein L 1 , R 4.2 , and R 4.3 are as described herein, including in embodiments, the compound has the , wherein L 1 , R 4.2 , R 4.3 , and R 4.4 are as described herein, the compound has the , wherein L 1 , R 4.1 , and R 4.3 are as described herein, including in embodiments.
  • the compound has the , wherein L 1 , R 4.1 , and R 4.4 are as described herein, the compound has the formula: , wherein L 1 , R 1 , R 4.2 , and R 4.4 are as described herein, embodiments, the compound has the formula: , wherein L 1 , R 1 , R 4.2 , and R 4.3 are as described herein, embodiments, the compound has the formula: , wherein L 1 , R 1 , R 4.2 , R 4.3 , and R 4.4 are as described herein, embodiments, the compound has the formula:
  • the compound has the formula: , wherein L 1 , R 1 , R 4.1 , and R 4.4 are as described herein, [0326] In embodiments, the compound has the formula: O H N N are as described herein, including in embodiments.
  • the compound has the , wherein R 4.2 and R 4.3 are as described herein, including in the compound has the as described herein, including in formula , wherein R 4.1 and R 4.3 are as described herein, including in embo , the compound has the formula: , wherein R 1 , R 4.2 , and R 4.3 are as described herein, including in the compound has the formula: , wherein R 1 , R 4.1 , and R 4.4 are as described herein, including in [0327] In embodiments, the compound has the formula: R 6 [0328] In embodiments, the compound has the formula: ). Ring A, R 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 are as described .
  • the compound has the formula: . Ring A, R 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 are as described [0330] In embodiments, the compound has the formula: , wherein R 4 is as described herein, including in embodiments. In embodiments, the compound has the , wherein R 4 is as described herein, including in has the , wherein R 4 is as described herein, including in embodiments. In embodiments, the compound has the formul , wherein R 4 is as described herein, including in embodiments. [0331] In embodiments, the compound has the In embodiments, the compound has the In embodiments, the compound has the .
  • the compound has the embodiments, the compound has the formula . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments,
  • the compound has the formula: n embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:n embodiments, the compound has the formula:n embodiments, the compound has the formula: la:la: la: la:la:la: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: O H N N N H O O N . 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: .
  • the compound has the In embodiments, the compound has the . In embodiments, the compound has the formula . In embodiments, the compound has the . In embodiments, the compound has the formula: O H N N . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . [0333] In embodiments, the compound has the . In embodiments, the compound has the formula . In embodiments, the compound . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: la: mula: N .
  • R 1 , z1, R 2 , R 4 , and z4 are as described herein, including in [0335]
  • the compound has the formula: . R 1 , z1, R 2 , R 4 , and z4 are as described herein, including in [0336]
  • the compound has the formula: are as described herein, including in [0337]
  • the compound has the formula: . R 2 , R 4 , and z4 are as described herein, including in [0338]
  • the compound has the formula: [0342]
  • the compound has the formul
  • the compound has the the compound has the .
  • the compound H N has the . [0343]
  • In the formula: . R 1 , z1, R 2 , R 4 , and z4 are as described herein, including [0345]
  • the compound has the formula: O R 2 N in in
  • the compound has the formula: .
  • R 4 is as described herein, including in embodiments.
  • the compound has the In embodiments, the compound has the In embodiments, the compound has the . In embodiments, the compound has the . In embodiments, the compound has the formul In embodiments, the compound has the . In embodiments, the compound has the . [0352] In embodiments, when R 1 is 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)”.
  • R 1.2 substituent group 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)”.
  • R 1 , 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 R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 1 substituents when two adjacent R 1 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)”.
  • R 1.1 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)”.
  • R 1.2 substituent group 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)”.
  • R 1 , 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 R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 1A 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)”.
  • R 1A.2 substituent group 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)”.
  • 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.
  • R 1B 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)”.
  • R 1B.2 substituent group 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)”.
  • 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.
  • 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)”.
  • R 1A.1 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)”.
  • R 1A.2 substituent group 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)”.
  • 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.
  • 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)”.
  • R 1B.1 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)”.
  • R 1B.2 substituent group 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)”.
  • 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.
  • R 1C 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)”.
  • R 1C.2 substituent group 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)”.
  • 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)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1C , R 1C.1 , R 1C.2 , and R 1C.3 , respectively.
  • R 1D 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)”.
  • R 1D.1 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)”.
  • R 1D.2 substituent group 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)”.
  • 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 R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1D , R 1D.1 , R 1D.2 , and R 1D.3 , respectively.
  • R 2 when R 2 is substituted, R 2 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)”.
  • R 2.1 substituent group 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)”.
  • R 2.2 substituent group 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)”.
  • R 2 , 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 R 2 , R 2.1 , R 2.2 , and R 2.3 , respectively.
  • R 3 when R 3 is substituted, R 3 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)”.
