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WO2018175958A1 - Thioredoxin modulators and uses thereof - Google Patents

Thioredoxin modulators and uses thereof 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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French (fr)
Inventor
Daniel K. Nomura
Kimberly E. ANDERSON
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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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

Described herein, inter alia, are compounds and methods for modulating thioredoxin.

Description

THIOREDOXIN MODULATORS AND USES THEREOF
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/476,585, filed March 24, 2017, which is incorporated herein by reference in their entirety and for all purposes.
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE
[0002] The Sequence Listing written in file 052103-506001WO_ST25.txt, created March 15, 2018, 1,285 bytes, machine format IBM-PC, MS Windows operating system, is hereby incorporated by reference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0003] This invention was made with government support under CA172667 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND
[0004] In the United States, it is estimated that over 200,000 women will have been diagnosed with breast cancer and nearly 40,000 women will have died of breast cancer in 2016. Studies over the past decade have uncovered certain breast cancer cell-types, such as estrogen/progesterone/HER2 receptor (ER/PR/HER2)-negative (triple-negative) breast cancers (TNBCs) that show poor prognosis and chemotherapy-resistance within breast tumors. Eliminating these breast cancer types are critical in reducing the mortality associated with breast cancer. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY
[0005] In an aspect is provided a compound having the formula:
Figure imgf000003_0001
(I).
[0006] L1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R1 is halogen, -CXX 3, -CHX^, -
Figure imgf000003_0002
OCH2X1, -OCHX1!, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0 R1C, - R1AORlc, 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. R2 is
hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -
OCH2X2, -OCHX22, -C(0)R2C, -C(0)OR2C, -C(0) R2AR2B, -OR2D, 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. Each R1A, R1B, R1C, R1D, R2A, R2B, R2C and R2D is independently hydrogen, -CX3, -CHX2, -CH2X, -COOH, -CO H2, 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; R1A and R1B substituents bonded to the same nitrogen atom may optionally be j oined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B 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, X1, X2, X3, and X4 are independently -F, -CI, -Br, or -I.
[0007] In an aspect is provided a pharmaceutical composition including a thioredoxin inhibitor and a pharmaceutically acceptable excipient. [0008] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0009] In an aspect is provided a method of treating cancer, the method including administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
[0010] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein.
[0011] In an aspect is provided a method of inhibiting thioredoxin activity including contacting the thioredoxin with a thioredoxin inhibitor. [0012] In an aspect is provided a method of inhibiting thioredoxin activity including contacting the thioredoxin with a compound described herein.
[0013] In an aspect is provided a thioredoxin protein covalently bonded to a thioredoxin inhibitor (a thioredoxin protein-thioredoxin inhibitor complex).
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIGS. 1A-1D. Screening of dichlorotriazine library in breast cancer cells. (FIG.
1 A) Dichlorotriazines have been shown to have preferred reactivity with lysines. A library of 58 dichlorotriazines was synthesized. (FIG. IB) This library was screened (10 μΜ) in 231MFP breast cancer cells for impairments in serum-free cell survival after 48 h compared to ACN-treated controls. The top hit from this screen was KEAl-97. (FIG. 1C) KEAl-97 (10 μΜ) impairs 231MFP serum-free cell survival and proliferation after 48 h. (FIG. ID)
Counterscreen of hits in MCF10A cells (10 μΜ, 48 h). Data are shown as average ± sem, n=3/group. Significance is expressed as *p<0.05 compared to control.
[0015] FIGS. 2A-2D. KEAl-97 targets thioredoxin. (FIG. 2A) IsoTOP-ABPP analysis of KEAl-97 (10 μΜ) 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 μΜ) 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 μΜ) prior to anti-His pulldown, SDS/PAGE, and blotting for caspase 3. Input caspase 3 is also shown. Data in (FIGS. 2B and 2C) are shown as average ± sem, data in (FIGS. 2A-2D) is n=3/group. Significance is expressed as *p<0.05 compared to control. [0016] FIGS. 3 A-3C. 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. (FIG. 3C) KEAl-97 treatment (10 mg/kg ip once per day) was initiated 16 days after the initiation of 231MFP tumor xenografts in immune-deficient SCID mice. Data in (FIGS. 3A-3C) are shown as average ± sem, data is n=3/group in (FIGS. 3A and 3 B) and n=8 mice/group in (C). Significance is expressed as *p<0.05 compared to control.
