WO2018175958A1 - Modulateurs de thiorédoxine et leurs utilisations - Google Patents

Modulateurs de thiorédoxine et leurs utilisations Download PDF

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Publication number
WO2018175958A1
WO2018175958A1 PCT/US2018/024134 US2018024134W WO2018175958A1 WO 2018175958 A1 WO2018175958 A1 WO 2018175958A1 US 2018024134 W US2018024134 W US 2018024134W WO 2018175958 A1 WO2018175958 A1 WO 2018175958A1
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unsubstituted
membered
substituted
independently
compound
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PCT/US2018/024134
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Daniel K. Nomura
Kimberly E. ANDERSON
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/42—One nitrogen atom
    • C07D251/44—One nitrogen atom with halogen atoms attached to the two other ring carbon atoms

Definitions

  • L 1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted
  • R 1 is halogen, -CX X 3 , -CHX ⁇ , -
  • R 1A R 1B OCH2X 1 , -OCHX 1 !, -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1C , - R 1A OR lc , 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 , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C and R 2D is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -COOH, -CO H2, substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be j oined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be j oined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • nl is an integer from 0 to 4.
  • ml and vl are independently an integer from 1 to 2.
  • X, X 1 , X 2 , X 3 , and X 4 are independently -F, -CI, -Br, or -I.
  • a pharmaceutical composition including a thioredoxin inhibitor and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein.
  • a method of inhibiting thioredoxin activity including contacting the thioredoxin with a thioredoxin inhibitor.
  • a method of inhibiting thioredoxin activity including contacting the thioredoxin with a compound described herein.
  • a thioredoxin protein covalently bonded to a thioredoxin inhibitor (a thioredoxin protein-thioredoxin inhibitor complex).
  • FIGS. 1A-1D Screening of dichlorotriazine library in breast cancer cells.
  • FIGS. 2A-2D KEAl-97 targets thioredoxin.
  • FIG. 2A IsoTOP-ABPP analysis of KEAl-97 (10 ⁇ ) in 231MFP breast cancer proteomes. Shown are individual isotopically light (acetonitrile-treated) to heavy (KEAl-97-treated) probe-modified peptide ratios for peptides identified in two out of three biological replicates. Structure of KEAl-97 is also shown.
  • FIG. 2B Gel -based ABPP studies showing competition of KEAl-97 against DCT- alkyne labeling (100 ⁇ ) of pure human TXN. Shown is a representative gel and a dose- response curve.
  • FIG. 2C TXN activity assay.
  • D KEAl-97 displacement of pure thioredoxin and caspase 3 interactions. Pure His-tagged TXN and caspase 3 were pre- incubated with acetonitrile or KEAl-97 (100 ⁇ ) prior to anti-His pulldown, SDS/PAGE, and blotting for caspase 3. Input caspase 3 is also shown.
  • KEAl-97 induces apoptosis and antitumorigenic effects in 231MFP breast cancer cells.
  • FIG. 3 A Caspase 3/7 activation using a CellEvent Caspase 3/7 Green Detection Reagent.
  • FIG. 3B KEAl-97 induces apoptosis in 231MFP breast cancer cells assessed by propidium iodine and FITC Annexin-V staining and quantified by flow cytometry.
  • FIGS. 4A-4B Screening the dichlorotriazine library in 231MFP cells.
  • FIG. 4A Cell proliferation screen with dichlorotriazine library. 231MFP cells were treated with DMSO or dichlorotriazine covalent ligands (10 ⁇ ) and proliferation was assessed after 48 h.
  • KEAl-97 displaces the interaction of thioredoxin with caspase 3 and induces apoptosis without affecting thioredoxin activity. Moreover, KEAl-97 leads to activation of caspases and induction of apoptosis in breast cancer cells and impairment in in vivo breast tumor xenograft growth. Our study highlights the utility of coupling the screening of covalent ligands with ABPP platforms to identify unique anticancer agent and target pairs.
  • 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, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). 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, 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.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-.
  • 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.
  • 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, B, or 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., O, N, P, S, B, As, or Si
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, B, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, B, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, B, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, B, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, B, or P).
  • 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- H-CH2-.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0)2R'- represents both -C(0)2R'- and -R'C(0)2-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0) R', - R'R", -OR, -SR, and/or -SO2R.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • cycloalkyl and heterocycloalkyl by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl 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,
  • a "cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-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(0)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.
  • 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).
  • 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-imidazoly
  • 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
  • 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 In embodiments, the alkylarylene group
  • An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , - CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 2 CH 3 - S0 3 H, -OS0 3 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 , substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
  • the alkylarylene is unsubstituted.
  • heterocycloalkyl 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.
  • - R'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(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., - C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like.
  • substituents on the ring rather than on a specific atom of a ring 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(0)-(CRR') q -U-, wherein T and U are
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CRR'-, -0-, - R-, -S-, -S(O) -, -S(0) 2 -, -S(0) 2 R'-, 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 - 0-, - R'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 R'-.
  • 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), Boron (B), and silicon (Si).
  • a "substituent group,” as used herein, means a group selected from the following moieties:
  • heteroalkyl unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5- C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
  • cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5- C 6 cycloalkyl
  • heterocycloalkyl e.g., 3 to 8 membered
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl unsubstituted aryl (e.g., C 6 -Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
  • unsubstituted alkyl e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • C1-C4 alkyl unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 - C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • a "size-limited substituent” or " size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio 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 Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl, and each substituted or unsubstituted heteroaryl is a
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
  • heterocycloalkyl substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 - C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • 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
  • 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 C 6 -Cio arylene
  • each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 10 membered
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio 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 Ci-Cs alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • 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 -Cio arylene
  • each substituted or unsubstituted heteroaryl ene 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 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 heteroaryl ene
  • 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 heteroaryl ene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
  • 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 heteroaryl ene
  • is substituted with at least one lower substituent group wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.
  • 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 heteroaryl ene
  • the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • Certain compounds of the present invention 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 invention.
  • the compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present invention 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.
  • 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.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • 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 invention.
  • 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 invention.
  • the compounds of the present invention 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 invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • Analog or “analogue” 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. [0060]
  • 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 C1-C20 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
  • R 13A , R 13B , R 13C , R 13D , etc. distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • a "covalent lysine modifier moiety" as used herein refers to a substituent that is capable of reacting with the amine functional group of a lysine amino acid (e.g., lysine corresponding to lysine 72 of human thioredoxin of SEQ ID NO: 1) to form a covalent bond.
  • a lysine amino acid e.g., lysine corresponding to lysine 72 of human thioredoxin of SEQ ID NO: 1
  • 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- tolyl sulfonic, 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 invention 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 invention may exist as salts, such as with pharmaceutically acceptable acids.
  • the present invention 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 invention 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 invention.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present invention 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 invention 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 invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • “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.
  • “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.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • 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
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a "thioredoxin inhibitor” and “TXN inhibitor” is a substance (e.g., oligonucleotide, protein, composition, or compound) that decreases an activity or function of thioredoxin relative to the activity or function of thioredoxin in the absence of the inhibitor (e.g., wherein the thioredoxin inhibitor binds thioredoxin).
  • a “thioredoxin inhibitor compound” or “TXN inhibitor compound” refers to a compound (e.g., compounds described herein) that reduces an activity of thioredoxin when compared to a control, such as absence of the compound or a compound with known inactivity.
  • the thioredoxin activity or function is inhibition of Caspase 3 activity. In embodiments, the thioredoxin activity or function is inhibition of apoptosis (e.g., of a cell). In embodiments, the thioredoxin inhibitor modulates an activity or function (e.g., Caspase 3 activity, apoptosis of a cell) of thioredoxin relative to a control (e.g., the absence of the compound). In embodiments, the thioredoxin inhibitor increases an activity or function of Caspase 3 relative to a control (e.g., the absence of the compound).
  • the thioredoxin inhibitor decreases an activity or function (e.g., nitrosation of Caspase 3) of thioredoxin relative to a control (e.g., the absence of the compound). In embodiments, the thioredoxin inhibitor compound reduces nitrosation of Caspase 3.
  • polypeptide peptide
  • protein protein
  • 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 polymer.
  • 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.
  • an amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural and/or spatial position within the protein as the given residue in a reference sequence.
  • a selected residue in a selected protein corresponds to K72 when the selected residue occupies the same essential structural and/or spatial position as K72 in SEQ ID NO: 1.
  • the position in the aligned selected protein aligning with K72 is said to correspond to K72.
  • a three dimensional structural alignment can also be used, e.g., where the three dimensional structure of the selected protein is aligned for maximum
  • 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 that can be produced in the reaction mixture.
  • species e.g. chemical compounds including biomolecules or cells
  • 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 protein or enzyme.
  • contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway (e.g., Thioredoxin-Caspase 3-apoptosis pathway).
  • activation means positively affecting (e.g.
  • activation means positively affecting (e.g. increasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the activator.
  • the terms may reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
  • activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein associated with a disease (e.g., a protein which is decreased in a disease relative to a non-diseased control).
  • Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • inhibition means negatively affecting (e.g.
  • inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
  • thioredoxin and “TXN” refer to a protein (including homologs, isoforms, and functional fragments thereof) with thioredoxin activity.
  • the term includes any recombinant or naturally-occurring form of thioredoxin or variants thereof that maintain thioredoxin activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%) activity compared to wildtype thioredoxin).
  • the thioredoxin protein encoded by the thioredoxin gene has the amino acid sequence set forth in or corresponding to Entrez 7295, UniProt P10599, or RefSeq (protein) P 003320.
  • the thioredoxin gene has the nucleic acid sequence set forth in RefSeq (mRNA) M 003329.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In embodiments, the sequence corresponds to
  • the sequence corresponds to M_003329.3.
  • the thioredoxin protein encoded by the thioredoxin gene has the amino acid sequence set forth in or corresponding RefSeq (protein) P 001231867.
  • the thioredoxin gene has the nucleic acid sequence set forth in RefSeq (mRNA)
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In embodiments, the sequence corresponds to NP 001231867.1. In embodiments, the sequence corresponds to NM 001244938.1.
  • the thioredoxin is a human thioredoxin, such as a human cancer causing thioredoxin. In embodiments, the thioredoxin is SEQ ID NO: l . [0080] SEQ ID NO: 1 (K72 residue underlined)
  • caspase 3 refers to a protein (including homologs, isoforms, and functional fragments thereof) with caspase 3 activity.
  • the term includes any recombinant or naturally-occurring form of caspase 3 or variants thereof that maintain caspase 3 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype caspase 3).
  • the caspase 3 protein encoded by the caspase 3 gene has the amino acid sequence set forth in or corresponding to Entrez 836, UniProt P42574, or RefSeq (protein) P 004337.
  • the caspase 3 gene has the nucleic acid sequence set forth in RefSeq (mRNA) M 004346.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to P 004337.2.
  • the sequence corresponds to M 004346.3.
  • the caspase 3 is a human caspase 3, such as a human cancer causing caspase 3.
  • the caspase 3 protein activity may be measured in vitro by protease activity, for example, cleaving a peptide bond at the carboxyl terminus of aspartic acid residue of a specific peptide substrate (e.g., tetra-peptide motif Asp-x-x-Asp) using its cysteine residue.
  • the caspase 3 protein activity may be directly or indirectly measured in vivo by cell apoptosis or cell proliferation.
  • 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.).
  • the terms "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 may be a cancer.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas ⁇ e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myedgkin's lymph
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, lymphomas, carcinomas and sarcomas.
  • exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head.
  • 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 & neck, liver, kidney, lung, non-small cell lung, melanoma,
  • mesothelioma mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, 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,
  • neuroblastoma 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
  • Non-Hodgkin' s lymphomas can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs.
  • Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma,
  • T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
  • 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 sar
  • 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
  • treating refers to any indicia of success in the therapy 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
  • 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, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing.
  • Patient 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 "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 a signaling pathway, or 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.”
  • 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. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. 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. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • administering means 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) compatible with the preparation.
  • 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
  • compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Anti-cancer agent and “anticancer agent” are used in accordance with their plain ordinary meaning and refers to a composition (e.g.
  • an anti-cancer agent is a chemotherapeutic.
  • an anti-cancer agent is an agent identified herein having utility in methods of treating cancer.
  • an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEKl, MEK2, or MEKl and MEK2) inhibitors (e.g.
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambuci
  • adecypenol adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
  • amidox amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
  • benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
  • calcipotriol calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
  • carboxamide-amino-triazole carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
  • didemnin B didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin
  • epirubicin epristeride
  • estramustine analogue epristeride
  • estrogen agonists epristeride
  • estrogen antagonists epristeride
  • estramustine analogue epristeride
  • estrogen agonists epristeride
  • estrogen antagonists epristeride
  • etanidazole etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin
  • hydrochloride forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin;
  • gallium nitrate galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lein
  • leuprolide+estrogen+progesterone leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;
  • marimastat masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;
  • mifepristone miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N- substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
  • octreotide okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;
  • palmitoylrhizoxin pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
  • pegaspargase peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor;
  • protein kinase C inhibitors microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium
  • oligonucleotides oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
  • spiromustine splenopentin
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stem-cell division inhibitors
  • stromelysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic glycosaminoglycans;
  • tallimustine tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
  • thrombopoietin mimetic thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
  • tyrphostins UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin,
  • azotomycin batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
  • cactinomycin calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;
  • decitabine dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; camrabine; fenretinide; floxuridine; fludarabine phosphate;
  • fluorouracil fluorocitabine
  • fosquidone fostriecin sodium
  • gemcitabine gemcitabine hydrochloride
  • hydroxyurea idarubicin hydrochloride
  • ifosfamide iimofosine
  • interleukin II interleukin II
  • interferon alfa-2a including recombinant interleukin II, or rlL.sub.2
  • interferon alfa-2a interferon alfa-2b
  • interferon alfa-nl interferon alfa-n3
  • interferon beta-la interferon gamma-lb
  • iproplatin irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mito
  • paclitaxel paclitaxel
  • Taxotere.TM compounds comprising the taxane skeleton, Erbulozole (i.e. R- 55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g.
  • Epothilones e.g. Epothilone A, Epothilone B, Epothilone C (i.e.
  • Epothilone A or dEpoA desoxyepothilone A or dEpoA
  • Epothilone D i.e. KOS-862, dEpoB, and desoxyepothilone B
  • Epothilone E Epothilone F
  • Epothilone B N-oxide Epothilone A N-oxide
  • 16-aza- epothilone B Epothilone A N-oxide
  • 21-aminoepothilone B i.e. BMS-310705
  • 21 -hydroxy epothilone D i.e.
  • WS-9885B GS-164 (Takeda), GS- 198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e.
  • AVE-8063A and CS- 39.HC1 AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR- 258062 A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC- 106969), T- 138067 (Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (i.e.
  • Caribaeoside Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e.
  • D-81862 A- 289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, eth
  • 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.
  • Control or "control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including
  • a thioredoxin associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with thioredoxin (e.g. cancer).
  • a thioredoxin modulator is a compound that increases or decreases the activity or function or level of activity or level of function of thioredoxin.
  • 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.
  • modulating is activating.
  • modulating is inhibiting.
  • a disease e.g. a protein associated disease, a cancer associated with thioredoxin activity, thioredoxin associated cancer, thioredoxin associated disease
  • the disease e.g. cancer
  • a symptom of the disease is caused by (in whole or inpart) the substance or substance activity or function.
  • a cancer associated with thioredoxin activity or function may be a cancer that results (entirely or partially) from aberrant thioredoxin function (e.g. enzyme activity, protein-protein interaction, signaling pathway) or a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant thioredoxin activity or function.
  • aberrant thioredoxin function e.g. enzyme activity, protein-protein interaction, signaling pathway
  • a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant thioredoxin activity or function.
  • a cancer associated with thioredoxin activity or function or a thioredoxin associated cancer may be treated with a thioredoxin modulator or thioredoxin inhibitor, in the instance where thioredoxin activity or function (e.g. signaling pathway activity) causes the cancer.
  • thioredoxin activity or function e.g. signaling pathway activity
  • aberrant refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function 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.
  • signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components.