  • R 3.1 substituent group 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)”.
  • R 3 , 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 R 3 , R 3.1 , R 3.2 , and R 3.3 , respectively.
  • R 4 when R 4 is substituted, R 4 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)”.
  • R 4.1 substituent group 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)”.
  • R 4.2 substituent group 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)”.
  • R 4 , 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 R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
  • R 4 substituents when two adjacent R 4 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 4.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.1 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)”.
  • R 4.2 substituent group 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)”.
  • R 4 , 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 R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
  • R 4A when R 4A is substituted, R 4A is substituted with one or more first substituent groups denoted by R 4A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A.1 substituent group when an R 4A.1 substituent group is substituted, the R 4A.1 substituent group is substituted with one or more second substituent groups denoted by R 4A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A.2 substituent group when an R 4A.2 substituent group is substituted, the R 4A.2 substituent group is substituted with one or more third substituent groups denoted by R 4A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A , R 4A.1 , R 4A.2 , and R 4A.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 4A , R 4A.1 , R 4A.2 , and R 4A.3 , respectively.
  • R 4B when R 4B is substituted, R 4B is substituted with one or more first substituent groups denoted by R 4B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B.1 substituent group when an R 4B.1 substituent group is substituted, the R 4B.1 substituent group is substituted with one or more second substituent groups denoted by R 4B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B.2 substituent group when an R 4B.2 substituent group is substituted, the R 4B.2 substituent group is substituted with one or more third substituent groups denoted by R 4B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B , R 4B.1 , R 4B.2 , and R 4B.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 4B , R 4B.1 , R 4B.2 , and R 4B.3 , respectively.
  • R 4A and R 4B 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 4A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A.1 when an R 4A.1 substituent group is substituted, the R 4A.1 substituent group is substituted with one or more second substituent groups denoted by R 4A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A.2 substituent group when an R 4A.2 substituent group is substituted, the R 4A.2 substituent group is substituted with one or more third substituent groups denoted by R 4A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4A.1 , R 4A.2 , and R 4A.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 [0367]
  • R 4A and R 4B 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 4B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B.1 substituent group when an R 4B.1 substituent group is substituted, the R 4B.1 substituent group is substituted with one or more second substituent groups denoted by R 4B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B.2 substituent group when an R 4B.2 substituent group is substituted, the R 4B.2 substituent group is substituted with one or more third substituent groups denoted by R 4B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4B.1 , R 4B.2 , and R 4B.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 4B.1 , R 4B.2 , and R 4B.3 , respectively.
  • R 4C when R 4C is substituted, R 4C is substituted with one or more first substituent groups denoted by R 4C.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4C.1 substituent group when an R 4C.1 substituent group is substituted, the R 4C.1 substituent group is substituted with one or more second substituent groups denoted by R 4C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4C.2 substituent group when an R 4C.2 substituent group is substituted, the R 4C.2 substituent group is substituted with one or more third substituent groups denoted by R 4C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4C , R 4C.1 , R 4C.2 , and R 4C.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 4C , R 4C.1 , R 4C.2 , and R 4C.3 , respectively.
  • R 4D when R 4D is substituted, R 4D is substituted with one or more first substituent groups denoted by R 4D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4D.1 when an R 4D.1 substituent group is substituted, the R 4D.1 substituent group is substituted with one or more second substituent groups denoted by R 4D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4D.2 substituent group when an R 4D.2 substituent group is substituted, the R 4D.2 substituent group is substituted with one or more third substituent groups denoted by R 4D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4D , R 4D.1 , R 4D.2 , and R 4D.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 4D , R 4D.1 , R 4D.2 , and R 4D.3 , respectively.
  • R 4.1 when R 4.1 is substituted, R 4.1 is substituted with one or more first substituent groups denoted by R 4.1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.1.1 substituent group when an R 4.1.1 substituent group is substituted, the R 4.1.1 substituent group is substituted with one or more second substituent groups denoted by R 4.1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.1.2 substituent group when an R 4.1.2 substituent group is substituted, the R 4.1.2 substituent group is substituted with one or more third substituent groups denoted by R 4.1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.1 , R 4.1.1 , R 4.1.2 , and R 4.1.3 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 R 4.1 , R 4.1.1 , R 4.1.2 , and R 4.1.3 , respectively.
  • R 4.2 when R 4.2 is substituted, R 4.2 is substituted with one or more first substituent groups denoted by R 4.2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2.1 substituent group when an R 4.2.1 substituent group is substituted, the R 4.2.1 substituent group is substituted with one or more second substituent groups denoted by R 4.2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2.2 substituent group when an R 4.2.2 substituent group is substituted, the R 4.2.2 substituent group is substituted with one or more third substituent groups denoted by R 4.2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2 , R 4.2.1 , R 4.2.2 , and R 4.2.3 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 R 4.2 , R 4.2.1 , R 4.2.2 , and R 4.2.3 , respectively.