[0017] 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 μΜ) and proliferation was assessed after 48 h. (FIG. 4B) Cell proliferation of MCFIOA cells were assessed for those agents that impaired 231MFP proliferation by >50 %. Data is shown as average ± sem, n=3/group.
DETAILED DESCRIPTION
[0018] Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to identify compounds that impair triple-negative breast cancer cell survival. Upon identifying a lead hit from this screen KEAl-97, we used activity-based protein profiling (ABPP) chemoproteomic approaches to identify that this compound targets lysine 72 of thioredoxin~a site previously shown to be important in mediating protein interactions with and inhibition of caspase 3 to suppress apoptosis. We show that 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. I. Definitions
[0019] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0020] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -
[0021] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t- butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
[0022] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
[0023] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, 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) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)- CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, - Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, -0-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and - CH2-0-Si(CH3)3. 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).
[0024] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2- H-CH2-. For
heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0)2R'- represents both -C(0)2R'- and -R'C(0)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0) R', - R'R", -OR, -SR, and/or -SO2R. Where
"heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
[0025] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for
heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
[0026] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0027] The term "acyl" means, unless otherwise stated, -C(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.
[0028] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2- naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
[0029] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or
heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
[0030] The symbol " denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0031] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.
[0032] The term "alkylarylene" as an arylene moiety covalently bonded to an alkylene moiety (also In embodiments, the alkylarylene group
has the form
Figure imgf000010_0001
[0033] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, - CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S02CH3 - S03H, -OS03H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.
[0034] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl,"
"heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0035] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, = R', =N-OR, - R'R", -SR, -halogen, - SiRR'R", -OC(0)R, -C(0)R, -C02R, -CO R'R", -OC(0) R'R", - R"C(0)R, -NR- C(0) R"R", - R"C(0)2R, - R-C( R'R"R")= R"", - R-C( R'R")= R"', -S(0)R, - S(0)2R, -S(0)2 R'R", - RSO2R', -NR R"R", -O R'R", - R'C(0) R" R"'R"", -CN, - N02, -NR'S02R", -NR'C(0)R", -NR'C(0)-OR", -NROR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, - R'R" includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., - C(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like).
[0036] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR, -NR'R", -SR, - halogen, -SiRR'R", -OC(0)R, -C(0)R, -C02R, -CONR'R", -OC(0)NR'R", -NR"C(0)R, - NR'-C(0)NR"R", -NR"C(0)2R, -NR-C(NR'R"R")=NR"", -NR-C(NR'R")=NR"', -S(0)R, - S(0)2R, -S(0)2NR'R", -NRS02R, -NRNR"R", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, - N02, -R, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, -NR'S02R", - NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.
[0037] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroaryl ene) may be depicted as
substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
[0038] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non- adjacent members of the base structure.
[0039] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR')q-U-, wherein T and U are
independently - R-, -0-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -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. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is - 0-, - R'-, -S-, -S(O)-, -S(0)2-, or -S(0)2 R'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0040] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), and silicon (Si).
[0041] A "substituent group," as used herein, means a group selected from the following moieties:
(A) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCb, -CHBr2, -CHF2, -CHI2, - CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03
H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -
Figure imgf000013_0001
-NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCH Br2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered
heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5- C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g., C6-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
(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCb, -CHBr2, -CHF2, -CHb, -
CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -
Figure imgf000013_0002
-NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OCI3,-OCHCb, -OCHBr2, -OCHb, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-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
(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -
CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, - H2, -COOH, -CO H2, -NO2, -SH, - S03H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC(0) HNH2, -NHC(0) H2, - HSO2H, - HC(0)H, - HC(0)OH, - HOH, -OCCb, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-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
(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -
CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or
C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0042] A "size-limited substituent" or " size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[0043] A "lower substituent" or " lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
[0044] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0045] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or
unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Cio arylene, and/or each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 10 membered
heteroaryl ene.