  • binding of a thioredoxin protein with a compound as described herein may reduce the interactions between the thioredoxin protein and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival.
  • electrophilic chemical moiety is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is electrophilic.
  • nucleophilic chemical moiety is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is nucleophilic.
  • Nucleic acid refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof.
  • polynucleotide e.g., oligonucleotide
  • oligo oligo
  • nucleotide refers, in the usual and customary sense, to a linear sequence of nucleotides.
  • nucleotide refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer.
  • Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof.
  • Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA.
  • Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof.
  • nucleic acids can be linear or branched.
  • nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides.
  • the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.
  • Nucleic acids can include one or more reactive moieties.
  • the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions.
  • the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.
  • the terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages.
  • phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phospho
  • nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.
  • LNA locked nucleic acids
  • Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made;
  • the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.
  • Nucleic acids can include nonspecific sequences. As used herein, the term
  • nonspecific sequence refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence.
  • a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.
  • an "antisense nucleic acid” as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g. single stranded morpholino oligo), or interfering with the endogenous activity of the target nucleic acid.
  • a specific target nucleic acid e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1
  • antisense nucleic acids are generally between 15 and 25 bases in length.
  • antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1).
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) in vitro.
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) in a cell. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) in an organism. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) under physiological conditions.
  • Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides.
  • the antisense nucleic acids hybridize to the corresponding RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) forming a double-stranded molecule.
  • the antisense nucleic acids interfere with the endogenous behavior of the RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to SEQ ID NO: 1) and inhibit its function relative to the absence of the antisense nucleic acid.
  • the double-stranded molecule may be degraded via the RNAi
  • Antisense nucleic acids may be single or double stranded nucleic acids.
  • Non-limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre-cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors.
  • complement refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides.
  • a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence.
  • nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid
  • nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence.
  • complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence.
  • complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.
  • sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing.
  • two sequences that are complementary to each other may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98%), 99%), or higher identity over a specified region).
  • antibody refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy" chain (about 50-70 kDa).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • variable heavy chain refers to the variable region of an immunoglobulin heavy chain, including an Fv, scFv , dsFv or Fab; while the terms “variable light chain,” “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv , dsFv or Fab.
  • antibody functional fragments include, but are not limited to, complete antibody molecules, antibody fragments, such as Fv, single chain Fv (scFv), complementarity determining regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2' and any combination of those or any other functional portion of an immunoglobulin peptide capable of binding to target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed. 2001).
  • various antibody fragments can be obtained by a variety of methods, for example, digestion of an intact antibody with an enzyme, such as pepsin; or de novo synthesis.
  • Antibody fragments are often synthesized de novo either chemically or by using recombinant DNA methodology.
  • the term antibody includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al, (1990) Nature 348:552).
  • the term "antibody” also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. Bivalent and bispecific molecules are described in, e.g., Kostelny et al. (1992) J. Immunol. 148: 1547, Pack and
  • Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%), 96%), 97%), 98%), 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like).
  • sequences are then said to be “substantially identical.”
  • This definition also refers to, or may be applied to, the compliment of a test sequence.
  • the definition also includes sequences that have deletions and/or additions, as well as those that have substitutions.
  • the preferred algorithms can account for gaps and the like.
  • identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • the irreversible covalent bond does not easily dissociate under normal biological conditions.
  • the irreversible covalent bond is formed through a chemical reaction between two species (e.g., electrophilic chemical moiety and nucleophilic moiety).
  • thioredoxin activity refers to the biological activity of the protein.
  • the thioredoxin activity may be antioxidant activity by facilitating the reduction of other proteins, for example by cysteine thiol-disulfide exchange, at a dithiol- disulfide active site.
  • thioredoxin protein-thioredoxin inhibitor complex refers to a thioredoxin protein bonded (e.g., covalently bonded) to a thioredoxin inhibitor (e.g., a compound described herein).
  • the term "leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the "leaving group reactive moiety", and a complementary reactive moiety (i.e. a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety.
  • a chemical reaction e.g., bond formation, reductive elimination, condensation, cross-coupling reaction
  • a complementary reactive moiety i.e. a chemical moiety that reacts with the leaving group reactive moiety
  • Non limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., CI), perfluoroalkylsulfonates (e.g. triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, and alkoxides.
  • organotin moieties e.g., organotin heteroalkyl
  • halogen e.g., CI
  • perfluoroalkylsulfonates e.g. triflate
  • tosylates mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides,
  • two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from the respective molecule.
  • a leaving group is a bioconjugate reactive moiety.
  • the leaving group is X 4 .
  • at least two leaving groups e.g., R 1 and R 13 ) are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch.
  • the leaving groups is designed to facilitate the reaction.
  • L 1 is a bond, -S(0) 2 -, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • L 1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 1 is halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , -
  • R 2 is hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH 2 X 2 , -OCHX 2 2 , -C(0)R 2C , -C(0)OR 2C , -C(0) R 2A R 2B , -OR 2D , substituted or
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B> R 2C and R 2D is independently
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • nl is an integer from 0 to 4.
  • the symbols ml and vl are independently an integer from 1 to 2.
  • the symbols X, X 1 , and X 2 are independently -F, -CI, -Br, or -I.
  • the symbols X 3 and X 4 are independently halogen, -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,
  • X 3 and X 4 are independently -F, -CI, -Br, or -I.
  • L 1 is a bond. In embodiments, L 1 is an unsubstituted alkylene. In embodiments, L 1 is an unsubstituted C1-C4 alkylene. In embodiments, L 1 is an unsubstituted methylene. In embodiments, L 1 is an unsubstituted heteroalkylene. In embodiments, L 1 is an unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 1 is - CH2CH2O-, -OCH2CH2-, -OCH2-, or -CH2O-. In embodiments, L 1 is an unsubstituted arylene. In embodiments, L 1 is an unsubstituted phenylene.
  • L 1 is -0-. In embodiments, L 1 is -C(O)- . In embodiments, L 1 is -C(0)0-. In embodiments, L 1 is -C(0) H-. In embodiments, L 1 is -CH 2 -. In
  • L 1 is -CH2CH2-. In embodiments, L 1 is -CH2CH2CH2-. In embodiments, L 1 1S -OCH2-. In embodiments, L 1 is -CH2O-. In embodiments, L 1 is -CH2CH2-. In embodiments, L 1 is unsubstituted phenylene. In embodiments, L 1 is -CH2CH2O-. In embodiments, L 1 is -OCH CH -. In embodiments L 1 is -OCH -. In embodiments, L 1 is -
  • L 1 is [0134] In embodiments, L 1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstit
  • L 1 is independently substituted or unsubstituted alkylene (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, L 1 is independently substituted alkylene (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, L 1 is independently unsubstituted alkylene (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, L 1 is substituted or unsubstituted Ci- C 4 alkylene. In embodiments, L 1 is substituted C1-C4 alkylene.
  • L 1 is unsubstituted C1-C4 alkylene. In embodiments, L 1 is independently unsubstituted methylene. In embodiments, L 1 is independently unsubstituted ethylene. In embodiments, L 1 is independently unsubstituted propylene. In embodiments, L 1 is independently unsubstituted isopropylene. In embodiments, L 1 is independently unsubstituted tert-butylene. In embodiments, L 1 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered.
  • L 1 is independently substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L 1 is independently unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L 1 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 1 is substituted 2 to 6 membered heteroalkylene. In embodiments, L 1 is unsubstituted 2 to 6 membered
  • L 1 is independently substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6). In embodiments, L 1 is independently substituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ). In embodiments, L 1 is independently unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • L 1 is or unsubstituted C 3 -C 6 cycloalkylene. In embodiments, L 1 is substituted C 3 -C 6 cycloalkylene. In embodiments, L 1 is unsubstituted C 3 -C 6 cycloalkylene. [0137] In embodiments, L 1 is independently substituted or unsubstituted
  • heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • L 1 is independently substituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • L 1 is independently unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • L 1 is substituted or unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 1 is substituted 5 to 6 membered heterocycloalkylene. In embodiments, L 1 is unsubstituted 5 to 6 membered
  • L 1 is independently substituted or unsubstituted arylene (e.g., C 6 - Cio or phenylene). In embodiments, L 1 is independently substituted arylene (e.g., C 6 -Cio or phenylene). In embodiments, L 1 is independently unsubstituted arylene (e.g., C 6 -Cio or phenylene). In embodiments, L 1 is substituted or unsubstituted phenylene. In embodiments, L 1 is substituted phenylene. In embodiments, L 1 is unsubstituted phenylene.
  • L 1 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L 1 is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L 1 is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L 1 is substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 1 is substituted 5 to 6 membered heteroarylene. In embodiments, L 1 is unsubstituted 5 to 6 membered
  • L 1 is independently bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, R 17 - substituted or unsubstituted alkylene (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2), R 17 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R 17 -substituted or unsubstituted cycloalkylene (e.g., C 3 - C 8 , C3-C6, C4-C6, or C5-C 6 ), R 17 -substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membere
  • L 1 is independently bond, -C(O)-, -C(0)NH-, -C(0)0-, -0-, unsubstituted alkylene (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ), unsubstituted
  • alkylene e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • unsubstituted heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered
  • heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted arylene e.g., C 6 -Cio or phenylene
  • unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • L 1 is R 17 -substituted or unsubstituted C1-C4 alkylene.
  • L 1 is unsubstituted C1-C4 alkylene.
  • L 1 is independently unsubstituted methylene.
  • L 1 is independently unsubstituted ethylene.
  • L 1 is independently methyl-substituted methylene.
  • R 17 is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX 17 3 , -CHX 17 2 , -CH 2 X 17 (e.g., -CF 3 , -CHF2, -CH 2 F, -CCI3, -CHCI2, -CH2CI, -CBr 3 , -CHBr 2 , -CH 2 Br, -CI 3 , -CHI 2 , or-CH 2 I), -OCX 17 3 , -OCH2X 17 , -OCHX 17 2 (e.g.,-OCF 3 , -0CC1 3 , -OCBr 3 , -OCI 3 ,-OCH 2 F, - OCH2CI, -OCH 2 Br, -OCH2I, -OCHF2, -OCHCI2, -OCHBr 2 , or - OCHI2), -CN,
  • R 18 -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 18 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 18 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 18 -substituted or unsubstituted aryl e.g., C 6 -Cio or phenyl
  • R 18 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 17 is independently oxo, halogen (e.g., - F, -CI, Br, -I), -CX 17 3 , -CHX 17 2 , -CH 2 X 17 (e.g., -CF 3 , -CHF 2 , -CH 2 F, -CCI3, -CHC1 2 , - CH 2 C1, -CBr 3 , -CHBr 2 , -CH 2 Br, -CI 3 , -CHI 2 , or-CH 2 I), -OCX 17 3 , -OCH 2 X 17 , -OCHX 17 2 (e.g.,-OCF 3 , -OCCb, -OCBr 3 , -OCI 3 ,-OCH 2 F, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCHF 2 , - OCHCl 2 , -OCHBr 2 , or -
  • X 17 is independently -F, -CI, -Br, or -I.
  • R 17 is hydrogen.
  • R 17 is R 18 -substituted or unsubstituted C1-C4 alkyl.
  • R 17 is unsubstituted Ci- C4 alkylene.
  • R 17 is independently unsubstituted methyl.
  • R 17 is independently unsubstituted ethyl.
  • R is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX 18 3 , -CHX 18 2 , -CH 2 X 18 (e.g., -CF 3 , -CHF 2 , -CH 2 F, -CCI3, -CHCI2, -CH2CI, -CBr 3 , -CHBr 2 , -CH 2 Br, -CI 3 , -CHI 2 , or-CH 2 I), -OCX 18 3 , -OCH2X 18 , -OCHX 18 2 (e.g.,-OCF 3 , -OCCb, -OCBr 3 , -OCI 3 ,-OCH 2 F, - OCH2CI, -OCH 2 Br, -OCH2I, -OCHF2, -OCHCI2, -OCHBr 2 , or - OCHI2), -CN, -CF 3
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 19 -substituted or unsubstituted aryl e.g., C 6 -Cio or phenyl
  • R 19 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 18 is independently oxo, halogen (e.g., - F, -CI, Br, -I), -CX 18 3 , -CHX 18 2 , -CH 2 X 18 (e.g., -CF 3 , -CHF 2 , -CH 2 F, -CCI3, -CHC1 2 , - CH 2 C1, -CBr 3 , -CHBr 2 , -CH 2 Br, -CI 3 , -CHI 2 , or-CH 2 I), -OCX 18 3 , -OCH 2 X 18 , -OCHX 18 2 (e.g.,-OCF 3 , -OCCb, -OCBr 3 , -OCI 3 ,-OCH 2 F, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCHF 2 , - OCHCl 2 , -OCHBr 2 , or -
  • X 18 is independently -F, -CI, -Br, or -I.
  • R 18 is R 19 -substituted or unsubstituted C1-C4 alkyl.
  • R 18 is unsubstituted C1-C4 alkylene.
  • R 18 is independently unsubstituted methyl.
  • R 18 is
  • R 19 is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX 19 3 , -CHX 19 2 , -CH 2 X 19
  • halogen e.g., -F, -CI, Br, -I
  • X 19 is independently -F, -CI, -Br, or -I.
  • R 19 is unsubstituted C1-C4 alkylene.
  • R 19 is independently unsubstituted methyl.
  • R 19 is
  • the compound has the formula: R 1 , R 2 , X 3 , X 4 are as described herein. In embodiments, the compound has the formula:
  • R 1 , R 2 X 3 , X 4 are as described herein. In embodiments, the
  • the compound has the formula: R 1 , R 2 , X 3 , X 4 are as described herein. In embodiments, the compound has the formula: . R 1 R 2 , X 3 , X 4 are as described herein. In embodiments, the
  • the compound has the formula .
  • R 1 R 2 , X 3 , X 4 are as
  • the compound has the formula:
  • R 1 R 2 , X 3 , X 4 are as described herein.
  • the compound has the formula:
  • R 1 , R 2 X 3 , X 4 are as described herein.
  • the X 4 are as described herein.
  • the compound has the formula: .
  • R 1 , R 2 X 3 , X 4 are as described herein.
  • the compound has the formula:
  • R 1 R 2 , X 3 , X 4 are as described herein.
  • the X 3 , X 4 are as described herein.
  • R 1 is -C(0)R 1C , -C(0)0R 1C , -C(0) R 1A R 1B (e.g., -C(0)H, - C(0)CH 3 , -C(0)C 6 H 5 , -C(0)OH, -C(0)OCH 3 , -C(0) H 2 , or -C(0) HCH 3 ), substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted 2 to 12 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci 2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 is -C(0)R 1C , -C(0)0R 1C , -C(0) R 1A R 1B (e.
  • R 1 is -C(0)-(unsubstituted phenyl), substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 is unsubstituted C4-C10 alkyl, substituted C1-C4 alkyl, unsubstituted C4-C10 alkenyl, unsubstituted 5 to 8 membered heteroalkyl, unsubstituted C5-C6 cycloalkyl, unsubstituted 5 to 6 membered heterocycloalkyl, unsubstituted biphenyl, unsubstituted benzodioxyl, unsubstituted tetramethyl tetrahydronaphthyl, unsubstituted dihydroindenyl, unsubstituted phenyl, unsubstituted naphthyl, unsubstituted benzodioxinyl, unsubstituted 5 to 6 membered heteroaryl, unsubstituted dioxoborolanyl, substituted phenyl, substituted biphenyl.
  • R 1 is unsubstituted C4-C10 alkenyl, unsubstituted 5 to 8 membered heteroalkyl, unsubstituted C5-C6 cycloalkyl, unsubstituted 5 to 6 membered heterocycloalkyl, unsubstituted benzodioxyl, unsubstituted tetrahydronaphthyl, unsubstituted dihydroindenyl, unsubstituted naphthyl, unsubstituted benzodioxinyl, unsubstituted 5 to 6 membered heteroaryl, unsubstituted tetramethyl dioxoborolanyl; or C1-C10 alkyl, phenyl, or biphenyl; each optionally substituted with from 1 to 3 substituents selected
  • R 1 is unsubstituted C1-C12 alkyl. In embodiments, R 1 is unsubstituted 2 to 12 membered heteroalkyl. In embodiments, R 1 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 1 is unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 is unsubstituted C 6 -Ci2 aryl.