  • R 4.3 when R 4.3 is substituted, R 4.3 is substituted with one or more first substituent groups denoted by R 4.3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.3.1 substituent group when an R 4.3.1 substituent group is substituted, the R 4.3.1 substituent group is substituted with one or more second substituent groups denoted by R 4.3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 4.3.2 substituent group is substituted, the R 4.3.2 substituent group is substituted with one or more third substituent groups denoted by R 4.3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.3 , R 4.3.1 , R 4.3.2 , and R 4.3.3 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 R 4.3 , R 4.3.1 , R 4.3.2 , and R 4.3.3 , respectively.
  • R 4.4 when R 4.4 is substituted, R 4.4 is substituted with one or more first substituent groups denoted by R 4.4.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.4.1 substituent group when an R 4.4.1 substituent group is substituted, the R 4.4.1 substituent group is substituted with one or more second substituent groups denoted by R 4.4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.4.2 substituent group when an R 4.4.2 substituent group is substituted, the R 4.4.2 substituent group is substituted with one or more third substituent groups denoted by R 4.4.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.4 , R 4.4.1 , R 4.4.2 , and R 4.4.3 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 R 4.4 , R 4.4.1 , R 4.4.2 , and R 4.4.3 , respectively.
  • R 5 when R 5 is substituted, R 5 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)”.
  • R 5.1 substituent group 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)”.
  • R 5 , 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 R 5 , R 5.1 , R 5.2 , and R 5.3 , respectively.
  • R 5 substituents when two adjacent R 5 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)”.
  • R 5.1 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)”.
  • R 5.2 substituent group 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)”.
  • R 5 , 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 R 5 , R 5.1 , R 5.2 , and R 5.3 , respectively.
  • R 5A 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)”.
  • R 5A.1 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)”.
  • R 5A.2 substituent group 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)”.
  • 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 , 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 5A , R 5A.1 , R 5A.2 , and R 5A.3 , respectively.
  • R 5B when R 5B is substituted, R 5B 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)”.
  • R 5B.1 substituent group 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)”.
  • R 5B.2 substituent group 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)”.
  • R 5B , R 5B.1 , R 5B.2 , and R 5B.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 5B , R 5B.1 , R 5B.2 , and R 5B.3 , respectively.
  • 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)”.
  • R 5A.1 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)”.
  • R 5A.2 substituent group 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)”.
  • 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 description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 5A.1 , R 5A.2 , and R 5A.3 , respectively.
  • 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)”.
  • R 5B.1 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)”.
  • R 5B.2 substituent group 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)”.
  • 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 , 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 5B.1 , R 5B.2 , and R 5B.3 , respectively.
  • R 5C 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)”.
  • R 5C.1 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)”.
  • R 5C.2 substituent group 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)”.
  • R 5C , R 5C.1 , R 5C.2 , and R 5C.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 5C , R 5C.1 , R 5C.2 , and R 5C.3 , respectively.
  • R 5D when R 5D is substituted, 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)”.
  • R 5D.1 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)”.
  • R 5D.2 substituent group 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)”.
  • 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 , 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 5D , R 5D.1 , R 5D.2 , and R 5D.3 , respectively.
  • R 6 when R 6 is substituted, R 6 is substituted with one or more first substituent groups denoted by R 6.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6.1 substituent group when an R 6.1 substituent group is substituted, the R 6.1 substituent group is substituted with one or more second substituent groups denoted by R 6.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6.2 substituent group when an R 6.2 substituent group is substituted, the R 6.2 substituent group is substituted with one or more third substituent groups denoted by R 6.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6 , R 6.1 , R 6.2 , and R 6.3 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 6 , R 6.1 , R 6.2 , and R 6.3 , respectively.
  • R 6A when R 6A is substituted, R 6A is substituted with one or more first substituent groups denoted by R 6A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A.1 substituent group when an R 6A.1 substituent group is substituted, the R 6A.1 substituent group is substituted with one or more second substituent groups denoted by R 6A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A.2 substituent group when an R 6A.2 substituent group is substituted, the R 6A.2 substituent group is substituted with one or more third substituent groups denoted by R 6A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A , R 6A.1 , R 6A.2 , and R 6A.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 6A , R 6A.1 , R 6A.2 , and R 6A.3 , respectively.
  • R 6B when R 6B is substituted, R 6B is substituted with one or more first substituent groups denoted by R 6B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B.1 substituent group when an R 6B.1 substituent group is substituted, the R 6B.1 substituent group is substituted with one or more second substituent groups denoted by R 6B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B.2 substituent group when an R 6B.2 substituent group is substituted, the R 6B.2 substituent group is substituted with one or more third substituent groups denoted by R 6B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B , R 6B.1 , R 6B.2 , and R 6B.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 6B , R 6B.1 , R 6B.2 , and R 6B.3 , respectively.