[0046] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted
heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or
unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Cio arylene, and/or each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0047] In embodiments, a substituted 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.
[0048] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted 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.
[0049] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted 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.
[0050] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroaryl ene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different.
[0051] 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. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0052] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0053] The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
[0054] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
[0055] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. [0056] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this invention.
[0057] 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. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[0058] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0059] "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. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0061] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be
distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally differently.
[0062] 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.
[0063] Description of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
[0064] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolyl sulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0065] Thus, 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.
[0066] 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.
[0067] In addition to salt forms, 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. Additionally, 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. [0068] 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.
[0069] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of
pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[0070] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0071] 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. In embodiments, 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). In embodiments, 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.
[0072] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
[0073] A polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.
[0074] 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. For example, 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. In some embodiments, where a selected protein is aligned for maximum homology with the human thioredoxin protein, the position in the aligned selected protein aligning with K72 is said to correspond to K72. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the three dimensional structure of the selected protein is aligned for maximum
correspondence with the human thioredoxin protein (SEQ ID NO: 1) and the overall structures compared. In this case, the amino acid that occupies the same essential structural position as K72 in the structural model relative to the reference sequence is said to correspond to the K72 residue.
[0075] "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.
[0076] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments 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).
[0077] As defined herein, the term "activation", "activate", "activating", "activator" and the like in reference to a protein-inhibitor interaction means positively affecting (e.g.
increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator. In embodiments 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. Thus, 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.
[0078] As defined herein, the term "inhibition", "inhibitor", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor interaction 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. In embodiments inhibition means negatively affecting (e.g.
decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments 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
embodiments, 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).
[0079] The terms "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). In embodiments, 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. In embodiments, the thioredoxin gene has the nucleic acid sequence set forth in RefSeq (mRNA) M 003329. In embodiments, 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
P_003320.2. In embodiments, the sequence corresponds to M_003329.3. In
embodiments, the thioredoxin protein encoded by the thioredoxin gene has the amino acid sequence set forth in or corresponding RefSeq (protein) P 001231867. In embodiments, the thioredoxin gene has the nucleic acid sequence set forth in RefSeq (mRNA)
NM 001244938. In embodiments, 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. In embodiments, 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)
MVKQIESKTA FQEALDAAGD KLVWDFSAT WCGPCKMIKP FFHSLSEKYS
NVI FLEVDVD DCQDVASECE V CMPTFQFF KKGQKVGE FS GANKEKLEAT INELV [0081] The term "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). In embodiments, 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. In embodiments, the caspase 3 gene has the nucleic acid sequence set forth in RefSeq (mRNA) M 004346. In embodiments, 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 P 004337.2. In embodiments, the sequence corresponds to M 004346.3. In embodiments, the caspase 3 is a human caspase 3, such as a human cancer causing caspase 3. In some embodiments, 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. In some embodiments, the caspase 3 protein activity may be directly or indirectly measured in vivo by cell apoptosis or cell proliferation.
[0082] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein {e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
[0083] 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. In some further instances, "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 myeloma. [0084] As used herein, the term "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, 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.
[0085] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.
[0086] As used herein, the term "lymphoma" refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease. Hodgkin's disease represents
approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin' s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma,
immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
[0087] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
[0088] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma. [0089] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky- cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.
[0090] The terms "treating", or "treatment" 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
degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In
embodiments, treating is preventing. In embodiments, treating does not include preventing.
[0091] "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. In some embodiments, a patient is human.
[0092] 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 (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. 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).
[0093] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those
concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0094] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, 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.
[0095] 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.
[0096] As used herein, the term "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. [0097] "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
coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0098] "Anti-cancer agent" and "anticancer agent" are used in accordance with their plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some embodiments, 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. XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), 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 (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126,
PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib
(Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20- epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene;
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; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin
SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;
epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; 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; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon;
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; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine;
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;
picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
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
Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense
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; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans;
tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin;
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,
Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;
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; fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II
(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; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;
nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol.TM (i.e.