  • R 1 is unsubstituted 5 to 12 membered heteroaryl. In embodiments, R 1 is unsubstituted C1-C10 alkyl. In embodiments, R 1 is unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R 1 is unsubstituted C5-C6 cycloalkyl. In embodiments, R 1 is unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R 1 is unsubstituted phenyl. In embodiments, R 1 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 1 is unsubstituted C4-C10 alkenyl.
  • R 1 is unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R 1 is unsubstituted biphenyl. In embodiments, R 1 is unsubstituted benzodioxyl. In embodiments, R 1 is unsubstituted tetramethyl tetrahydronaphthyl. In embodiments, R 1 is unsubstituted tetrahydronaphthyl. In embodiments, R 1 is unsubstituted dihydroindenyl. In embodiments, R 1 is unsubstituted phenyl. In embodiments, R 1 is unsubstituted naphthyl.
  • R 1 is unsubstituted benzodioxinyl. In embodiments, R 1 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 1 is unsubstituted dioxoborolanyl. In embodiments, R 1 is unsubstituted C4-C10 alkenyl. In embodiments, R 1 is unsubstituted tetramethyl
  • R 1 is -C(0)-(unsubstituted phenyl) .
  • R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted iso-butyl. In embodiments, R 1 is independently unsubstituted t- butyl.
  • R 1 is independently unsubstituted pentyl. In embodiments, R 1 is independently unsubstituted n-pentyl. In embodiments, R 1 is independently unsubstituted hexyl. In embodiments, R 1 is independently unsubstituted n-hexyl. In embodiments, R 1 is independently unsubstituted heptyl. In embodiments, R 1 is independently unsubstituted n- heptyl. In embodiments, R 1 is independently unsubstituted octyl. In embodiments, R 1 is independently unsubstituted n-octyl. In embodiments, R 1 is independently unsubstituted nonyl.
  • R 1 is independently unsubstituted n-nonyl. In embodiments, R 1 is independently unsubstituted decyl. In embodiments, R 1 is independently unsubstituted n- decyl. In embodiments, R 1 is independently unsubstituted undecyl. In embodiments, R 1 is independently unsubstituted n-undecyl. In embodiments, R 1 is independently unsubstituted dodecyl. In embodiments, R 1 is independently unsubstituted n-dodecyl. In embodiments, R 1 is independently unsubstituted benzyl. In embodiments, R 1 is independently unsubstituted Ci-Cio alkyl.
  • R 1 is independently halo- substituted methyl. In embodiments, R 1 is independently halo- substituted ethyl. In embodiments, R 1 is independently halo- substituted isopropyl. In embodiments, R 1 is independently halo- substituted n-propyl. In embodiments, R 1 is independently halo- substituted n-butyl. In embodiments, R 1 is independently halo- substituted t-butyl. In embodiments, R 1 is independently halo-substituted n-pentyl. In embodiments, R 1 is independently halo-substituted benzyl. In embodiments, R 1 is independently halo-substituted Ci-Cio alkyl. In embodiments, R 1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 1 is independently
  • R 1 is independently
  • R 1 is independently
  • R 1 is independently
  • R 1 is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 7 to 9 membered heteroalkyl.
  • R 1 is independently unsubstituted 5 membered heteroaryl. In embodiments, R 1 is independently unsubstituted 6 membered heteroaryl. In embodiments, R 1 is independently unsubstituted pyridyl. In embodiments, R 1 is independently unsubstituted 2- pyridyl. In embodiments, R 1 is independently unsubstituted 3-pyridyl. In embodiments, R 1 is independently unsubstituted 4-pyridyl. In embodiments, R 1 is independently unsubstituted pyridazinyl. In embodiments, R 1 is independently unsubstituted pyrimidinyl. In
  • R 1 is independently unsubstituted pyrazinyl. In embodiments, R 1 is independently unsubstituted triazinyl. In embodiments, R 1 is independently unsubstituted pyrrolyl. In embodiments, R 1 is independently unsubstituted 2-pyrrolyl. In embodiments, R 1 is independently unsubstituted 3 -pyrrolyl. In embodiments, R 1 is independently unsubstituted furanyl. In embodiments, R 1 is independently unsubstituted 2-furanyl. In embodiments, R 1 is independently unsubstituted 3-furanyl. In embodiments, R 1 is independently unsubstituted thienyl.
  • R 1 is independently unsubstituted 2-thienyl. In embodiments, R 1 is independently unsubstituted 3- thienyl. In embodiments, R 1 is independently unsubstituted pyrazolyl. In embodiments, R 1 is independently unsubstituted isoxazolyl. In embodiments, R 1 is independently unsubstituted isothiazolyl. In embodiments, R 1 is independently unsubstituted imidazolyl. In embodiments, R 1 is independently unsubstituted oxazolyl. In embodiments, R 1 is independently unsubstituted thiazolyl. In embodiments, R 1 is
  • R 1 is independently unsubstituted phenyl.
  • R 1 is independently unsubstituted biphenyl.
  • R 1 is independently unsubstituted 2-biphenyl.
  • R 1 is independently unsubstituted 3-biphenyl.
  • R 1 is independently unsubstituted 4-biphenyl.
  • R 1 is unsubstituted pyrrolidinyl.
  • R 1 is unsubstituted tetrahydrofuranyl. In embodiments, R 1 is unsubstituted tetrahydrothienyl. In embodiments, R 1 is unsubstituted piperidinyl. In embodiments, R 1 is unsubstituted piperazinyl. In embodiments, R 1 is unsubstituted tetrahydropyranyl. In embodiments, R 1 is unsubstituted thianyl. In embodiments, R 1 is unsubstituted morpholinyl. In embodiments, R 1 is unsubstituted dioxanyl. In embodiments, R 1 is unsubstituted oxazinyl. In embodiments, R 1 is unsubstituted benzo[d][l,3]dioxol.
  • R 1 is R 20 -substituted C1-C12 alkyl. In embodiments, R 1 is R 20 - substituted 2 to 12 membered heteroalkyl. In embodiments, R 1 is R 20 -substituted C3-C8 cycloalkyl. In embodiments, R 1 is R 20 -substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 is R 20 -substituted C6-C12 aryl. In embodiments, R 1 is R 20 -substituted 5 to 12 membered heteroaryl. In embodiments, R 1 is R 20 -substituted C1-C10 alkyl. In
  • R 1 is R 20 -substituted 2 to 10 membered heteroalkyl. In embodiments, R 1 is R 20 -substituted C5-C6 cycloalkyl. In embodiments, R 1 is R 20 -substituted 5 to 6 membered heterocycloalkyl. In embodiments, R 1 is R 20 -substituted phenyl. In embodiments, R 1 is R 20 - substituted 5 to 6 membered heteroaryl. In embodiments, R 1 is R 20 -substituted C4-C10 alkenyl. In embodiments, R 1 is R 20 -substituted 5 to 8 membered heteroalkyl. In
  • R 1 is R 20 -substituted biphenyl. In embodiments, R 1 is R 20 -substituted benzodioxyl. In embodiments, R 1 is R 20 -substituted tetramethyl tetrahydronaphthyl. In embodiments, R 1 is R 20 -substituted tetrahydronaphthyl. In embodiments, R 1 is R 20 - substituted dihydroindenyl. In embodiments, R 1 is R 20 -substituted phenyl. In embodiments, R 1 is R 20 -substituted naphthyl.
  • R 1 is R 20 -substituted benzodioxinyl. In embodiments, R 1 is R 20 -substituted 5 to 6 membered heteroaryl. In embodiments, R 1 is R 20 - substituted dioxoborolanyl. In embodiments, R 1 is R 20 -substituted C4-C10 alkenyl. In embodiments, R 1 is R 20 -substituted tetramethyl dioxoborolanyl. In embodiments, R 1 is -C(O)-(R 20C -substituted phenyl) . In embodiments, R 1 is R 20 - substituted pyrrolidinyl.
  • R 1 is R 20 -substituted tetrahydrofuranyl. In embodiments, R 1 is R 20 - substituted tetrahydrothienyl. In embodiments, R 1 is R 20 -substituted piperidinyl. In embodiments, R 1 is R 20 -substituted piperazinyl. In embodiments, R 1 is R 20 -substituted tetrahydropyranyl. In embodiments, R 1 is R 20 -substituted thianyl. In embodiments, R 1 is R 20 -substituted morpholinyl. In embodiments, R 1 is R 20 -substituted dioxanyl. In embodiments, R 1 is R 20 - substituted oxazinyl. In embodiments, R 1 is R 20 -substituted benzo[d][l,3]dioxol.
  • R 1 is independently R 20 -substituted methyl. In embodiments, R 1 is independently R 20 -substituted ethyl. In embodiments, R 1 is independently R 20 -substituted propyl. In embodiments, R 1 is independently R 20 -substituted isopropyl. In embodiments, R 1 is independently R 20 -substituted n-propyl. In embodiments, R 1 is independently R 20 - substituted butyl. In embodiments, R 1 is independently R 20 -substituted n-butyl. In embodiments, R 1 is independently R 20 -substituted iso-butyl.
  • R 1 is independently R 20 -substituted t-butyl. In embodiments, R 1 is independently R 20 -substituted pentyl. In embodiments, R 1 is independently R 20 -substituted n-pentyl. In embodiments, R 1 is independently R 20 -substituted hexyl. In embodiments, R 1 is independently R 20 -substituted n- hexyl. In embodiments, R 1 is independently R 20 -substituted heptyl. In embodiments, R 1 is independently R 20 -substituted n-heptyl. In embodiments, R 1 is independently R 20 -substituted octyl.
  • R 1 is independently R 20 -substituted n-octyl. In embodiments, R 1 is independently R 20 -substituted nonyl. In embodiments, R 1 is independently R 20 -substituted n- nonyl. In embodiments, R 1 is independently R 20 -substituted decyl. In embodiments, R 1 is independently R 20 -substituted n-decyl. In embodiments, R 1 is independently R 20 -substituted undecyl. In embodiments, R 1 is independently R 20 -substituted n-undecyl. In embodiments, R 1 is independently R 20 -substituted dodecyl.
  • R 1 is independently R 20 - substituted n-dodecyl. In embodiments, R 1 is independently R 20 -substituted benzyl. In embodiments, R 1 is independently R 20 -substituted C1-C10 alkyl. [0151] In embodiments, R 1 is independently R 20 -substituted 2 to 6 membered heteroalkyl.
  • R 1 is independently R 20 -substituted 2 to 7 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 2 to 8 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 2 to 9 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 2 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 3 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 4 to 10 membered heteroalkyl.
  • R 1 is independently R 20 -substituted 5 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 7 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 8 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently R 20 -substituted 7 to 9 membered heteroalkyl.
  • R 1 is independently R 20 -substituted 5 membered heteroaryl. In embodiments, R 1 is independently R 20 -substituted 6 membered heteroaryl. In embodiments, R 1 is independently R 20 -substituted pyridyl. In embodiments, R 1 is independently R 20 - substituted 2-pyridyl. In embodiments, R 1 is independently R 20 -substituted 3-pyridyl. In embodiments, R 1 is independently R 20 -substituted 4-pyridyl. In embodiments, R 1 is independently R 20 -substituted pyridazinyl.
  • R 1 is independently R 20 - substituted pyrimidinyl. In embodiments, R 1 is independently R 20 -substituted pyrazinyl. In embodiments, R 1 is independently R 20 -substituted triazinyl. In embodiments, R 1 is independently R 20 -substituted pyrrolyl. In embodiments, R 1 is independently R 20 -substituted 2-pyrrolyl. In embodiments, R 1 is independently R 20 -substituted 3-pyrrolyl. In
  • R 1 is independently R 20 -substituted furanyl. In embodiments, R 1 is independently R 20 -substituted 2-furanyl. In embodiments, R 1 is independently R 20 - substituted 3-furanyl. In embodiments, R 1 is independently R 20 -substituted thienyl. In embodiments, R 1 is independently R 20 -substituted 2-thienyl. In embodiments, R 1 is independently R 20 -substituted 3- thienyl. In embodiments, R 1 is independently R 20 - substituted pyrazolyl. In embodiments, R 1 is independently R 20 -substituted isoxazolyl.
  • R 1 is independently R 20 -substituted isothiazolyl. In embodiments, R 1 is independently R 20 -substituted imidazolyl. In embodiments, R 1 is independently R 20 - substituted oxazolyl. In embodiments, R 1 is independently R 20 -substituted thiazolyl. In embodiments, R 1 is independently R 20 -substituted phenyl. In embodiments, R 1 is independently R 20 -substituted biphenyl. In embodiments, R 1 is independently R 20 -substituted 2-biphenyl. In embodiments, R 1 is independently R 20 -substituted 3-biphenyl. In
  • R 1 is independently R 20 -substituted 4-biphenyl. [0153] In embodiments, R 1 is unsubstituted biphenyl. In embodiments, R 1 is
  • R is s, R iments, R 1 In embodiments, R 1 is In embodiments, R 1 is . In embodiments, R 1 is
  • R 1 is In embodiments, R 1 is
  • R is . In embodiments, R 1 is
  • R 1 is odiments, R 1 is odiments, R 1 is embodiments, R 1 is embodiments, R 1 is . In embodiments, R 1 is
  • R 1 is independently -CX ⁇ (e.g., -CF 3 , -CC1 3 , -CBr 3 , -CI 3 ).
  • R 1 is independently -CHX ⁇ (e.g, -CHF 2 , CHCl 2 ,-CHBr 2 , or -CHI 2 ).
  • R 1 is independently -CH2X 1 (e.g., -CH 2 F, -CH2CI, -CH 2 Br, or -CH 2 I).
  • R 1 is independently -OCX ⁇ (e.g., -OCF 3 , -OCCh, -OCBr 3 , -OCI 3 ).
  • R 1 is independently -OCH2X 1 (e.g., -OCH2F, -OCH2CI, -OCH 2 Br, or - OCH2I). In embodiments, R 1 is independently -OCHX ⁇ (e g, -OCHF2, OCHCl 2 ,-OCHBr 2 , or -OCHI2). In embodiments, R 1 is independently -CN. In embodiments, R 1 is
  • R 1 is independently -SO v iNR 1A R 1B (e.g., -SONH2, - S0 2 NH 2 ,-SONHCH 3 , or -S0 2 NHCH 3 ). In embodiments, R 1 is
  • -NHC(0)NR 1A R 1B independently -NHC(0)NR 1A R 1B (e.g., -NHC(0)NH 2 , - NHC(0)NHCH 3 , or -
  • R 1 is independently -N(0) m i (e.g.,. -NO, -NO2).
  • R 1 is independently -NR 1A R 1B (e.g., -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 ).
  • R 1 is independently -C(0)R 1C (e.g., -C(0)H, or -C(0)CH 3 ).
  • R 1 is independently -C(0)-0R 1C (e.g., -C(0)OH, or -C(0)OCH 3 ).
  • R 1 is independently -C(0)NR 1A R 1B (e.g., -C(0)NH 2 , or -C(0)NHCH 3 ).
  • R 1 is independently -OR 1D (e.g., -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 or- OC(CH 3 ) 3 ).
  • R 1 is independently - R 1A S0 2 R 1D (e.g., -NHSO2H).
  • R 1 is independently - R 1A C(0)R lc (e.g., - HC(0)H, or- HC(0)CH 3 ).
  • R 1 is independently - R 1A C(0)0R 1C (e.g., - HC(O)OH). In embodiments, R 1 is independently - R 1A 0R 1C (e.g., -NHOH). In embodiments, R 1 is independently -OH. In embodiments, R 1 is independently -NH 2 . In embodiments, R 1 is independently -COOH. In embodiments, R 1 is independently -CONH2. In embodiments, R 1 is independently -NO2. In embodiments, R 1 is independently -SH. In embodiments, R 1 is independently halogen. In embodiments, R 1 is independently -F. In embodiments, R 1 is independently -CI. In embodiments, R 1 is independently -Br.