  • R 6A and R 6B 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 6A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A.1 when an R 6A.1 substituent group is substituted, the R 6A.1 substituent group is substituted with one or more second substituent groups denoted by R 6A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A.2 substituent group when an R 6A.2 substituent group is substituted, the R 6A.2 substituent group is substituted with one or more third substituent groups denoted by R 6A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6A.1 , R 6A.2 , and R 6A.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 6A.1 , R 6A.2 , and R 6A.3 , respectively.
  • R 6A and R 6B 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 6B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B.1 when an R 6B.1 substituent group is substituted, the R 6B.1 substituent group is substituted with one or more second substituent groups denoted by R 6B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B.2 substituent group when an R 6B.2 substituent group is substituted, the R 6B.2 substituent group is substituted with one or more third substituent groups denoted by R 6B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6B.1 , R 6B.2 , and R 6B.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 6B.1 , R 6B.2 , and R 6B.3 , respectively.
  • R 6C when R 6C is substituted, R 6C is substituted with one or more first substituent groups denoted by R 6C.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6C.1 when an R 6C.1 substituent group is substituted, the R 6C.1 substituent group is substituted with one or more second substituent groups denoted by R 6C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6C.2 substituent group when an R 6C.2 substituent group is substituted, the R 6C.2 substituent group is substituted with one or more third substituent groups denoted by R 6C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6C , R 6C.1 , R 6C.2 , and R 6C.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 6C , R 6C.1 , R 6C.2 , and R 6C.3 , respectively.
  • R 6D when R 6D is substituted, R 6D is substituted with one or more first substituent groups denoted by R 6D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6D.1 when an R 6D.1 substituent group is substituted, the R 6D.1 substituent group is substituted with one or more second substituent groups denoted by R 6D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6D.2 substituent group when an R 6D.2 substituent group is substituted, the R 6D.2 substituent group is substituted with one or more third substituent groups denoted by R 6D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6D , R 6D.1 , R 6D.2 , and R 6D.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 6D , R 6D.1 , R 6D.2 , and R 6D.3 , respectively.
  • R 3 and R 6 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 3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3.1 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)”.
  • R 3.2 substituent group 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)”.
  • R 3.1 , R 3.2 , and R 3.3 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 3.1 , R 3.2 , and R 3.3 , respectively.
  • R 3 and R 6 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 6.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6.1 when an R 6.1 substituent group is substituted, the R 6.1 substituent group is substituted with one or more second substituent groups denoted by R 6.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6.2 substituent group when an R 6.2 substituent group is substituted, the R 6.2 substituent group is substituted with one or more third substituent groups denoted by R 6.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 6.1 , R 6.2 , and R 6.3 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 6.1 , R 6.2 , and R 6.3 , respectively.
  • R 7 when R 7 is substituted, R 7 is substituted with one or more first substituent groups denoted by R 7.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 7.1 substituent group when an R 7.1 substituent group is substituted, the R 7.1 substituent group is substituted with one or more second substituent groups denoted by R 7.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 7.2 substituent group when an R 7.2 substituent group is substituted, the R 7.2 substituent group is substituted with one or more third substituent groups denoted by R 7.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 7 , R 7.1 , R 7.2 , and R 7.3 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 7 , R 7.1 , R 7.2 , and R 7.3 , respectively.
  • R 8 when R 8 is substituted, R 8 is substituted with one or more first substituent groups denoted by R 8.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 8.1 substituent group when an R 8.1 substituent group is substituted, the R 8.1 substituent group is substituted with one or more second substituent groups denoted by R 8.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 8.2 substituent group is substituted, the R 8.2 substituent group is substituted with one or more third substituent groups denoted by R 8.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 8 , R 8.1 , R 8.2 , and R 8.3 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 8 , R 8.1 , R 8.2 , and R 8.3 , respectively.
  • R 9 when R 9 is substituted, R 9 is substituted with one or more first substituent groups denoted by R 9.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 9.1 substituent group when an R 9.1 substituent group is substituted, the R 9.1 substituent group is substituted with one or more second substituent groups denoted by R 9.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 9.2 substituent group when an R 9.2 substituent group is substituted, the R 9.2 substituent group is substituted with one or more third substituent groups denoted by R 9.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 9 , R 9.1 , R 9.2 , and R 9.3 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 9 , R 9.1 , R 9.2 , and R 9.3 , respectively.
  • Ring A when Ring A is substituted, Ring A is substituted with one or more first substituent groups denoted by R A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R A.1 substituent group when an R A.1 substituent group is substituted, the R A.1 substituent group is substituted with one or more second substituent groups denoted by R A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R A.2 substituent group when an R A.2 substituent group is substituted, the R A.2 substituent group is substituted with one or more third substituent groups denoted by R A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • Ring A, R A.1 , R A.2 , and R A.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 Ring A, R A.1 , R A.2 , and R A.3 , respectively.