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. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC- D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e.
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, 21-aminoepothilone B (i.e. BMS-310705), 21 -hydroxy epothilone D (i.e.
Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, 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. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET- P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetyl acetonate, T- 138026 (Tularik), Monsatrol, lnanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desm ethyl el eutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),
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, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha- interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA- DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to mIn, 90Y, or 131I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab
(Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI- 1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST- 1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like.
[0099] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization. [0100] "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
embodiments and examples).
[0101] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule. In some embodiments, 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. [0102] The term "modulate" is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. In embodiments, modulating is activating. In embodiments, modulating is inhibiting.
[0103] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease, a cancer associated with thioredoxin activity, thioredoxin associated cancer, thioredoxin associated disease) means that the disease (e.g. cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or inpart) the substance or substance activity or function. For example, a cancer associated with thioredoxin activity or function (e.g., thioredoxin function of inhibiting caspase 3 activity or thioredoxin activity of inhibiting apoptosis) 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. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, 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.
[0104] The term "aberrant" as used herein 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.
[0105] The term "signaling pathway" as used herein 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. For example, 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. [0106] The term "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.
[0107] The term "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.
[0108] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof. The terms "polynucleotide," "oligonucleotide," "oligo" or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term "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. The term "duplex" in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, 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. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.
[0109] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, 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. By way of example, 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.
[0110] 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. Other analog 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. 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;
alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.
[0111] 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. By way of example, 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. [0112] 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. See, e.g., Weintraub, Scientific American, 262:40 (1990). Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) are generally between 15 and 25 bases in length. Thus, 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). 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 vitro. 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 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.
[0046] In the cell, 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. Furthermore, the double-stranded molecule may be degraded via the RNAi
pathway. The use of antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)). Further, antisense molecules which bind directly to the DNA may be used. 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.
[0092] The term "complement," as used herein, 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. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The 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
sequence. Where the 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. Examples of 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. A further example of 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.
[0113] As described herein the complementarity of 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. Thus, 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).
[0114] The term "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.
[0115] 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. The terms "variable heavy chain," " VH," or "VH" refer 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.
[0116] Examples of 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). As appreciated by one of skill in the art, 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. Thus, the term antibody, as used herein, 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
Pluckthun (1992) Biochemistry 31 : 1579, Hollinger et al.( 1993), PNAS. USA 90:6444, Gruber et al. (1994) J Immunol. 152:5368, Zhu et al. (1997) Protein Sci . 6:781, Hu et al. (1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer Res. 53 :4026, and McCartney, et al.
(1995) Protein Eng. 8:301. [0117] "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.
[0118] The terms "identical" or percent "identity," in the context of two or more 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). Such 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. As described below, the preferred algorithms can account for gaps and the like. Preferably, 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.
[0119] The term "irreversible covalent bond" is used in accordance with its plain ordinary meaning in the art and refers to the resulting association between atoms or molecules of (e.g., electrophilic chemical moiety and nucleophilic moiety) wherein the probability of
dissociation is low. In embodiments, the irreversible covalent bond does not easily dissociate under normal biological conditions. In embodiments, the irreversible covalent bond is formed through a chemical reaction between two species (e.g., electrophilic chemical moiety and nucleophilic moiety).
[0120] The term "thioredoxin activity" as used herein refers to the biological activity of the protein. In embodiments, 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. [0121] The term "thioredoxin protein-thioredoxin inhibitor complex" as used herein refers to a thioredoxin protein bonded (e.g., covalently bonded) to a thioredoxin inhibitor (e.g., a compound described herein).
[0122] 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. Thus, the leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair. 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. In embodiments, 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. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, the leaving group is X4. In embodiments, at least two leaving groups (e.g., R1 and R13) are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch. In embodiments, the leaving groups is designed to facilitate the reaction.
II. Compounds
[0123] In an aspect is provided a compound having the formula:
Figure imgf000047_0001
(I).
[0124] L1 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. In embodiments, L1 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.