  • R 1 is independently -I. In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CH 2 F. In embodiments, R 1 is independently -OCF 3 . In embodiments, R 1 is independently -OCH2F. In embodiments, R 1 is independently -OCHF2. In embodiments, R 1 is independently -OCH 3 . In embodiments, R 1 is independently - OCH 2 CH 3 . In embodiments, R 1 is independently -OCH 2 CH 2 CH 3 . In embodiments, R 1 is independently -OCH(CH 3 ) 2 . In embodiments, R 1 is independently -OC(CH 3 ) 3 .
  • R 1 is independently -SCH 3 . In embodiments, R 1 is independently -SCH 2 CH 3 . In embodiments, R 1 is independently -SCH 2 CH 2 CH 3 . In embodiments, R 1 is independently - SCH(CH 3 ) 2 . In embodiments, R 1 is independently -SC(CH 3 ) 3 . In embodiments, R 1 is independently -CH 3 . In embodiments, R 1 is independently -CH 2 CH 3 . In embodiments, R 1 is independently -CH 2 CH 2 CH 3 . In embodiments, R 1 is independently -CH(CH 3 ) 2 . In embodiments, R 1 is independently -C(CH 3 ) 3 .
  • R 1 is independently halogen, -CX X 3 , -CHX X 2 , -
  • R 1 is independently halogen, -CXS, -CHX ⁇ , - CH2X 1 , -OCX , -OCH2X 1 , -OCHX 1 !, -CN, -SOniR 1D , -SO v i R 1A R 1B , - HC(0) R 1A R 1B , -N (O)mi, -NR 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0) R i c -NR 1A C(0)OR lc , -NR 1A OR lc (e.g.
  • R 1 is independently -F, -CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , - CI 3 , -CHF2, -CHCl 2 ,-CHBr2,-CHl2,-CH 2 F, -CH2CI, -CH 2 Br ,-CH 2 I, -OCF 3 , -OCCb, - OCBr 3 , -OCI 3 , -OCHF2, -OCHCI2, -OCHBr 2 , -OCHI2, -OCH2F, -OCH 2 Br, -OCH2CI, - OCH2I, -CN, -SH, -S0 3 H, -SO4H, -SO2NH2, -NO2, -NH 2 , -C(0)H, -C(0)CH 3 , -C(0)OH, - C(0)OCH 3 , -CONH2, -OH,
  • R 1 is independently -F, -CI, -Br, -I, -CF 3 , -CCb, -CBr 3 , -Cb, -CHF 2 , -CHCl 2 ,-CHBr2,-CHl2 , -CH 2 F, -CH2CI, -CH 2 Br - CH 2 I, -OCF 3 , -OCCb, -OCBr 3 , -OCb, -OCHF2, -OCHC , -OCHBr 2 , -OCHI2, -OCH2F, - OCH 2 Br, -OCH2CI, -OCH2I, -CN, -SH, -S0 3 H, -S0 4 H, -SO2NH2, -NO2, -NH 2 , -C(0)H, - C(0)CH 3 , -C(0)OH, -C(0)OC
  • R 1 is independently substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently substituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently unsubstituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently substituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5- C 6 ).
  • R 1 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 - C 6 , or C5-C 6 ). In embodiments, R 1 is independently substituted or unsubstituted
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • R 1 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1 is independently substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1 is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1 is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently hydrogen. In embodiments, R 1A is independently -CX 1A 3 (e.g. -CF 3 , -CC1 3 , -CBr 3 , or -CI 3 ). In embodiments, R 1A is independently -CHX 1A 2 (e.g., CHF 2 , -CHCl 2 ,-CHBr 2 or -CHI 2 ). In embodiments, R 1A is independently -CH 2 X 1A ,(e.g. -CH 2 F, -CH2CI, -CH 2 Br,or -CH 2 I). In embodiments, R 1A is independently -CN. In embodiments, R is independently -COOH. In embodiments, R is independently -CO H2. In embodiments, X 1A is independently -F, -CI, -Br, or -I.
  • R 1A is independently -CF, -CI, -Br, or -I.
  • R 1A is independently substituted or unsubstituted alkyl (e.g., Ci- C12, Ci-C 8 , C1-G5, C1-C4, or C1-C2). In embodiments, R 1A is independently substituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1A is independently unsubstituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1A is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1A is
  • R 1A independently substituted C1-C4 alkyl. In embodiments, R 1A is independently unsubstituted C1-C4 alkyl. In embodiments, R 1A is independently unsubstituted methyl. In embodiments, R 1A is independently unsubstituted ethyl. In embodiments, R 1A is independently
  • R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted tert-butyl. In embodiments, R 1A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 1A is independently substituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1A is independently unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1A is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 - C 6 , C4-C6, or C5-C 6 ).
  • R 1A is independently substituted cycloalkyl (e.g., C 3 - C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1A is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C6).
  • R 1A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A is independently 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). In embodiments, R 1A is independently substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1A is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1A is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is hydrogen.
  • R 1B is -CX 1B 3 (e.g. -CF 3 , - CC1 3 , -CBr 3 , or -CI 3 ).
  • R 1B is -CHX 1B 2 (e.g., CHF 2 , -CHCl 2 ,-CHBr 2 or - CHI 2 ).
  • R 1B is -CH 2 X 1B (e.g. -CH 2 F, -CH 2 C1, -CH 2 Br,or -CH 2 I).
  • R 1B is -CN.
  • R 1B is -COOH.
  • R 1B is -CO H 2 .
  • X 1B is independently -F, -CI, -Br, or -I.
  • R 1B is independently substituted or unsubstituted alkyl (e.g., Ci- Ci 2 , Ci-C 8 , C1-G5, C1-C4, or Ci-C 2 ). In embodiments, R 1B is independently substituted alkyl (e.g., Ci-Ci 2 , Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1B is independently unsubstituted alkyl (e.g., Ci-Ci 2 , Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1B is substituted or unsubstituted C1-C4 alkyl.
  • R 1B is substituted C1-C4 alkyl.
  • R 1A is unsubstituted C1-C4 alkyl.
  • R 1B is independently unsubstituted methyl.
  • R 1B is independently unsubstituted ethyl.
  • R 1B is independently unsubstituted propyl.
  • R 1B is independently unsubstituted isopropyl.
  • R 1B is independently unsubstituted tert-butyl.
  • R 1B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently substituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 1B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1B is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-G5).
  • R 1B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to
  • R 1E is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, R 1B is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1B is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may 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).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may 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).
  • 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.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • substituents bonded to the same nitrogen atom may be j oined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1C is independently hydrogen. In embodiments, R 1C is independently -CX 1C 3 (e.g. -CF 3 , -CC1 3 , -CBr 3 , or -CI 3 ). In embodiments, R 1C is
  • R 1C is independently -CHX 1C 2 (e.g., CHF 2 , -CHCl 2 ,-CHBr 2 or -CHI 2 ). .
  • R 1C is independently -CH 2 X lc (e.g. -CH 2 F, -CH 2 C1, -CH 2 Br,or -CH 2 I).
  • R 1C is independently -CN.
  • R 1C is independently -COOH.
  • R 1C is independently -CO H 2 .
  • X 1C is independently -F, -CI, -Br, or -I.
  • R is independently substituted or unsubstituted alkyl (e.g., Ci- Ci2, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently substituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently unsubstituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently substituted or unsubstituted C1-C4 alkyl.
  • R 1C is
  • R 1A is independently unsubstituted C1-C4 alkyl.
  • R 1C is independently unsubstituted methyl.
  • R 1C is independently unsubstituted ethyl.
  • R 1C is independently
  • R 1C is independently unsubstituted isopropyl. In embodiments, R 1C is independently unsubstituted tert-butyl. In embodiments, R 1C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 1C is independently substituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1C is independently unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1C is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 - C 6 , C4-C6, or C5-C 6 ).
  • R 1C is independently substituted cycloalkyl (e.g., C 3 - C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1C is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • R 1C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1C is independently 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). In embodiments, R 1C is independently substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1C is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1C is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently hydrogen. In embodiments, R 1D is independently -CX 1D 3 (e.g. -CF 3 , -CC1 3 , -CBr 3 , or -CI 3 ). In embodiments, R 1D is independently -CHX 1D 2 (e.g., CHF 2 , -CHCl 2 ,-CHBr 2 or -CHI 2 ). In embodiments, R 1D is independently -CH 2 X 1D (e.g. -CH 2 F, -CH 2 C1, -CH 2 Br, or -CH 2 I). In embodiments, R 1D is independently -CN. In embodiments, R 1D is independently -COOH. In embodiments, R 1D is independently -CO H 2 . In embodiments, X 1D is independently -F, -CI, -Br, or -I.
  • R 1D is independently substituted or unsubstituted alkyl (e.g., Ci- Ci 2 , Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1D is independently substituted alkyl (e.g., Ci-Ci 2 , Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1D is independently unsubstituted alkyl (e.g., Ci-Ci 2 , Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1D is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1D is
  • R 1D independently substituted C1-C4 alkyl. In embodiments, R 1D is independently unsubstituted C1-C4 alkyl. In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl. In embodiments, R 1D is independently
  • R 1D is independently unsubstituted isopropyl. In embodiments, R 1D is independently unsubstituted tert-butyl. In embodiments, R 1D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 1D is independently substituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1D is independently unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1D is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 - C 6 , C4-C6, or C5-C 6 ).
  • R 1D is independently substituted cycloalkyl (e.g., C 3 - C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1D is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C6).
  • R 1D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0167] In embodiments, R 1 is independently
  • halogen -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , -OCH2X 1 , -OCHX ⁇ (e.g. -F, CI, -Br, -I, -CF 3 , - CC , -CBr 3 , -CI 3 , -CHF2, -CHCl2,-CHBr 2 ,-CHl2,-CH 2 F, -CH2CI, -CH 2 Br ,-CH 2 I, -OCF 3 , - OCCb, -OCBr 3 , -OCI 3 , -OCHF2, -OCHCI2, -OCHBr 2 , -OCHI2, -OCH2F, -OCH 2 Br, - OCH2CI, or -OCH2I), -CN, -OH, - H 2 , -COOH, -CO H2, -NO2, -SH, -S0 3
  • X 1 is independently -F, -CI, -Br, or -I.
  • R 1 is independently hydrogen.
  • R 1 is independently unsubstituted methyl.
  • R 1 is independently unsubstituted ethyl.
  • R 20 is independently oxo
  • halogen -CX 20 3 , -CHX 20 2 , -CH 2 X 20 , -OCX 20 3 , -OCH 2 X 20 , -OCHX 20 2 , (e.g. -F, CI, -Br, -I, - CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCb,-CHBr2,-CHl2,-CH 2 F, -CH 2 C1, -CH 2 Br ,-CH 2 I, - OCF 3 , -OCCb, -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCb, -OCHBr 2 , -OCHI 2 , -OCH 2 F, -OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH,
  • R 20 is independently halogen, -CX 20 3 , -CHX 20 2 , -CH 2 X 20 , -OCX 20 3 , -OCH2X 20 , -OCHX 20 2 , (e.g.
  • R 20 is independently halogen, -CX 20 3 , -CHX 20 2 , -CH 2 X 20 , -OCX 20 3 , -OCH2X 20 , -OCHX 20 2 , (e.g.
  • R 20 is R 21 -substituted or unsubstituted C1-C4 alkyl. In embodiments, R 20 is R 21 -substituted C1-C4 alkyl. In embodiments, R 20 is independently unsubstituted C1-C4 alkyl.
  • R 1 is independently substituted with one of R 20 , two of R 20 , three of R 20 , four R 20 , or five of R 20 .
  • R 1 is independently substituted with (R 20 ) Z 2o.
  • z20 is independently an integer from 0 to 5.
  • z20 is independently an integer from 0 to 4.
  • z20 is independently an integer from 0 to 3.
  • z20 is independently an integer from 0 to 2.
  • z20 is independently an integer from 0 to 1.
  • z20 is independently 0.
  • z20 is independently 1.
  • z20 is independently 2.
  • z20 is independently 3.
  • z20 is independently 4.
  • z20 is independently 5.
  • R 20 is independently -Br. In embodiments, R 20 is independently - F. In embodiments, R 20 is independently -CI. In embodiments, R 20 is independently -CN. In embodiments, R 20 is independently -CF 3 . In embodiments, R 20 is independently -CH 3 . In embodiments, R 20 is independently -CH2CH3. In embodiments, R 20 is independently -C 6 H5. In embodiments, R 20 is independently -OH. In embodiments, R 20 is independently -OCH 3 . In embodiments, R 20 is independently -OCH2CH3.
  • R 20 is independently oxo. In embodiments, R 20 is independently halogen. In embodiments, R 20 is independently -CX 20 3 . In embodiments, R 20 is
  • R 20 is independently -CHX 20 2. In embodiments, R 20 is independently -CH2X 20 . In embodiments, R 20 is independently -OCX 20 3 , . In embodiments, R 20 is independently -OCH2X 20 . In embodiments, R 20 is independently -OCHX 20 2. In embodiments, R 20 is independently -CN. In embodiments, R 20 is independently -OH. In embodiments, R 20 is independently -NH2. In embodiments, R is independently -COOH. In embodiments, R is independently -CO H2. In embodiments, R 20 is independently -NO2. In embodiments, R 20 is independently -SH. In embodiments, R 20 is independently -SO3H. In embodiments, R 20 is independently -SO4H In embodiments, R 20 is independently -SO2 H2. In embodiments, R 20 is independently
  • -CX 20 -CHX 20 -CH 2 X 20 -OCX 20 -OCH2X 20 ⁇ -OCHX 20 e.g. -F, CI, -Br, -I, -CF3, -CCl 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr2,-CHI 2 ,-CH 2 F, -CH2CI, -CH 2 Br - CH 2 I, -OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF2, -OCHCI2, -OCHBr 2 , -OCHI2, -OCH2F, - OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H,
  • NHC (0)H, -NHC(0)-OH, -NHOH, R 21 - substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2), R 21 -substituted or unsubstituted heteroalkyl (e.g., 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R 21 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ), R 21 -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 member
  • halogen -CX 20,1 3 , -CHX 20 -CH2X 20'1 , -OCX 20,1 3 , -OCH2X 20 -OCHX 20 (e.g. -F, CI, -Br, -I, -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr2,-CHI 2, -CH 2 F, -CH2CI, -CH 2 Br - CH 2 I, -OCF 3 , -OCCl 3 , -OCBr 3 , -OCI 3 , -OCHF2, -OCHCI2, -OCHBr 2 , -OCHI2, -OCH2F, - OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -
  • X 20 1 is independently -F, -CI, -Br, or -I.
  • R 20 1 is independently unsubstituted methyl.
  • R 20 1 is independently unsubstituted ethyl.
  • R 20 1 is independently -Br.
  • R 20 1 is independently -F.
  • R 20 1 is independently -CI.
  • R 20 1 is independently -CN.
  • R 20 1 is independently -CF 3 .
  • R 20 1 is independently -CH 3 .
  • R 20 1 is independently -CH2CH3.
  • R 20 1 is independently -C 6 H5.
  • R 20 1 is independently -OH.
  • R 20 1 is independently -OCH 3 .
  • R 20 1 is independently -OCH 2 CH 3 . In embodiments, R 20 1 is independently oxo. In embodiments, R 20 1 is independently halogen. In embodiments, R 20 1 is
  • R 20 1 is independently -CX 20 1 3 .
  • R 20 1 is independently -CHX 20 J 2 .
  • R 20 1 is independently -CH 2 X 20 ⁇ .
  • R 20 1 is independently -OCX 20,1 3 , .
  • R 20 1 is independently -OCH2X 20 l .
  • R 20 1 is
  • R 20 1 is independently -OCHX 20 J 2 .
  • R 20 1 is independently -CN.
  • R 20 1 is independently -OH.
  • R 20 1 is independently -NH 2 .
  • R 20 1 is independently -COOH.
  • R 20 1 is independently -CONH2.
  • R 20 1 is independently -NO2.
  • R 20 1 is independently -SH.
  • R 20 1 is independently -S0 3 H.
  • R 20 1 is independently -SO4H.