  • Ring B when Ring B is substituted, Ring B is substituted with one or more first substituent groups denoted by R B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R B.1 substituent group when an R B.1 substituent group is substituted, the R B.1 substituent group is substituted with one or more second substituent groups denoted by R B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R B.2 substituent group when an R B.2 substituent group is substituted, the R B.2 substituent group is substituted with one or more third substituent groups denoted by R B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • Ring B, R B.1 , R B.2 , and R B.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 Ring B, R B.1 , R B.2 , and R B.3 , respectively.
  • the compound is a compound as described herein, including in embodiments.
  • the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III.
  • compositions [0397] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0398] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. In embodiments, the compound is a compound of formula (I), (II), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (VIa), (VIb), (VII), (VIII), (IX), (X), or (XI), including embodiments thereof.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid in a mixture with the finely divided active component (e.g., a compound provided herein).
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Dragees cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).
  • compositions of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampules are convenient unit dosages.
  • the compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • Pharmaceutical admixtures suitable for use in the present invention are well-known to those of skill in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component (e.g., compounds described herein) in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as ethyl or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, aspartame or saccharin.
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolarity.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dis
  • Oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997.
  • the pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • a method of treating a cancer in a subject in need thereof comprising: ( i) detecting a level of Myc family protein expression in a cancer cell sample obtained from the subject; and (ii) administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: (O)-, -C(O)NR 7 -, -NR 7 C(O)N 8 R -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O) 2 -, -P(O)(OR 7 )-, -OP(O)(OR 7 )O-, -OP(O)(OR 7 )-, -P(O)(OR 7 )O-,
  • Embodiment P2 The method of embodiment P1, wherein the level of Myc family protein expression is elevated relative to a standard control.
  • Embodiment P3. A method of treating a cancer in a subject in need thereof, wherein the subject has a Myc family protein associated cancer, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein -, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O) 2 -, -P(O)(OR 7 )-, -
  • Embodiment P4 The method of one of embodiments P1 to P3, wherein the Myc family protein is c-Myc, N-Myc, or L-Myc.
  • Embodiment P5. The method of one of embodiments P1 to P4, wherein the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adrenocortical carcinoma, ampullary carcinoma, basal cell carcinoma, bladder cancer, bladder urothelial carcinoma, brain lower grade glioma, breast cancer, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, colon cancer, colorectal adenocarcinoma, cutaneous squamous cell carcinoma, cutaneous T cell lymphoma, diffuse glioma, diffuse large B cell lymphoma, endometrial carcinoma, esophageal adenocarcinoma, gastric adeno
  • Embodiment P6 The method of one of embodiments P1 to P5, wherein the compound has the formula: I); wherein Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl; R 4 is independently a halogen, -CX 4 3, -CHX 4 2, -CH2X 4 , -OCX 4 3, -OCHX 4 2, -OCH2X 4 , -CN, -SOn4R 4D , -SOv4NR 4A R 4B , ⁇ NR 4C NR 4A R 4B , ⁇ ONR 4A R 4B , ⁇ NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O)m4, -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C ,
  • Embodiment P10 The method of embodiment P6, wherein the compound has the . P6, wherein the compound has the . P6, wherein the compound has the . P6, wherein the compound has the . P1 to P12, wherein L 1 is -O-, -NH-, -NCH 3 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2-, -S(O)2NH-, -S(O)2-, -OS(O)2O-, -S(O) 2 O-, -OS(O) 2 -, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O
  • Embodiment P14 The method of one of embodiments P1 to P12, wherein L 1 is -O-.
  • Embodiment P15 The method of one of embodiments P1 to P12, wherein L 1 is –S-.
  • Embodiment P16 The method of one of embodiments P1 to P12, wherein L 1 is –S(O) 2 -.
  • Embodiment P17 The method of one of embodiments P1 to P12, wherein L 1 is –S(O) 2 -.
  • R 1 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • Embodiment P18 The method of one of embodiments P1 to P16, wherein R 1 is independently halogen, -CF3, -OH, -NH2, -SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P19 Embodiment P19.
  • Embodiment P20 The method of one of embodiments P1 to P16, wherein R 1 is independently halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, -OH, -NH2, -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
  • Embodiment P20 The method of one of embodiments P1 to P16, wherein R 1 is independently halogen, -OH, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.
  • Embodiment P21 The method of one of embodiments P1 to P20, wherein z1 is 1.
  • Embodiment P22 The method of one of embodiments P1 to P16, wherein z1 is 0.
  • Embodiment P23 The method of one of embodiments P1 to P16, wherein z1 is 0.
  • R 2 is hydrogen, –CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH2, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P24 The method of one of embodiments P1 to P22, wherein R 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.