[0125] R1 is halogen, -CX^, -CHX^, -CH2X1, -OCX^, -
OCFFiX1, -OCHX^, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0 R1C, - R1A0R1C, 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.
[0126] R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX2 2, -C(0)R2C, -C(0)OR2C, -C(0) R2AR2B, -OR2D, 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.
[0127] Each R1A, R1B, R1C, R1D, R2A, R2B> R2C and R2D is independently
hydrogen, -CX3, -CHX2, -CH2X, -COOH, -CO H2, 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; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0128] The symbol nl is an integer from 0 to 4.
[0129] The symbols ml and vl are independently an integer from 1 to 2. [0130] The symbols X, X1, and X2 are independently -F, -CI, -Br, or -I. [0131] The symbols X3 and X4 are independently halogen, -CC13, -CBr3, -CF3, -CI3,
CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CO H2, -NO2, -SH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2B1-, -OCH2I, -OCH2F, unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), or a leaving group. In
embodiments, X3 and X4 are independently -F, -CI, -Br, or -I.
[0132] In embodiments, L1 is a bond. In embodiments, L1 is an unsubstituted alkylene. In embodiments, L1 is an unsubstituted C1-C4 alkylene. In embodiments, L1 is an unsubstituted methylene. In embodiments, L1 is an unsubstituted heteroalkylene. In embodiments, L1 is an unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L1 is - CH2CH2O-, -OCH2CH2-, -OCH2-, or -CH2O-. In embodiments, L1 is an unsubstituted arylene. In embodiments, L1 is an unsubstituted phenylene.
[0133] In embodiments, L1 is -0-. In embodiments, L1 is -C(O)- . In embodiments, L1 is -C(0)0-. In embodiments, L1 is -C(0) H-. In embodiments, L1 is -CH2-. In
embodiments, L1 is -CH2CH2-. In embodiments, L1 is -CH2CH2CH2-. In embodiments, L1 1S -OCH2-. In embodiments, L1 is -CH2O-. In embodiments, L1 is -CH2CH2-. In embodiments, L1 is unsubstituted phenylene. In embodiments, L1 is -CH2CH2O-. In embodiments, L1 is -OCH CH -. In embodiments L1 is -OCH -. In embodiments, L1 is -
CH2O-. In embodi . In
embodiments, L1 is
Figure imgf000049_0001
[0134] In embodiments, L1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, 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., C3-C8, C3-C6, C4-C6, or C5-C6), 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 unsubstituted arylene (e.g., C6-Cio or phenyl), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0135] In embodiments, L1 is independently substituted or unsubstituted alkylene (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2). In embodiments, L1 is independently substituted alkylene (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, L1 is independently unsubstituted alkylene (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, L1 is substituted or unsubstituted Ci- C4 alkylene. In embodiments, L1 is substituted C1-C4 alkylene. In embodiments, L1 is unsubstituted C1-C4 alkylene. In embodiments, L1 is independently unsubstituted methylene. In embodiments, L1 is independently unsubstituted ethylene. In embodiments, L1 is independently unsubstituted propylene. In embodiments, L1 is independently unsubstituted isopropylene. In embodiments, L1 is independently unsubstituted tert-butylene. In embodiments, L1 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). In embodiments, L1 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, L1 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, L1 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1 is substituted 2 to 6 membered heteroalkylene. In embodiments, L1 is unsubstituted 2 to 6 membered
heteroalkylene.
[0136] In embodiments, L1 is independently substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L1 is independently substituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L1 is independently unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L1 is or unsubstituted C3-C6 cycloalkylene. In embodiments, L1 is substituted C3-C6 cycloalkylene. In embodiments, L1 is unsubstituted C3-C6 cycloalkylene. [0137] In embodiments, L1 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). In embodiments, L1 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). In embodiments, L1 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). In embodiments, L1 is substituted or unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L1 is substituted 5 to 6 membered heterocycloalkylene. In embodiments, L1 is unsubstituted 5 to 6 membered
heterocycloalkylene.