  • R 20 1 is independently -SO2NH2.
  • R 20 1 is independently -NHNH2.
  • R 20 1 is independently -ONH 2 .
  • R 20 2 is independently hydrogen, oxo,
  • halogen -CX 20 2 3 , -CHX 20 2 2 , -CH 2 X 20 2 , -OCX 20 2 3 , -OCH2X 20 2 , -OCHX 20 2 2 , (e.g.
  • halogen -CX 20 2 3 , -CHX 20 2 2 , -CH 2 X 20 2 , -OCX 20 2 3 , -OCH2X 20 2 , -OCHX 20 2 2 (e.g. -F, CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br ,-
  • X 20 2 is independently -F, -CI, -Br, or -I.
  • R 20 2 is independently unsubstituted methyl.
  • R 20 2 is independently unsubstituted ethyl.
  • R 20 2 is independently -Br.
  • R 20 2 is independently -F.
  • R 20 2 is independently -CI.
  • R 20 2 is independently -CN.
  • R 20 2 is independently -CF 3 .
  • R 20 2 is independently -CH 3 .
  • R 20 2 is independently - ⁇ 3 ⁇ 40 ⁇ 3 .
  • R 20 2 is independently -C 6 H5.
  • R 20 2 is independently -OH.
  • R 20 2 is independently -OCH 3 .
  • R 20 2 is independently -0 ⁇ 3 ⁇ 40 ⁇ 3 . In embodiments, R 20 2 is independently oxo. In embodiments, R 20 2 is independently halogen. In embodiments, R 20 2 is
  • R 20 2 is independently -CX 20 2 3 .
  • R 20 2 is independently -CHX 20 2 2.
  • R 20 2 is independently -CH 2 X 20 2 .
  • R 20 2 is independently -OCX 20 2 3 , .
  • R 20 2 is independently -OCH2X 20 2 .
  • R 20 2 is
  • R 20 2 is independently -OCHX 20 2 2.
  • R 20 2 is independently -CN.
  • R 20 2 is independently -OH.
  • R 20 2 is independently - H 2 .
  • R 20 2 is independently -COOH.
  • R 20 2 is independently -CO H 2 .
  • R 20 2 is independently -N0 2 .
  • R 20 2 is independently -SH.
  • R 20 2 is independently -SO3H.
  • R 20 2 is independently -SO4H.
  • R 20 2 is independently -SO2 H2.
  • R 20 2 is independently -NHNH2.
  • R 20 2 is independently -ONH 2 .
  • R 20 3 is independently hydrogen, oxo,
  • NHC (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 12 membered, 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-C 6 ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or pheny
  • X 20 3 is independently -F, -CI, -Br, or -I.
  • R 20 3 is independently unsubstituted methyl.
  • R 20 3 is independently unsubstituted ethyl.
  • R 20 3 is independently -Br.
  • R 20 3 is independently -F.
  • R 20 3 is independently -CI.
  • R 20 3 is independently -CN.
  • R 20 3 is independently -CF3.
  • R 20 3 is independently -CH3.
  • R 20 3 is independently -CH2CH3.
  • R 20 3 is independently -C5H5.
  • R 20 3 is independently -OH.
  • R 20 3 is independently -OCH3.
  • R 20 3 is independently unsubstituted methyl.
  • R 20 3 is independently unsubstituted ethyl.
  • R 20 3 is independently -Br.
  • R 20 3 is independently -F.
  • R 20 3 is independently -CI.
  • R 20 3 is independently -CN
  • R 20 3 is independently -OCH2CH3. In embodiments, R 20 3 is independently oxo. In embodiments, R 20 3 is independently halogen. In embodiments, R 20 3 is
  • R 20 3 is independently -CHX 20 3 2 . In embodiments, R 20 3 is independently -CH 2 X 20 3 . In embodiments, R 20 3 is independently -OCX 20 3 3 , . In embodiments, R 20 3 is independently -OCH2X 20 3 . In embodiments, R 20 3 is
  • R 20 3 is independently -OCHX 20 3 2.
  • R 20 3 is independently -CN.
  • R 20 3 is independently -OH.
  • R 20 3 is independently -NH2.
  • R 20 3 is independently -COOH.
  • R 20 3 is independently -CONH2.
  • R 20 3 is independently -NO2.
  • R 20 3 is independently -SH.
  • R 20 3 is independently -SO3H.
  • R 20 3 is independently -SO4H.
  • R 20 3 is independently -SO2NH2.
  • R 20 3 is independently -NHNH2.
  • R 20 3 is independently -ONH2.
  • R 20 4 is independently hydrogen, oxo,
  • halogen -CX 20 4 3 , -CHX 20 4 2 , -CH 2 X 20 4 , -OCX 20 4 3 , -OCH2X 20 4 , -OCHX 20 4 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr 3 , -CI3, -CHF2, -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br -
  • halogen -CX 20 -CHX 20 4 2 , -CH 2 X 20 4 , -OCX 20 4 3 , -OCH2X 20 4 , -OCHX 20 4 2 (e.g. -F, CI, -Br, -I, -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHl2,-CH 2 F, -CH2CI, -CH 2 Br - CH 2 I, -OCF 3 , -OCCb, -OCBr 3 , -OCI 3 , -OCHF2, -OCHCI2, -OCHBr 2 , -OCHI2, -OCH2F, - OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH, -CONH2,
  • X 20 4 is independently -F, -CI, -Br, or -I.
  • R 20 4 is independently unsubstituted methyl.
  • R 20 4 is independently unsubstituted ethyl.
  • R 20 4 is independently -Br.
  • R 20 4 is independently -F.
  • R 20 4 is independently -CI.
  • R 20 4 is independently -CN.
  • R 20 4 is independently -CF 3 .
  • R 20 4 is independently -CH 3 .
  • R 20 4 is independently -CH2CH3.
  • R 20 4 is independently -C 6 H5.
  • R 20 4 is independently -OH.
  • R 20 4 is independently -OCH 3 .
  • R 20 4 is independently unsubstituted methyl.
  • R 20 4 is independently unsubstituted ethyl.
  • R 20 4 is independently -Br.
  • R 20 4 is independently -F.
  • R 20 4 is independently -CI.
  • R 20 4 is independently -OCH2CH3. In embodiments, R 20 4 is independently oxo. In embodiments, R 20 4 is independently halogen. In embodiments, R 20 4 is
  • R 20 4 is independently -CX 20 4 3 .
  • R 20 4 is independently -CHX 20 .
  • R 20 4 is independently -CH 2 X 20 4 .
  • R 20 4 is independently -OCX 20 4 3 , .
  • R 20 4 is independently -OCH2X 20 4 .
  • R 20 4 is independently -OCHX 20 4 2 .
  • R 20 4 is independently -CN.
  • R 20 4 is independently -OH.
  • R 20 4 is independently - H 2 .
  • R 20 4 is independently -COOH.
  • R 20 4 is independently -CO H 2 .
  • R 20 4 is independently -N0 2 .
  • R 20 5 is independently hydrogen, oxo,
  • halogen -CX 20 5 3 , -CHX 20 5 2 , -CH 2 X 20 5 , -OCX 20 5 3 , -OCH2X 20 5 , -OCHX 20 5 2 (e.g.
  • halogen -CX 20 5 3 , -CHX 20 5 2 , -CH 2 X 20 5 , -OCX 20 5 3 , -OCH2X 20 5 , -OCHX 20 5 2 , -CN, -OH, -NH 2, -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • X 20 5 is independently -F, -CI, -Br, or -I.
  • R 20 5 is independently unsubstituted methyl.
  • R 20 5 is independently unsubstituted ethyl.
  • R 20 5 is independently -Br.
  • R 20 5 is independently -F.
  • R 20 5 is independently -CI.
  • R 20 5 is independently -CN.
  • R 20 5 is independently -CF 3 .
  • R 20 5 is independently -CH 3 .
  • R 20 5 is independently -CH2CH3.
  • R 20 5 is independently -C 6 H5.
  • R 20 5 is independently -OH.
  • R 20 5 is independently -OCH 3 . In embodiments, R 20 5 is independently -OCH 2 CH 3 . In embodiments, R 20 5 is independently oxo. In embodiments, R 20 5 is independently halogen. In embodiments, R 20 5 is independently -CX 20 5 3 . In embodiments, R 20 5 is
  • R 20 5 is independently -CH 2 X 20 5 .
  • R 20 5 is independently -OCX 20 5 3 , . In embodiments, R 20 5 is
  • R 20 5 is independently -OCH2X 20 5 .
  • R 20 5 is independently -OCHX 20 5 2 .
  • R 20 5 is independently -CN.
  • R 20 5 is independently -OH.
  • R 20 5 is independently -NH 2 .
  • R 20 5 is independently -COOH.
  • R 20 5 is independently -CONH2.
  • R 20 5 is
  • R 20 5 is independently -NO2. In embodiments, R 20 5 is independently -SH. In embodiments, R 20 5 is independently -S0 3 H. In embodiments, R 20 5 is independently -SO4H. In embodiments, R 20 5 is independently -SO2NH2. In embodiments, R 20 5 is independently -NHNH 2 . In
  • z21 is 4. In embodiments, z21 is 5. [0178] R is independently oxo,
  • halogen -CX 21 3 , -CHX 21 2 , -CH 2 X 21 , -OCX 21 3 , -OCH 2 X 21 , -OCHX 21 2 (e.g. -F, CI, -Br, -I, - CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCb,-CHBr2,-CHl2,-CH 2 F, -CH 2 C1, -CH 2 Br ,-CH 2 I, - OCF 3 , -OCCb, -OCBr 3 , -OCI 3 , -OCHF 2 , -OCHCb, -OCHBr 2 , -OCHb, -OCH 2 F, -OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH, -CONH
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 22 -substituted or unsubstituted aryl e.g., C 6 -Ci 2 , C 6 -Cio, or phenyl
  • R 22 -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 21 is independently oxo, halogen, -CX 21 3 , -CHX 21 2 , -CH 2 X 21 , -OCX 21 3 , -OCH2X 21 , -OCHX 21 2 (e.g.
  • 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5- C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -Ci 2 , C 6 -Cio, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered
  • X 21 is independently -F, -CI, -
  • R 22 is independently oxo
  • halogen -CX 22 3 , -CHX 22 2 , -CH 2 X 22 , -OCX 22 3 , -OCH2X 22 , -OCHX 22 2 (e.g. -F, CI, -Br, -I, - CF 3 , -CCb, -CBr 3 , -Cb, -CHF 2 , -CHCb,-CHBr2,-CHl2,-CH 2 F, -CH2CI, -CH 2 Br ,-CH 2 I, - OCF 3 , -OCCb, -OCBr 3 , -OCb, -OCHF2, -OCHCb, -OCHBr 2 , -OCHb, -OCH2F, -OCH 2 Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH
  • 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5- C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -Ci2, C 6 -Cio, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered
  • X 22 is independently -F, -CI, -Br
  • R 1A is independently
  • R 20A - sub stituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 20A - sub stituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 20A - sub stituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 20A -sub stituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered,
  • R 1A is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 1A is independently -F, -CI, -Br, or -I.
  • R 1A is independently hydrogen.
  • R 1A is independently unsubstituted methyl.
  • R 1A is independently unsubstituted ethyl.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a R 20A -sub stituted 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 R 20A - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to
  • R 1A and R 1B substituents bonded to the same nitrogen atom 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 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • 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
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a R 20A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom 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).
  • R 20A is independently oxo
  • halogen -CX 20A 3 , -CHX 20A 2 , -CH 2 X 20A , -OCX 20A 3 , -OCH 2 X 20A , -OCHX 20A 2 (e.g. -F, CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH 2 C1, -CH 2 Br ,-
  • -F CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH 2 C1, -CH 2 Br ,-
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 21A -substituted or unsubstituted aryl e.g., C 6 -Ci 2 , C 6 - Cio, or phenyl
  • R 21A -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to
  • R 20A is
  • halogen -CX 20A 3 , -CHX 20A 2 , -CH 2 X 20A , -OCX 20A 3 , -OCH 2 X 20A , -OCHX 20A 2 (e.g.
  • R 21A is independently oxo
  • R 22A is independently selected from the group consisting of R 22A , R 22A -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 22A - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 21A is
  • halogen -CX 21A 3 , -CHX 21A 2 , -CH 2 X 21A , -OCX 21A 3 , -OCH 2 X 21A , -OCHX 21A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr 3 , -CI3, -CHF2, -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br ,-
  • X 21A is independently -F, -CI, -Br, or -I. In embodiments, R 21A is independently unsubstituted methyl. In embodiments, R 21A is independently unsubstituted ethyl. [0184] R 22A is independently oxo,
  • X 22A is independently -F, -CI, -Br, or -I.
  • R 22A is independently unsubstituted methyl.
  • R 22A is independently unsubstituted ethyl.
  • R 1B is independently
  • R 20B - substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 20B -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 20B -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 20B - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6
  • R 1B is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -C 12 , C 6
  • X 1B is independently -F, -CI, -Br, or -I.
  • R 1B is independently hydrogen.
  • R 1B is independently unsubstituted methyl.
  • R 1B is independently unsubstituted ethyl.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a R 20B -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 R 20B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 20B -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 20B -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10
  • R 1A and R 1B substituents bonded to the same nitrogen atom 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 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • 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
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a R 20B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom 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).
  • R 20B is independently oxo
  • halogen -CX 20B 3 , -CHX 20B 2 , -CH 2 X 20B , -OCX 20B 3 , -OCH 2 X 20B , -OCHX 20B 2 (e.g.
  • R 21B is independently selected from a group consisting of aryl and a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl
  • R 21B is independently selected from a compounded or unsubstituted heteroaryl.
  • R 20B is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl that is a aryl
  • halogen -CX 20B 3 , -CHX 20B 2 , -CH 2 X 20B , -OCX 20B 3 , -OCH 2 X 20B , -OCHX 20B 2 (e.g.
  • R 21B is independently oxo
  • R 22B is independently selected from any one of the groups consisting of the following groups: a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, a cycloalkyl, e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R 22B -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 22B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membere
  • X 21B is independently -F, -CI, -Br, or -I. In embodiments, R 21B is independently unsubstituted methyl. In embodiments, R 21B is independently unsubstituted ethyl. [0189] R 22B is independently oxo,
  • halogen -CX 22B 3 , -CHX 22B 2 , -CH 2 X 22B , -OCX 22B 3 , -OCH 2 X 22B , -OCHX 22B 2 (e.g.
  • X 22B is independently -F, -CI, -Br, or -I.
  • R 22B is independently unsubstituted methyl.
  • R 22B is independently unsubstituted ethyl.
  • R 1C is independently
  • R 20C -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 20C -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 20C -substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6
  • R 20C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 member
  • R 1C is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , C1-C4, or Ci-C 2
  • 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6
  • X 1C is independently -F, -CI, -Br, or -I.
  • R 1C is independently hydrogen.
  • R 1C is independently unsubstituted methyl.
  • R 1C is independently unsubstituted ethyl.
  • R 1C is independently unsubstituted phenyl.
  • R 1C is independently R 20C -substituted phenyl.
  • R 20C is independently oxo
  • halogen -CX 20C 3 , -CHX 20C 2 , -CH 2 X 20C , -OCX 20C 3 , -OCH 2 X 20C , -OCHX 20C 2 (e.g.
  • R 21C substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 2ic -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 20C is
  • X 20C is independently -F, -CI, -Br, or -I.
  • R 20C is independently unsubstituted methyl.
  • R 20C is independently unsubstituted ethyl.
  • R 20C is independently -Br.
  • R 20C is independently -F.
  • R 20C is independently -CI.
  • R 20C is independently - CN.
  • R 20C is independently -CF 3 .
  • R 20C is
  • R 20C is independently -CH 3 .
  • R 20C is independently -CH 2 CH 3 .
  • R 20C is independently -C 6 H5.
  • R 20C is independently -OH.
  • R 20C is independently -OCH 3 .
  • R 20C is independently -OCH 2 CH 3 .
  • R 21C is independently oxo
  • R 22C -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - Cio, or phenyl), or R -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 21C is
  • R 22C is independently oxo
  • X 22C is independently -F, -CI, -Br, or -I.