  • Embodiment P25 The method of one of embodiments P1 to P22, wherein R 2 is hydrogen.
  • Embodiment P26 The method of one of embodiments P1 to P22, wherein R 2 is hydrogen.
  • R 3 is hydrogen, –CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P27 The method of one of embodiments P1 to P25, wherein R 3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.
  • Embodiment P28 The method of one of embodiments P1 to P25, wherein R 3 is hydrogen.
  • Embodiment P29 The method of one of embodiments P1 to P25, wherein R 3 is hydrogen.
  • R 6 is hydrogen, halogen, -CF 3 , –CHF 2 , –CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • Embodiment P30 The method of one of embodiments P1 to P28, wherein R 6 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • Embodiment P31 The method of one of embodiments P1 to P28, wherein R 6 is , , one and R 6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Embodiment P33 Embodiment P33.
  • Embodiment P34 The method of one of embodiments P1 to P25, wherein R 3 and R 6 are joined to form an unsubstituted pyrrolidinyl.
  • Embodiment P35 The method of one of embodiments P1 to P25, wherein R 3 and R 6 are joined to form an unsubstituted piperidinyl.
  • Embodiment P36 The method of one of embodiments P1 to P25, wherein R 3 and R 6 are joined to form an unsubstituted piperidinyl.
  • R 4 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • Embodiment P37 The method of one of embodiments P6 to P35, wherein R 4 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P38 Embodiment P38.
  • Embodiment P40 The method of one of embodiments P6 to P35, wherein R 4 is independently halogen, -CF 3 , –CHF 2 , –CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, unsubstituted methyl, or unsubstituted methoxy.
  • Embodiment P40 The method of one of embodiments P6 to P35, wherein R 4 is independently –OR 4D .
  • Embodiment P41 The method of embodiment P40, wherein R 4D is independently hydrogen or substituted or unsubstituted alkyl.
  • Embodiment P42 is independently hydrogen or substituted or unsubstituted alkyl.
  • Embodiment P43 The method of embodiment P40, wherein R 4D is independently hydrogen or unsubstituted C1-C5 alkyl.
  • Embodiment P44 The method of embodiment P40, wherein R 4D is independently hydrogen or unsubstituted methyl.
  • Embodiment P45 The method of embodiment P40, wherein R 4D is independently unsubstituted methyl.
  • Embodiment P46 The method of one of embodiments P6 to P45, wherein z4 is 1.
  • Embodiment P47 Embodiment P47.
  • Embodiment P48 The method of one of embodiments P6 to P35, wherein z4 is 0. [0456] Embodiment P48.
  • R 5 is independently halogen, -CF3, –CHF2, –CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
  • Embodiment P49 The method of one of embodiments P6 to P47, wherein R 5 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P50 Embodiment P50.
  • Embodiment P52 The method of one of embodiments P6 to P51, wherein z5 is 1.
  • Embodiment P53 The method of one of embodiments P6 to P47, wherein z5 is 0.
  • Embodiment P54 The method of one of embodiments P6 to P47, wherein z5 is 0.
  • Embodiment P55 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P56 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted thienyl.
  • Embodiment P57 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted 2-thienyl.
  • Embodiment P58 Embodiment P58.
  • Embodiment P59 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted pyridyl.
  • Embodiment P60 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted 2-pyridyl.
  • Embodiment P61 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted 3-pyridyl.
  • Embodiment P62 Embodiment P62.
  • Embodiment P63 The method of one of embodiments P1 to P5, wherein Ring A is a substituted or unsubstituted 4-pyridyl.
  • Embodiment P64 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted naphthyl.
  • Embodiment P65 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted 1-naphthyl.
  • Embodiment P66 Embodiment P66.
  • Embodiment P67 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted quinolinyl.
  • Embodiment P68 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted 2-quinolinyl.
  • Embodiment P69 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted 3-quinolinyl.
  • Embodiment P70 Embodiment P70.
  • Embodiment P71 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted isoquinolinyl.
  • Embodiment P72 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted 1-isoquinolinyl.
  • Embodiment P73 The method of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted 3-isoquinolinyl.
  • Embodiment P74 Embodiment P74.
  • AOH1996 targets a cancer-associated form of PCNA (caPCNA) by altering the protein-protein interface between caPCNA and its many binding partners.
  • AOH1996 does this by inserting into the PCNA-interacting protein-box (PIP-box) pocket that is, in part, defined by the interdomain connecting loop (IDCL), the site of interaction between PCNA and most of its many binding partners.
  • PIP-box PCNA-interacting protein-box
  • IDCL interdomain connecting loop
  • AOH1996 inhibits DNA replication, DNA repair, and transcription-replication conflict (TRC) resolution leading to cell cycle arrest and apoptosis.