  • R 22C is independently unsubstituted methyl.
  • R 22C is independently unsubstituted ethyl. [0195] In embodiments, R is independently
  • R 20D -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 20D -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 20D -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 20D -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to
  • R 1D is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 1D is independently -F, -CI, -Br, or -I.
  • R 1D is independently hydrogen.
  • R 1D is independently unsubstituted methyl.
  • R 1D is independently unsubstituted ethyl.
  • R 20D is independently oxo
  • halogen -CX 20D 3 , -CHX 20D 2 , -CH 2 X 20D , -OCX 20D 3 , -OCH 2 X 20D , -OCHX 20D 2 (e.g.
  • R 21D -substituted or unsubstituted aryl e.g., C 6 -Ci 2 , C 6 - C10, or phenyl
  • R 21D -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R is independently oxo
  • halogen -CX 20D 3 , -CHX 20D 2 , -CH 2 X 20D , -OCX 20D 3 , -OCH 2 X 20D , -OCHX 20D 2 (e.g.
  • R 21D is independently oxo
  • R 22D is independently selected from the group consisting of R 22D -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 22D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 21D is
  • R 22D is independently oxo
  • halogen -CX 22D 3 , -CHX 22D 2 , -CH 2 X 22D , -OCX 22D 3 , -OCH 2 X 22D , -OCHX 22D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr 3 , -CI3, -CHF2, -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br ,-
  • z20 is independently an integer from 0 to 5. In embodiments, z20 is independently an integer from 0 to 4. In embodiments, z20 is independently an integer from 0 to 3. In embodiments, z20 is independently an integer from 0 to 2. In embodiments, z20 is independently an integer from 0 to 1. In embodiments, z20 is independently 0. In embodiments, z20 is independently 1. In embodiments, z20 is independently 2. In embodiments, z20 is independently 3. In embodiments, z20 is independently 4. In embodiments, z20 is independently 5.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula: , R 2U , z20, X 3 , and X 4 are as described herein.
  • Each R may be same or different, and each z20 ma be same or different.
  • the compound has the formula: X 4
  • L 1 , R 2 , R 20 X 3 , and X 4 are as described herein.
  • the compound has the
  • R 20 - 1 , R 20 2 , and R 20 3 may each independently be an R 20 moiety.
  • R 20 1 is halogen.
  • R 20 1 is -F.
  • R 20 1 is -CI.
  • R 20 1 is -Br.
  • R 20 1 is -I.
  • R 20 1 is -CN.
  • R 20 1 is -CH 3 .
  • R 20 1 is -CH 2 CH 3 .
  • R 20 1 is -OCH 3 .
  • R 20 1 is -OCH 2 CH 3 . In embodiments, R 20 1 is -OCH 2 CH 3 . In embodiments, R 20 1 is -CF 3 . In embodiments, R 20 1 is -CH 2 CF 3 . In embodiments, R 20 1 is -OCF 3 . In embodiments, R 20 1 is -OCH 2 CF 3 . In embodiments, R 20 2 is halogen. In embodiments, R 20 2 is -F. In embodiments, R 20 2 is -CI. In embodiments, R 20 2 is -Br. In embodiments, R 20 2 is - I. In embodiments, R 20 2 is -CN. In embodiments, R 20 2 is -CH 3 .
  • R 20 2 is - CH 2 CH 3 . In embodiments, R 20 2 is -OCH 3 . In embodiments, R 20 2 is -OCH 2 CH 3 . In embodiments, R 20 2 is -OCH 2 CH 3 . In embodiments, R 20 2 is -CF 3 . In embodiments, R 20 2 is - CH 2 CF 3 . In embodiments, R 20 2 is -OCF 3 . In embodiments, R 20 2 is -OCH 2 CF 3 . In embodiments, R 20 3 is halogen. In embodiments, R 20 3 is -F. In embodiments, R 20 3 is -CI. In embodiments, R 20 3 is -Br. In embodiments, R 20 3 is -I.
  • R 20 3 is -CN. In embodiments, R 20 3 is -CH 3 . In embodiments, R 20 3 is -CH 2 CH 3 . In embodiments, R 20 3 is - OCH 3 . In embodiments, R 20 3 is -OCH 2 CH 3 . In embodiments, R 20 3 is -OCH 2 CH 3 . In embodiments, R 20 3 is -CF 3 . In embodiments, R 20 3 is -CH 2 CF 3 . In embodiments, R 20 3 is - OCF 3 . In embodiments, R 20 3 is -OCH 2 CF 3 . In embodiments, R 20 is halogen. In
  • R 20 is -F. In embodiments, R 20 is -CI. In embodiments, R 20 is -Br. In embodiments, R 20 is -I. In embodiments, R 20 is -CN. In embodiments, R 20 is -CH 3 . In
  • the compound has the formula:
  • X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula: . L 1 , R 2 , R 20 z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • R 20 , X 3 , and X 4 are as described herein.
  • R 20 is halogen.
  • R 20 is -F.
  • R 20 is -CI.
  • R 20 is -Br.
  • R 20 is -I.
  • R 20 is -CN.
  • R 20 is -CH3.
  • R 20 is - CH2CH3.
  • R 20 is -OCH3.
  • R 20 is -OCH2CH3.
  • R 20 is -OCH2CH3.
  • R 20 is -OCH2CH3.
  • R 20 is -CF 3 .
  • R 20 is - CH2CF3.
  • R 20 is -OCF3.
  • R 20 is -OCH2CF3.
  • R 20 is -OCH2CF3.
  • the compound has the formula: L 1 , R 2 , R 20 , X 3 , and X 4 are as described herein.
  • R 20 is halogen.
  • R 20 is -F.
  • R 20 is -CI.
  • R 20 is -Br.
  • R 20 is -I.
  • R 20 is -CN.
  • R 20 is -CH 3 .
  • R 20 is -CH2CH3.
  • R 20 is -OCH3.
  • R 20 is -OCH2CH3.
  • R 20 is -CF3.
  • R 20 is -CH2CF3.
  • R 20 is -OCF3.
  • R 20 is -OCH2CF3.
  • the compound has the formula:
  • L 1 , R 2 , R 20 2 , R 20 3 , X 3 , and X 4 are as described herein.
  • the compound has the formula: . L 1 , R 2 , R 20 - 1 ,
  • R 20 3 , X 3 , and X 4 are as described herein.
  • R 20 - 1 , R 20 2 , and R 20 3 may each independently be an R 20 moiety.
  • R 20 1 is halogen.
  • R 20 1 is -F.
  • R 20 1 is -CI.
  • R 20 1 is -Br.
  • R 20 1 is -I.
  • R 20 1 is -CN.
  • R 20 1 is -CH 3 .
  • R 20 1 is -CH 2 CH 3 .
  • R 20 1 is -OCH 3 . In embodiments, R 20 1 is -OCH 2 CH 3 . In embodiments, R 20 1 is -OCH 2 CH 3 . In embodiments, R 20 1 is -CF 3 . In embodiments, R 20 1 is -CH 2 CF 3 . In embodiments, R 20 1 is -OCF 3 . In embodiments, R 20 1 is -OCH 2 CF 3 . In embodiments, R 20 2 is halogen. In embodiments, R 20 2 is -F. In embodiments, R 20 2 is -CI. In embodiments, R 20 2 is -Br. In embodiments, R 20 2 is -I. In embodiments, R 20 2 is -CN.
  • R 20 2 is - CH 3 . In embodiments, R 20 2 is -CH 2 CH 3 . In embodiments, R 20 2 is -OCH 3 . In embodiments, R 20 2 is -OCH 2 CH 3 . In embodiments, R 20 2 is -OCH 2 CH 3 . In embodiments, R 20 2 is -CF 3 . In embodiments, R 20 2 is -CH 2 CF 3 . In embodiments, R 20 2 is -OCF 3 . In embodiments, R 20 2 is - OCH 2 CF 3 . In embodiments, R 20 3 is halogen. In embodiments, R 20 3 is -F. In embodiments, R 20 3 is -CI. In embodiments, R 20 3 is -Br. In embodiments, R 20 3 is -I. In embodiments, R 20 3 is -CN. In embodiments, R 20 3 is -CH 3 . In embodiments, R 20 3 is -CH 2 CH 3 . In
  • R 20 3 is -OCH 3 . In embodiments, R 20 3 is -OCH 2 CH 3 . In embodiments, R 20 3 is -OCH 2 CH 3 . In embodiments, R 20 3 is -CF 3 . In embodiments, R 20 3 is -CH 2 CF 3 . In embodiments, R 20 3 is -OCF 3 . In embodiments R 20 3 is -OCH 2 CF 3 . In embodiments, the
  • X 4 are as described herein.
  • the compound has the formula: L 1 , R 2 , R 20 2 , R 203 X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • R 20 , X 3 , and X 4 are as described herein.
  • R 20 is independently halogen.
  • two R 20 on adjacent carbons are joined to form an unsubstituted C 5 cycloalkyl.
  • two R 20 on adjacent carbons are joined to form a substituted C 5 cycloalkyl.
  • two R 20 on adjacent carbons are joined to form an R 21 -substituted C 5 cycloalkyl.
  • two R 20 on adjacent carbons are joined to form an unsubstituted 6 to 7 membered heterocycloalkyl.
  • two R 20 on adjacent carbons are joined to form a substituted 6 to 7 membered heterocycloalkyl.
  • two R 20 on adjacent carbons are joined to form an R 21 - substituted 6 to 7 membered heterocycloalkyl.
  • the compound has the formula:
  • R 2 , R 20 , 3 , and X 4 are as described herein.
  • the compound has the
  • R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula: R , R z20, X , and X are as described herein.
  • the compound has the formula: R 2 R
  • X 3 , and X 4 are as described herein.
  • the compound has the formula: R .
  • R 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • R 1 is -OCH3.
  • R 1 is unsubstituted C1-C3 alkoxy.
  • the compound has the formula:
  • L 1 , R 2 , R 20 z20, X 3 , and X 4 are as described herein.
  • the compound has the
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • R 21 , z21, X 3 , and X 4 are as described herein.
  • Each R may be same or different, and each z21 may be same or different.
  • the compound has the formula: L 1 , R 2 ,
  • R , z20, X , and X are as described herein.
  • the compound has the
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • the compound has the formula: L
  • the compound has the
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • Each R 20 may be same or different, and each z20 may be same or different.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • Each R20 may be same or different and each 20 may be same or different.
  • the compound has the formula: iA
  • the compound has the
  • L 1 , R 2 , R 21 , z21, X 3 , and X 4 are as described herein.
  • Each R may be same or different, and each z21 may be same or different.
  • each z21 may be same or different.
  • the compound has the formula: L 1 , R 2 , R 20 , z20,
  • X 3 and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula: , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 2 , R 20C , X 3 , and X 4 are as described herein.
  • z20C is independently an integer from 0 to 5. In embodiments, z20C is
  • z20C is independently an integer from 0 to 4. In embodiments, z20C is independently an integer from 0 to 3. In embodiments, z20C is independently an integer from 0 to 2. In embodiments, z20C is independently an integer from 0 to 1. In embodiments, z20C is independently 0. In embodiments, z20C is independently 1. In embodiments, z20C is independently 2. In embodiments, z20C is independently 3. In embodiments, z20C is independently 4. In embodiments, z20C is independently 5. In embodiments, the compound has the formula:
  • the com ound has the formula:
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • the compound has the formula: -C 4 alkoxy)-(R 20 ) z20
  • L 1 , R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • Each R 20 may be same or different, and each z20 may be same or different.
  • the compound has the formula: X 4 . L 1 ,
  • R 2 , R 20 , z20 X 3 , and X 4 are as described herein.
  • the compound has the
  • R 2 , R 20 , z20, X 3 , and X 4 are as described herein.
  • R 2 is hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , substituted or
  • R 2 is hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , unsubstituted Ci-C 3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R 2 is hydrogen.
  • R 2 is independently -CX 2 3 . In embodiments, R 2 is independently - CHX 2 2. In embodiments, R 2 is independently -CH 2 X 2 . In embodiments, R 2 is
  • R 2 is independently -OCX 2 3 .
  • R 2 is independently -OCH 2 X 2 .
  • R 2 is independently -OCHX 2 2.
  • R 2 is independently -C(0)R 2C .
  • R 2 is independently -C(0)OR 2C .
  • R 2 is
  • R 2 is independently -OR 2D .
  • R 2 is independently -OH. In embodiments, R 2 is independently -COOH. In embodiments, R 2 is independently -CO H2. In embodiments, R 2 is independently -CF3. In embodiments, R 2 is independently -CHF2. In embodiments, R 2 is independently -CH2F. In embodiments, R 2 is independently -OCF3. In embodiments, R 2 is independently -OCH2F. In embodiments, R 2 is independently -OCHF2. In embodiments, R 2 is independently -OCH3. In embodiments, R 2 is independently -OCH2CH3. In embodiments, R 2 is independently - OCH2CH2CH3. In embodiments, R 2 is independently -OCH(CH3)2.
  • R 2 is independently -OC(CH3)3. In embodiments, R 2 is independently -CH3. In embodiments, R 2 is independently -CH2CH3. In embodiments, R 2 is independently -CH2CH2CH3. In embodiments, R 2 is independently -CH(CH3)2. In embodiments, R 2 is independently - C(CH3)3. In embodiments, R 2 is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2 is independently substituted C1-C4 alkyl. In embodiments, R 2 is independently substituted C1-C4 alkyl. In embodiments, R 2 is
  • R 2 is independently
  • substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-Ce, C1-C4, or C1-C2
  • substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • substituted or unsubstituted cycloalkyl e.g., C3-C 8 , C3-C6, C4-C6, or C5-C 6
  • substituted or unsubstituted heterocycloalkyl e.g.
  • R 2 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 ,
  • R 2 is independently substituted alkyl (e.g., Ci-C 8 ,
  • R 2 is independently unsubstituted alkyl (e.g., Ci-
  • R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted tert-butyl. In embodiments, R 2 is independently 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).
  • heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered.
  • R 2 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 2 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 2 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2 is independently 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). In embodiments, R 2 is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • aryl e.g., C 6 -C 12 , C 6 -Cio, or phenyl
  • R 2 is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, R 2 is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, R 2 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2 is independently unsubstituted heteroaryl
  • R 2A is independently hydrogen. In embodiments, R 2A is independently -CX 2A 3. In embodiments, R 2A is independently -CHX 2A 2 . In embodiments, R 2A is independently -CH 2 X 2A . In embodiments, R 2A is independently -CN. In
  • R 2A is independently -COOH. In embodiments, R 2A is
  • X 2A is independently -F, -CI, -Br, or -I.
  • R 2A is independently substituted or unsubstituted alkyl (e.g., Ci-).
  • R 2A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 2A is independently unsubstituted alkyl
  • R 2A is independently unsubstituted methyl. In embodiments, R 2A is independently unsubstituted ethyl. In embodiments, R 2A is independently unsubstituted propyl. In embodiments, R 2A is independently unsubstituted isopropyl. In embodiments, R is independently unsubstituted tert-butyl.
  • R 2A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 2A is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 2A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently substituted or
  • R 2A is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2A is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2A is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2B is independently hydrogen. In embodiments, R 2B is independently -CX 2B 3. In embodiments, R 2B is independently -CHX 2B 2. In embodiments, R 2B is independently -CH2X 2B . In embodiments, R 2B is independently -CN. In embodiments, R 2B is independently -COOH. In embodiments, R 2B is independently -CO H2. In embodiments, R 2B is independently hydrogen. In embodiments, R 2B is independently -CX 2B 3. In embodiments, R 2B is independently -CHX 2B 2. In embodiments, R 2B is independently -CH2X 2B . In embodiments, R 2B is independently -CN. In embodiments, R 2B is independently -COOH. In embodiments, R 2B is independently -CO H2. In
  • X 2B is independently -F, -CI, -Br, or -I.
  • R 2B is independently substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2B is independently substituted alkyl (e.g., Ci-Cs, Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R is independently unsubstituted methyl. In embodiments, R 2B is independently unsubstituted ethyl. In embodiments, R 2B is
  • R 2B is independently unsubstituted propyl.