  • TRC transcription-replication conflict
  • These effects are cancer specific and AOH1996 has little effect on non-cancerous cells even at 6-fold the effective dose in cancer cells.
  • Oncogenic c-Myc MYC
  • MYC Oncogenic c-Myc
  • MYC multimeric complexes assemble immediately adjacent to stalled replication forks and are thought to stabilize the stalled fork and contribute to TRC resolution.
  • SPT5 MYC-interacting transcription elongation factor
  • MYC dissociates from many of its binding sites in active promoters and assembles in multimeric structures immediately adjacent to stalled replication forks.
  • the MYC multimer in addition to sequestering SPT5, stabilizes the replication fork through interaction with proteins known to be involved in fork stabilization such as FANCD2 and BRCA1.
  • FANCD2 and BRCA1 proteins known to be involved in fork stabilization
  • AOH1996, an inhibitor of PCNA suppresses MYC expression in conjunction with elevated levels of P21, and G2 phase arrest.
  • AOH1996 interferes with MYC mediated transcription and/or the recruitment/assembly of MYC multimers to stalled replication forks within minutes of treatment with AOH1996.
  • AOH1996 pancreatic ductal adenocarcinoma (PDAC) cell lines that are highly metastatic due to high MYC expression and/or MYC amplification resulted in a significant decrease in biological processes associated with angiogenesis and cell migration suggesting a potential role for AOH1996 in inhibition of metastases.
  • PDAC pancreatic ductal adenocarcinoma
  • AOH1996 To identify any cancer type or genomic alterations that AOH1996 may preferentially target, we submitted AOH1996 to the NCI Developmental Therapeutics Program (DTP) for testing in their NCI-60 Human Tumor Cell Lines Screen.
  • the NCI-60 screen consists of 60 human cell lines from 9 different cancer types and is used by the DTP to determine growth inhibition values for a compound of interest. Values for growth inhibition by AOH1996 was calculated by the NCI for each of the cancer cell lines and have previously been published (Gu L et al., 2023). We used these growth inhibition values to evaluate genomic alterations that correlate with AOH1996 sensitivity.
  • the cBioPortal database was used to identify genomic alterations in each of the cancer cell lines (Cerami E et al., 2012; Gao J et al., 2013). We found that cancer cell lines with copy number amplification of the oncogene MYC were found to be significantly more sensitive to AOH1996 than the rest of the cell lines in the NCI-60 (FIG.1A). Application of the Student’s t test to the two groups returned a p value of .0014 indicating significance beyond the .05 value commonly used to determine significance. [0494] We assembled a panel of MYC amplified cancer cell lines along with two non- malignant cell lines to test for sensitivity to AOH1996 (FIG.1B).
  • the cancer cell lines were derived from breast (MCF7), colorectal (HCT116, RKO) ovarian (OVCAR8) and lung (NCI- H358, HCC827, NCI-H1975), cancers that are often driven by MYC amplification and overexpression.
  • the non-malignant cell lines were derived from breast (HMEC-1) and lung (HSAEC).
  • a 72-hour dose response assay was conducted using serial dilutions of AOH1996 starting from a high concentration of 4 ⁇ M.
  • the sulforhodamine B (SRB) assay was used to quantify cell survival and growth inhibition after the 72-hour dosing period.
  • the IC 50 values for the MYC amplified cancer cells ranged from 423 nM to 789 nM with a mean IC50 of 549 nM and a standard deviation of 115 nM for the group.
  • the non-malignant cell lines were relatively unaffected by AOH1996 dosing having a survival rate of 82.4% for HSAEC cells and 70.2% for HMEC-1 cells at 4 ⁇ M of AOH1996. This compares to survival in the MYC amplified cancer cell lines that ranged from 40.4% to 9.8% with a mean survival rate of 21.0% and standard deviation of 13.3%. [0495] AOH1996 suppresses MYC expression.
  • AOH1996 was able to suppress MYCN expression in the two NB cell lines (SK-N-BE2C and BE2C) with amplified MYCN, but not in the third NB cell line (SK-N-FI) where MYCN is not amplified and MYCN protein levels were not effected by treatment with AOH1996 in the assay tested.
  • HCT116 cells were serum starved for 36 hours before releasing into complete media with and without 1 ⁇ M of AOH1996 over a course of time. The cells were fixed and permeabilized and a proximity ligation assay was performed for MYC-PCNA interactions. Under these conditions, untreated cells averaged 2.6 ⁇ 1.2 foci per cell where foci were present while treatment of cells with AOH1996 for 15 minutes to 4 hours abrogated MYC-PCNA interactions (FIG.3).
  • PCNA and MYC colocalize in early S-phase.
  • PCNA is a central component of the eukaryotic replication complex found at replication forks during S phase.
  • MYC expression is elevated at the G1/S phase transition and as a transcription factor leads to the transcription of genes required for cells to move from G1 to S phase.