  • R 2B is independently unsubstituted isopropyl.
  • R 2B is independently unsubstituted tert-butyl.
  • R 2B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • R 2B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • R 2B is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • R 2B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2B is independently 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). In embodiments, R 2B is
  • R 2B is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2B is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2B is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2A and R 2B substituents bonded to the same nitrogen atom may 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).
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R and R substituents bonded to the same nitrogen atom may 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).
  • 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.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • substituents bonded to the same nitrogen atom may be j oined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2C is independently hydrogen. In embodiments, R 2C is independently -CX 2C 3 . In embodiments, R 2C is independently -CHX 2C 2. In embodiments, R 2C is independently -CIHhX 20 . In embodiments, R 2C is independently -CN. In embodiments, R 2C is independently -COOH. In embodiments, R 2C is independently -CO H2. In embodiments, R 2C is independently hydrogen. In embodiments, R 2C is independently -CX 2C 3 . In embodiments, R 2C is independently -CHX 2C 2. In embodiments, R 2C is independently -CIHhX 20 . In embodiments, R 2C is independently -CN. In embodiments, R 2C is independently -COOH. In embodiments, R 2C is independently -CO H2. In
  • X 2C is independently -F, -CI, -Br, or -I.
  • R 2C is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2C is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2C is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2C is independently unsubstituted methyl. In embodiments, R 2C is independently unsubstituted ethyl. In embodiments, R 2C is
  • R 2C is independently unsubstituted propyl.
  • R 2C is independently unsubstituted isopropyl.
  • R 2C is independently unsubstituted tert-butyl.
  • R 2C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2C is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 2C is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2C is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-G5).
  • R is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2C is independently 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). In embodiments, R 2C is
  • R 2C is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2D is independently hydrogen. In embodiments, R 2D is independently -CX 2D 3 . In embodiments, R 2D is independently -CHX 2D 2. In embodiments, R 2D is independently -CIHhX 20 . In embodiments, R 2D is independently -CN. In
  • R 2D is independently -COOH. In embodiments, R 2D is
  • X 2D is independently -F, -CI, -Br, or -I.
  • R 2D is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently unsubstituted methyl. In embodiments, R 2D is independently unsubstituted ethyl.
  • R 2D is independently unsubstituted propyl. In embodiments, R 2D is independently unsubstituted isopropyl. In embodiments, R 2D is independently unsubstituted tert-butyl. In embodiments, R 2D is independently 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). In embodiments, R 2D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2D is independently 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). In embodiments, R 2D is
  • R 2D is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2 is independently
  • R 23 -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-Ce, C1-C4, or C1-C2
  • R 23 - substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 23 -substituted or unsubstituted cycloalkyl e.g., C3-C 8 , C3-C6, C4-C6, or C5-C 6
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 23 -substituted or unsubstituted aryl e.g., C 6 -C 12 , C 6 -Cio, or phenyl
  • R 23 -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 2 is independently hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH2X 2 , -OCHX 2 2 , -OH, -COOH, -CO H2, unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , 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-C 8 , C3-C6, C4-G5, or C5-C 6 ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered,
  • R 23 is independently oxo
  • R 23 is independently oxo
  • R 23 is independently unsubstituted ethyl.
  • R 24 is independently oxo
  • R 24 is independently oxo
  • R 24 is independently unsubstituted ethyl.
  • R 25 is independently oxo,
  • R 25 is independently unsubstituted ethyl. [0219] In embodiments, R is independently
  • R 23A -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 23A -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 23A -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 23A -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 2A is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 2A is independently -F, -CI, -Br, or -I.
  • R 2A is independently hydrogen.
  • R 2A is independently unsubstituted methyl.
  • R 2A is independently unsubstituted ethyl.
  • R 2A is R 23A -substituted or unsubstituted C1-C4 alkyl.
  • R 2A is R 23A -substituted C1-C4 alkyl. In embodiments, R 2A is unsubstituted Ci- C 4 alkyl.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a R 23A -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
  • R 23A -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 2A and R 2B substituents bonded to the same nitrogen atom 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 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be j oined to form a R 23A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R and R substituents bonded to the same nitrogen atom 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).
  • R 23A is independently oxo
  • R 24A is 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), R 24A -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 24A - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 23A is a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • halogen -CX 23A 3 , -CHX 23A 2 , -CH 2 X 23A , -OCX 23A 3 , -OCH 2 X 23A , -OCHX 23A 2 (e.g. -F, CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br ,-
  • X 23A is independently -F, -CI, -Br, or -I. In embodiments, R 23A is independently unsubstituted methyl. In embodiments, R 23A is independently unsubstituted ethyl. [0222] R 24A is independently oxo,
  • R 25A is a -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 25A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 24A is
  • X 24A is independently -F, -CI, -Br, or -I. In embodiments, R 24A is independently unsubstituted methyl. In embodiments, R 24A is independently unsubstituted ethyl. [0223] R 25A is independently oxo,
  • R 2B is independently
  • R 23B -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 23B -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 23B -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 23B - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered,
  • R 2B is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 2B is independently -F, -CI, -Br, or -I.
  • R 2B is independently hydrogen.
  • R 2B is independently unsubstituted methyl.
  • R 2B is independently unsubstituted ethyl.
  • R and R substituents bonded to the same nitrogen atom may optionally be joined to form a R 23B -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 R 23B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 23B -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • R 23B -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered,
  • R 2A and R 2B substituents bonded to the same nitrogen atom 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 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • 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
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be j oined to form a R 23B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A and R 2B substituents bonded to the same nitrogen atom 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).
  • R 23B is independently oxo
  • NHC (O)H, -NHC(0)-OH, -NHOH, R 24B -substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci- C 6 , C1-C4, or C1-C2), R 24B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R 24B -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C5, or C5-C 6 ), R 24B - substituted or
  • R 24B is independently selected from the group consisting of R 24B -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 24B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 23B is
  • X 23B is independently -F, -CI, -Br, or -I.
  • R 23B is independently unsubstituted methyl.
  • R 23B is independently unsub stituted ethyl .
  • R 24B is independently oxo
  • R 25B is independently selected from the group consisting of R 25B -substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 - C10, or phenyl), or R 25B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 24B is selected from the group consisting of R 25B -substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 - C10, or phenyl), or R 25B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 24B is
  • R 25B is independently oxo
  • X 25B is independently -F, -CI, -Br, or -I.
  • R 25B is independently unsubstituted methyl.
  • R 25B is independently unsubstituted ethyl.
  • R 25B is unsubstituted C1-C4 alkyl.
  • R 2C is independently
  • R 23C -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 23C -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 23C -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 23C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 2C is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 2C is independently -F, -CI, -Br, or -I.
  • R 2C is independently hydrogen.
  • R 2C is independently unsubstituted methyl.
  • R 2C is independently unsubstituted ethyl.
  • R 2C is R 23C -substituted or unsubstituted C1-C4 alkyl.
  • R 2C is R 23C -substituted C1-C4 alkyl. In embodiments, R 2C is unsubstituted Ci- C 4 alkyl.
  • R 23C is independently oxo
  • R 24C -substituted or unsubstituted aryl e.g., C 6 -Ci2, C 6 - C10, or phenyl
  • R 24C -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 23C is
  • R 24C is independently oxo
  • R 25C -substituted or unsubstituted aryl e.g., C 6 -Ci 2 , C 6 - Cio, or phenyl
  • R 25C -substituted or unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 24C is
  • R 25C is independently oxo
  • R 2D is independently
  • R 23D -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 23D -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R 23D -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 23D -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 2D is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • unsubstituted aryl e.g., C 6 -
  • X 2D is independently -F, -CI, -Br, or -I.
  • R 2D is independently hydrogen.
  • R 2D is independently unsubstituted methyl.
  • R 2D is independently unsubstituted ethyl.
  • R 2D is R 23D -substituted or unsubstituted C 1 -C 4 alkyl.
  • R 2D is R 23D -substituted C 1 -C 4 alkyl. In embodiments, R 2D is unsubstituted Ci- C 4 alkyl.
  • R 23D is independently oxo
  • R 24D is a membered or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 24D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 23D is a membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • halogen -CX 23D 3 , -CHX 23D 2 , -CH 2 X 23D , -OCX 23D 3 , -OCH 2 X 23D , -OCHX 23D 2 (e.g. -F, CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CHF 2 , -CHCl2,-CHBr 2 ,-CHI 2 -CH 2 F, -CH2CI, -CH 2 Br ,-
  • X 23D is independently -F, -CI, -Br, or -I. In embodiments, R 23D is independently unsubstituted methyl. In embodiments, R 23D is independently unsubstituted ethyl. [0235] R 24D is independently oxo,
  • NHC (O)H, -NHC(0)-OH, -NHOH, R 25D -substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci- C 6 , C1-C4, or Ci-C 2 ), R 25D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R 25D -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C5, or C5-C 6 ), R 25D -substituted or
  • R 25D is -substituted or unsubstituted aryl (e.g., C 6 -Ci 2 , C 6 - C10, or phenyl), or R 25D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 24D is
  • X 24D is independently -F, -CI, -Br, or -I. In embodiments, R 24D is independently unsubstituted methyl. In embodiments, R 24D is independently unsubstituted ethyl. [0236] R 25D is independently oxo,
  • X 25D is independently -F, -CI, -Br, or -I.
  • R 25D is independently unsubstituted methyl.
  • R 25D is independently unsub stituted ethyl .
  • the compound has the formula: .
  • R 1 , X 3 , X 4 are as described herein.
  • R 1 is independently R 20 -sub stituted 5 membered heteroaryl.
  • R 1 is independently R 20 -sub stituted 6 membered heteroaryl.
  • R 1 is independently R 20 -substituted pyridyl.
  • R 1 is independently R 20 -sub stituted 2-pyridyl.
  • R 1 is independently R 20 - substituted 3-pyridyl.
  • R 1 is independently R 20 -substituted 4-pyridyl.
  • R 1 is independently R 20 -substituted pyridazinyl. In embodiments, R 1 is independently R 20 -sub stituted pyrimidinyl. In embodiments, R 1 is independently R 20 - substituted pyrazinyl. In embodiments, R 1 is independently R 20 -substituted triazinyl. In embodiments, R 1 is independently R 20 -substituted pyrrolyl. In embodiments, R 1 is independently R 20 -sub stituted 2-pyrrolyl. In embodiments, R 1 is independently R 20 - substituted 3-pyrrolyl. In embodiments, R 1 is independently R 20 -substituted furanyl.
  • R 1 is independently R 20 -substituted 2-furanyl. In embodiments, R 1 is independently R 20 -sub stituted 3-furanyl. In embodiments, R 1 is independently R 20 - substituted thienyl. In embodiments, R 1 is independently R 20 -substituted 2-thienyl. In embodiments, R 1 is independently R 20 -substituted 3- thienyl. In embodiments, R 1 is independently R 20 -substituted pyrazolyl. In embodiments, R 1 is independently R 20 - substituted isoxazolyl. In embodiments, R 1 is independently R 20 -substituted isothiazolyl.
  • R 1 is independently R 20 -substituted imidazolyl. In embodiments, R 1 is independently R 20 -substituted oxazolyl. In embodiments, R 1 is independently R 20 -substituted thiazolyl. In embodiments, R 1 is independently R 20 -substituted phenyl. In embodiments, R 1 is independently R 20 -substituted biphenyl. In embodiments, R 1 is independently R 20 - substituted 2-biphenyl. In embodiments, R 1 is independently R 20 -substituted 3-biphenyl. In embodiments, R 1 is independently R 20 -substituted 4-biphenyl. In embodiments, the
  • the compound has the formula: R 1 , X 3 , X 4 are as described herein. In embodiments, the compound has the formula:
  • R 1 , X 3 , X 4 are as described herein.
  • the X 3 , X 4 are as described herein.
  • R 1 , X 3 , X 4 are as described herein.
  • the compound has the formula .
  • R 1 , X 3 , X 4 are as described herein.
  • the compound has the
  • R 1 X 3 , X 4 are as described herein.
  • the compound has the formula:
  • R X , X are as described herein.
  • the compound has the formula: R 1 , X 3 , X 4 are as described herein. In embodiments, the compound has the formula:
  • the compound has the formula: R X 3 , X 4 are as described herein.
  • X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X 1 is -F. In embodiments, X 1 is -CI. In embodiments, X 1 is -Br. In embodiments, X 1 is -I. In embodiments, X 2 is -F. In embodiments, X 2 is -CI. In embodiments, X 2 is -Br. In embodiments, X 2 is -I. In embodiments, X 3 is -F. In embodiments, X 3 is -CI. In embodiments, X 3 is -Br.
  • X 3 is -I. In embodiments, X 4 is -F. In embodiments, X 4 is -CI. In embodiments, X 4 is -Br. In embodiments, X 4 is -I. In embodiments, X 3 and X 4 are independently -CI or -Br. In embodiments, X 3 and X 4 are -CI. In embodiments, X 4 is a leaving group (e.g., -CI) when participating in a reaction between the compound (e.g., a compound described herein) and a thioredoxin protein.
  • a leaving group e.g., -CI
  • X 3 and X 4 are independently halogen, -CCI3, -CBr 3 , -CF 3 , -CI 3 , CHCI2, -CHBr 2 , -CHF2, -CHI2, -CH2CI, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, - H 2 ,
  • X 3 and X 4 are independently unsubstituted alkyl (e.g., Ci-Cs alkyl, C1-C5 alkyl, or C1-C4 alkyl), or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • X 3 and X 4 are independently -CH 3 .
  • the compound has the formula: R 1 and R 2 are
  • the compound has the formula:
  • R 1 and R 2 are as described herein.
  • the compound has the formula:
  • R 1 and R 2 are as described herein.
  • the compound has the formula: R 1 and R 2 are as described herein.
  • the compound has the formula: R 1 a nd R 2 are as
  • the compound has the formula CI
  • R 1 and R 2 are as described herein.
  • the compound has the formula
  • R 1 and R 2 are as described herein.
  • R 1 has the formula: CI ⁇ N Y ⁇ "Y R 17 " R1 has the formula: CI . R 1 and R 2 are as described herein.
  • the compound has the formula: R 1 a nd R 2 are as described herein. In embodiments, the compound has the formula:
  • R 1 and R 2 are as described herein.
  • the ⁇ ⁇ compound has the formula: CI R 1 a nd R 2 are as described
  • the compound has the formula:
  • the compound has the formula:
  • nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4. In embodiments, ml is 1. In embodiments, ml is 2. In embodiments, vl is 1. In embodiments, vl is 2.
  • the compound has the formula:
  • R 2 , X 3 , X 4 , L 1 , R 20 and z20 are as described herein.
  • L 1 is a bond. In embodiments, L 1 is a unsubstituted C1-C2 alkylene. In embodiments, L 1 is a unsubstituted phenylene.
  • the compound has a formula:
  • R 2 is hydrogen
  • the compound has a formula:
  • R 2 , X 3 , X 4 , R 20 and z20 are as described herein. 0247] In embodiments, the compound has a formula:
  • R 2 , X 3 , X 4 , R 20 and z20 are as described herein.
  • X 3 and X 4 are each independently -Br, -F, or -CI.
  • z20 is 0, 1, 2 or 3. In embodiments, R 20
  • z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 1 and R 20 is halogen. In embodiments, z20 is 1 and R 20 is -F. In embodiments, z20 is 1 and R 20 is -CI. In embodiments, z20 is 1 and R 20 is -Br. In embodiments, z20 is 1 and R 20 is -I. In embodiments, z20 is 1 and R 20 is -CN. In embodiments, z20 is 1 and R 20 is -N0 2 . In embodiments, z20 is 1 and R 20 is -CF 3 . In embodiments, z20 is 1 and R 20 is -CH 3 .
  • z20 is 1 and R 20 is -CH 2 CH 3 . In embodiments, z20 is 1 and R 20 is OH, -OCH 3 . In embodiments, z20 is 1 and R 20 is and -OCH 2 CH 3 .
  • X 3 and X 4 are independently -CI or -Br. In embodiments, X 3 and X 4 are-Cl. In embodiments, X 3 and X 4 are independently -Br. In embodiments, X 3 is -CI and X 4 is -Br. In embodiments, X 3 is -Br and X 4 is -CI.