  • Transcription-replication conflicts occur when the transcription complex encounters the replication complex on the same template DNA. In these instances, the cell must resolve the TRC to continue these core processes and maintain genomic integrity, as stalled replication forks can result in lethal double-strand DNA breaks.
  • TRCs are most likely to occur in early S phase (St Germain et al., 2022). Recent studies have found that MYC complexes consisting of multiple MYC molecules are recruited to sites of TRC and likely play a role in resolving TRCs (Solvie D. et al., 2022). So, in addition to MYC contributing to interactions with PCNA at TRCs as part of the transcription apparatus, TRCs may cause the recruitment of MYC multimer complexes and interact with PCNA in that manner.
  • HCT116 cells were serum starved for 36 hours in media + .1% FBS. The cells were then released into complete media for 30 minutes, during which time BrdU was incorporated into replicating cells. The cells were then fixed and permeabilized. A proximity ligation assay was performed between BrdU and MYC to indicate instances where replication forks encountered MYC.
  • the cells were further stained with the PC10 antibody conjugated to Alexa Fluor 488 to act as a marker for the timing of MYC-PCNA interactions.
  • PCNA as a central component of the replication fork was present at the site of MYC-BrdU foci.
  • the replication fork encountered MYC in the early stages of S phase and in areas of apparent euchromatin, chromatin known to have high levels of gene transcription (FIG.4B). This suggests MYC-PCNA interactions occur at TRCs. This may be due to a replication complex encountering a transcription complex or perhaps recruitment of MYC multimers to TRCs. [0501] AOH1996 disrupts interaction of MYC with SPT5.
  • SPT5 is a transcription elongation factor that directly binds to MYC and is recruited by MYC to promoters where it is transferred to RNA polymerase II (Pol II) in a reaction that requires CDK7. Both MYC and SPT5 are required for fast and processive transcription elongation (Baluapuri A. et al., 2019). In addition, cancer cells that express high levels of MYC, sequester SPT5 into complexes consisting of many MYC molecules, which may be an important event for effective resolution of TRCs (Solvie D. et al.2022).
  • the sequestration of SPT5 may serve to slow the rate at which transcription occurs including the transcription of growth-suppressive genes, thus contributing to MYC-driven uncontrolled cellular growth (Baluapuri A. et al., 2019).
  • SPT5 serum starved the MYC amplified colorectal cancer cell line, HCT116, for 36 hours before releasing into complete media with and without 1 ⁇ M of AOH1996 for 30 minutes.
  • the cells were fixed and permeabilized and a proximity ligation assay using primary antibodies to MYC and SPT5 was performed (FIG.5).
  • MYC-SPT5 foci were markedly reduced in cells treated for 30 minutes with AOH1996.

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Abstract

L'invention concerne, entre autres, l'utilisation d'inhibiteurs de PCNA pour le traitement de cancers associés à la famille des gènes Myc.
PCT/US2025/017943 2024-03-01 2025-02-28 Inhibiteurs de pcna pour le traitement de cancers associés à la famille des gènes myc Pending WO2025184571A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987006940A1 (fr) * 1986-05-06 1987-11-19 The Regents Of The University Of California ANALYSES ET ANTICORPS DES PROTEINES N-myc
US5601820A (en) * 1994-07-07 1997-02-11 Children's Hospital Of Philadelphia Compositions and methods of making and using human full length TRK-B
US20160296482A1 (en) * 2015-04-10 2016-10-13 Rll, Llc Anticancer therapeutic agents
US20210078938A1 (en) * 2015-09-17 2021-03-18 City Of Hope Pcna inhibitors
WO2022261296A1 (fr) * 2021-06-09 2022-12-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composés qui se lient à des structures g-quadruplexes non canoniques et leurs procédés de fabrication et d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987006940A1 (fr) * 1986-05-06 1987-11-19 The Regents Of The University Of California ANALYSES ET ANTICORPS DES PROTEINES N-myc
US5601820A (en) * 1994-07-07 1997-02-11 Children's Hospital Of Philadelphia Compositions and methods of making and using human full length TRK-B
US20160296482A1 (en) * 2015-04-10 2016-10-13 Rll, Llc Anticancer therapeutic agents
US20210078938A1 (en) * 2015-09-17 2021-03-18 City Of Hope Pcna inhibitors
WO2022261296A1 (fr) * 2021-06-09 2022-12-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composés qui se lient à des structures g-quadruplexes non canoniques et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GU, L ET AL.: "The Anticancer Activity of a First-in-class Smallmolecule Targeting PCNA", CLINICAL CANCER RESEARCH, vol. 24, no. 23, 1 December 2018 (2018-12-01), pages 6053 - 6065, XP055822145, DOI: 10.1158/1078-0432.CCR- 18-0592 *

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