  • the compound is In embodiments, the compound is
  • the compound is [0252] In embodiments, the compound is KEA1-97. In embodiments, the compound is KEAl-100. In embodiments, the compound is KEAl-83. In embodiments, the compound is
  • the compound is KEAl-50. In embodiments, the compound is
  • the compound is KEAl-62. In embodiments, the compound is
  • the compound is KEAl-69. In embodiments, the compound is
  • the compound is KEAl-90. In embodiments, the compound is
  • the compound is KEAl-37. In embodiments, the compound is
  • the compound is KEAl-64. In embodiments, the compound is
  • the compound is KEAl-72. In embodiments, the compound is
  • the compound is KEAl-59. In embodiments, the compound is
  • the compound is KEAl-80. In embodiments, the compound is
  • the compound is KEAl-57. In embodiments, the compound is
  • the compound is KEAl-43. In embodiments, the compound is
  • the compound is KEAl-78. In embodiments, the compound is
  • the compound is KEAl-73. In embodiments, the compound is
  • the compound is KEAl-70. In embodiments, the compound is
  • the compound is KEAl-67. In embodiments, the compound is
  • the compound is KEAl-79. In embodiments, the compound is
  • the compound is KEAl-38. In embodiments, the compound is
  • the compound is KEAl-56. In embodiments, the compound is
  • the compound is KEAl-40. In embodiments, the compound is
  • the compound is KEAl-85. In embodiments, the compound is
  • the compound is KEAl-45. In embodiments, the compound is
  • the compound is KEAl-53. In embodiments, the compound is KEAl-63. In embodiments, the compound is
  • the compound is KEAl-74. In embodiments, the compound is
  • the compound is KEAl-30. In embodiments, the compound is
  • the compound is KEAl-60. In embodiments, the compound is
  • the compound is KEAl-71. In embodiments, the compound is
  • the compound is KEAl-93. In embodiments, the compound is KEA1-81.
  • a compound as described herein may include multiple instances of R 20 or R 23 , and/or other variables.
  • each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity.
  • R and/or R may be referred to, for example, as R 20 1 , R 20 2 , R 20 3 , R 20 4 , R 20 5 , R 23 R 23 2 , R 23 3 , R 23 4 , or R 23 5 , respectively, wherein the definition of R 20 is assumed by R 20 1 , R 20 2 , R 20 3 , R 20 4 , R 20 5 ; and/or R 23 is assumed by R 23 R 23 2 , R 23 3 , R 23 4 , R 23 5 .
  • the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure).
  • a compound described herein is a racemic mixture of all stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a single stereoisomer. In embodiments, unless otherwise indicated, a compound described herein is a single enantiomer. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim).
  • a Caspase 3 inhibitor In an aspect is provided a Caspase 3 inhibitor.
  • the Thioredoxin inhibitor is a compound described herein.
  • the Caspase 3 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-Caspase 3 antibody, anti-Caspase 3 binding antibody fragment, anti-thioredoxin antibody, anti- thioredoxin binding antibody fragment), or compound (e.g., compound described herein).
  • the Caspase 3 inhibitor contacts one or more amino acids corresponding to K72 of human thioredoxin.
  • the Caspase 3 inhibitor covalently binds an amino acid corresponding to K72 in human thioredoxin.
  • binding of the Caspase 3 inhibitor to thioredoxin e.g., binding, such as covalent binding, to the amino acid on thioredoxin corresponding to K72 of human thioredoxin
  • modulates e.g. reduces, inhibits, prevents contact between the inhibitor bound thioredoxin and Caspase 3.
  • modulation of the contact between thioredoxin and Caspase 3 reduces inhibition of Caspase 3 activity by thioredoxin.
  • modulation of the contact between thioredoxin and Caspase 3 increases the level of activity of Caspase 3 (e.g. in a cell). In embodiments, modulation of the contact between thioredoxin and Caspase 3 increasese apoptosis (e.g., in a cell containing the inhibitor bound thioredoxin).
  • the compound is a compound described herein, including in an aspect, embodiment, claim, figure, table, example, or scheme.
  • -I ⁇ -R 1 is not unsubstituted unsaturated alkyl. In embodiments, - I ⁇ -R 1 is not unsubstituted C2-C6 unsaturated alkyl. In embodiments, -I ⁇ -R 1 is not
  • -I ⁇ -R 1 is not unsubstituted C2-C5 unsaturated alkyl.
  • -I ⁇ -R 1 is not unsubstituted C2-C4 unsaturated alkyl.
  • -I ⁇ -R 1 is not unsubstituted C2-C3 unsaturated alkyl.
  • -L -R is not embodiments, -L -R is not .
  • -I ⁇ -R 1 is not ⁇ 4 .
  • -I ⁇ -R 1 is not-(CH2)4CCH.
  • -I ⁇ -R 1 is not -(CH 2 ) 3 CCH.
  • -I ⁇ -R 1 is not -(CH 2 ) 2 CCH.
  • -I ⁇ -R 1 is not -CH2CCH.
  • -I ⁇ -R 1 is not -CCH.
  • -I ⁇ -R 1 is not ethynyl. In embodiments, -I ⁇ -R 1 is not 1-propynyl.
  • -I ⁇ -R 1 is not 3-propynyl. In embodiments, -I ⁇ -R 1 is not 3-butynyl. In
  • the compound is not H . In embodiment, the compound is not
  • the compound is not H In embodiment, the compound is not H In
  • the compound is not In embodiment, the compound is not
  • -I ⁇ -R 1 is not-(CH 2 ) 4 CCR 20 . In embodiments, -I ⁇ -R 1 is not -(CH 2 ) 3 CCR 20 . In embodiments, -I ⁇ -R 1 is not -(CH 2 ) 2 CCR 20 . In embodiments, -I ⁇ -R 1 is not -CH2CCR 20 . In embodiments, -I ⁇ -R 1 is not -CCR 20 . In embodiments, -R 1 is not - CCR 20 . In embodiments, -I ⁇ -R 1 is not unsubstituted alkyl. In embodiments, -I ⁇ -R 1 is not unsubstituted C2-C6 alkyl.
  • -I ⁇ -R 1 is not unsubstituted C2-C5 alkyl. In embodiments, -I ⁇ -R 1 is not unsubstituted C2-C4 alkyl. In embodiments, -I ⁇ -R 1 is not unsubstituted C2-C3 alkyl.
  • the compound is not KEA1-97. In embodiments, the compound is not KEAl-100. In embodiments, the compound is not KEA1-83. In embodiments, the compound is not KEA1-48. In embodiments, the compound is not KEA1 -50. In
  • the compound is not KEA1-88. In embodiments, the compound is not KEA1- 62. In embodiments, the compound is not KEA1 -94. In embodiments, the compound is not KEAl-69. In embodiments, the compound is not KEAl-46. In embodiments, the compound is not KEA1-90. In embodiments, the compound is not KEA1-55. In embodiments, the compound is not KEA1-37. In embodiments, the compound is not KEA1 -91. In
  • the compound is not KEA1-64. In embodiments, the compound is not KEA1- 75. In embodiments, the compound is not KEA1 -72. In embodiments, the compound is not KEA1-61. In embodiments, the compound is not KEA1-59. In embodiments, the compound is not KEA1-76. In embodiments, the compound is not KEA1-80. In embodiments, the compound is not KEA1 -77. In embodiments, the compound is not KEA1 -57. In
  • the compound is not KEA1-49. In embodiments, the compound is not KEA1- 43. In embodiments, the compound is not KEA1 -95. In embodiments, the compound is not KEA1-78. In embodiments, the compound is not KEA1-54. In embodiments, the compound is not KEA1-73. In embodiments, the compound is not KEA1-23. In embodiments, the compound is not KEA1 -70. In embodiments, the compound is not KEA1-36. In embodiments, the compound is not KEA1-49. In embodiments, the compound is not KEA1- 43. In embodiments, the compound is not KEA1 -95. In embodiments, the compound is not KEA1-78. In embodiments, the compound is not KEA1-54. In embodiments, the compound is not KEA1-73. In embodiments, the compound is not KEA1-23. In embodiments, the compound is not KEA1 -70. In embodiments, the compound is not
  • the compound is not KEA1-67. In embodiments, the compound is not KEA1- 42. In embodiments, the compound is not KEA1 -79. In embodiments, the compound is not KEAl-39. In embodiments, the compound is not KEAl-38. In embodiments, the compound is not KEA1-22. In embodiments, the compound is not KEA1-56. In embodiments, the compound is not KEA1 -32. In embodiments, the compound is not KEA1 -40. In
  • the compound is not KEA1-58. In embodiments, the compound is not KEA1- 85. In embodiments, the compound is not KEA1-68. In embodiments, the compound is not KEAl-45. In embodiments, the compound is not KEAl-53. In embodiments, the compound is not KEA1-63. In embodiments, the compound is not KEA1-47. In embodiments, the compound is not KEA1 -74. In embodiments, the compound is not KEA1 -41. In embodiments, the compound is not KEA1-30. In embodiments, the compound is not KEA1- 98. In embodiments, the compound is not KEAl-60. In embodiments, the compound is not KEAl-31. In embodiments, the compound is not KEAl-71. In embodiments, the compound is not KEA1-84. In embodiments, the compound is not KEA1-93. In embodiments, the compound is not KEA1 -81.
  • a pharmaceutical composition including a thioredoxin inhibitor and a pharmaceutically acceptable excipient.
  • the thioredoxin inhibitor is a compound described herein.
  • the thioredoxin inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Caspase 3 antibody, anti-Caspase 3 binding antibody fragment, anti-thioredoxin antibody, anti- thioredoxin binding antibody fragment), or compound (e.g., compound described herein).
  • the thioredoxin inhibitor is included in a therapeutically effective amount.
  • a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments of the
  • the second agent is an agent for treating cancer.
  • the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the second agent is an anti-cancer agent for treating breast cancer.
  • the anti-cancer agent is tamoxifen, docetaxel, paclitaxel, platinum agents (e.g., cisplatin, carboplatin), vinorelbine, capecitabine, liposomal doxorubicin, gemcitabine, mitoxantrone, ixabepilone, albumin-bound paclitaxel (nab- paclitaxel, abraxane), eribuiin, toremifene, fulvestrant, letrozole, anastrozole, exemestane, megestrol, trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib, palbociclib, ribociclib, or everoli
  • platinum agents e.g
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
  • the thioredoxin inhibitor is a compound described herein.
  • the thioredoxin inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Caspase 3 antibody, anti-Caspase 3 binding antibody fragment, anti- thioredoxin antibody, anti-thioredoxin binding antibody fragment), or compound (e.g., compound described herein).
  • the thioredoxin inhibitor is included in a therapeutically effective amount.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein.
  • an effective amount of a thioredoxin inhibitor may be administered by intraperitoneal injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intravenous injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intramuscular injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intra-arteriole injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intradermal injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by subcutaneous injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intraperitoneal injection.
  • an effective amount of a thioredoxin inhibitor may be administered by intraventricular injection. In embodiments, an effective amount of a thioredoxin inhibitor may be administered by intracranial injection.
  • the cancer is breast cancer. In embodiments, the cancer is estrogen receptor positive breast cancer. In embodiments, the cancer is estrogen receptor (ER) negative breast cancer. In embodiments, the cancer is tamoxifen resistant breast cancer. In embodiments, the cancer is HER2 negative breast cancer. In embodiments, the cancer is HER2 positive breast cancer. In embodiments, the cancer is low grade (well differentiated) breast cancer. In embodiments, the cancer is intermediate grade (moderately differentiated) breast cancer. In embodiments, the cancer is high grade (poorly differentiated) breast cancer.
  • the cancer is stage 0 breast cancer. In embodiments, the cancer is stage I breast cancer. In embodiments, the cancer is stage II breast cancer. In embodiments, the cancer is stage III breast cancer. In embodiments, the cancer is stage IV breast cancer. In embodiments, the cancer is triple negative breast cancer. [0265] In an aspect is provided a method of treating a disease associated with thioredoxin activity including administering to a subject in need thereof an effective amount of a thioredoxin inhibitor. In embodiments, the thioredoxin inhibitor is a compound described herein.
  • the thioredoxin inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Caspase 3 antibody, anti-Caspase 3 binding antibody fragment, anti-thioredoxin antibody, anti-thioredoxin binding antibody fragment), or compound (e.g., compound described herein).
  • the disease is associated with aberrant thioredoxin activity.
  • the thioredoxin activity is reduction of Caspase 3 activity. In embodiments, the thioredoxin inhibitor increases Caspase 3 activity. In embodiments, the thioredoxin inhibitor increases apoptosis (e.g., of a cell). In embodiments, the thioredoxin activity is inhibition of Caspase 3 activity. In embodiments, the thioredoxin activity is inhibition of apoptosis.
  • the method includes administering a second agent (e.g. therapeutic agent). In embodiments, the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
  • the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the anti-cancer agent is tamoxifen, docetaxel, Paclitaxel, Platinum agents (cisplatin, carboplatin), Vinorelbine, Capecitabine, Liposomal doxorubicin, Gemcitabine, Mitoxantrone, Jxabepilone, Albumin- bound paclitaxel (nab-paclitaxel, Abraxane), Eribulin, Toremifene, Fulvestrant, Letrozole, Anastrozole, Exemestane, Megestrol, Trastuzumab, Pertuzumab, Ado-trastuzumab emtansine, Lapatinib, Palbociclib, ribociclib, or Everolimus.
  • a method of inhibiting thioredoxin activity including contacting the thioredoxin with a thioredoxin inhibitor.
  • the thioredoxin is a human thioredoxin.
  • the thioredoxin inhibitor is a compound described herein.
  • the thioredoxin inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Caspase 3 antibody, anti-Caspase 3 binding antibody fragment, anti-thioredoxin antibody, anti-thioredoxin binding antibody fragment), or compound (e.g., compound described herein).
  • the thioredoxin inhibitor is provided in a therapeutically effective amount.
  • the thioredoxin inhibitor contacts an amino acid corresponding to K72 of SEQ ID NO: 1.
  • the thioredoxin activity is inhibition of Caspase 3 activity. In embodiments, the thioredoxin activity is inhibition of apoptosis. In embodiments, the thioredoxin activity is not reduction of all thioredoxin protein activity (e.g., regulation of oxidative stress). In embodiments, the thioredoxin inhibitor increases Caspase 3 activity. In embodiments, the thioredoxin inhibitor increases apoptosis (e.g., of a cell). In embodiments, the thioredoxin inhibitor activates Caspase 3.
  • the thioredoxin inhibitor increases Caspase 3 activity, relative to a control (e.g., the absence of the thioredoxin inhibitor). In embodiments, the thioredoxin inhibitor activates apoptosis.
  • the thioredoxin activity or function is inhibition of Caspase 3 activity. In embodiments, the thioredoxin activity or function is inhibition of apoptosis (e.g., of a cell). In embodiments, the thioredoxin inhibitor modulates an activity or function (e.g., Caspase 3 activity, apoptosis of a cell) of thioredoxin relative to a control (e.g., the absence of the compound). In embodiments, the thioredoxin inhibitor increases an activity or function of Caspase 3 relative to a control (e.g., the absence of the compound).

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Abstract

L'invention concerne, entre autres, des composés et des méthodes pour moduler la thiorédoxine.<i />
PCT/US2018/024134 2017-03-24 2018-03-23 Modulateurs de thiorédoxine et leurs utilisations WO2018175958A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [O] 18 October 2012 (2012-10-18), XP055544463, Database accession no. 60725974 *
DATABASE PUBCHEM [O] 8 August 2005 (2005-08-08), XP055544486, Database accession no. 35298 *
DATABASE PUBCHEM [O] 8 July 2005 (2005-07-08), XP055544422, Database accession no. 16763 *
DATABASE PUBCHEM [O] 8 July 2005 (2005-07-08), XP055544425, Database accession no. 35295 *
TONISSEN ET AL.: "Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy", MOL. NUTR. FOOD RES., vol. 53, 2009, pages 87 - 103, XP055430778 *

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