[0138] In embodiments, L1 is independently substituted or unsubstituted arylene (e.g., C6- Cio or phenylene). In embodiments, L1 is independently substituted arylene (e.g., C6-Cio or phenylene). In embodiments, L1 is independently unsubstituted arylene (e.g., C6-Cio or phenylene). In embodiments, L1 is substituted or unsubstituted phenylene. In embodiments, L1 is substituted phenylene. In embodiments, L1 is unsubstituted phenylene.
[0139] In embodiments, L1 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1 is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1 is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1 is substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L1 is substituted 5 to 6 membered heteroarylene. In embodiments, L1 is unsubstituted 5 to 6 membered
heteroarylene.
[0140] In embodiments, L1 is independently bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, R17- substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R17-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), R17-substituted or unsubstituted cycloalkylene (e.g., C3- C8, C3-C6, C4-C6, or C5-C6), R17-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), R17- substituted or unsubstituted arylene (e.g., C6-Cio or phenylene), or R17-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1 is independently bond, -C(O)-, -C(0)NH-, -C(0)0-, -0-, unsubstituted alkylene (e.g., Ci-C8, Ci-C6, 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., C3-C8, C3-C6, C4-C6, or C5-C6), 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), unsubstituted arylene (e.g., C6-Cio or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1 is R17-substituted or unsubstituted C1-C4 alkylene. In embodiments, L1 is unsubstituted C1-C4 alkylene. In embodiments, L1 is independently unsubstituted methylene. In embodiments, L1 is independently unsubstituted ethylene. In embodiments, L1 is independently methyl-substituted methylene.
[0141] R17 is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX17 3, -CHX17 2, -CH2X17 (e.g., -CF3, -CHF2, -CH2F, -CCI3, -CHCI2, -CH2CI, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, or-CH2I), -OCX17 3, -OCH2X17, -OCHX17 2 (e.g.,-OCF3, -0CC13, -OCBr3, -OCI3,-OCH2F, - OCH2CI, -OCH2Br, -OCH2I, -OCHF2, -OCHCI2, -OCHBr2, or - OCHI2), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2,
-NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, - NHC(0)-OH, -NHOH, R18-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R18-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), R18-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R18-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), R18-substituted or unsubstituted aryl (e.g., C6-Cio or phenyl), or R18-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R17 is independently oxo, halogen (e.g., - F, -CI, Br, -I), -CX17 3, -CHX17 2, -CH2X17 (e.g., -CF3, -CHF2, -CH2F, -CCI3, -CHC12, - CH2C1, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, or-CH2I), -OCX17 3, -OCH2X17, -OCHX17 2 (e.g.,-OCF3, -OCCb, -OCBr3, -OCI3,-OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCHF2, - OCHCl2, -OCHBr2, or -OCHI2), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X17 is independently -F, -CI, -Br, or -I. In embodiments, R17 is hydrogen. In embodiments, R17 is R18-substituted or unsubstituted C1-C4 alkyl. In embodiments, R17 is unsubstituted Ci- C4 alkylene. In embodiments, R17 is independently unsubstituted methyl. In embodiments, R17 is independently unsubstituted ethyl. [0142] R is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX18 3, -CHX18 2, -CH2X18 (e.g., -CF3, -CHF2, -CH2F, -CCI3, -CHCI2, -CH2CI, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, or-CH2I), -OCX18 3, -OCH2X18, -OCHX182 (e.g.,-OCF3, -OCCb, -OCBr3, -OCI3,-OCH2F, - OCH2CI, -OCH2Br, -OCH2I, -OCHF2, -OCHCI2, -OCHBr2, or - OCHI2), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2,
-NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, - NHC(0)-OH, -NHOH, R19-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R19-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), R19-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R19-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), R19-substituted or unsubstituted aryl (e.g., C6-Cio or phenyl), or R19-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R18 is independently oxo, halogen (e.g., - F, -CI, Br, -I), -CX18 3, -CHX18 2, -CH2X18 (e.g., -CF3, -CHF2, -CH2F, -CCI3, -CHC12, - CH2C1, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, or-CH2I), -OCX18 3, -OCH2X18, -OCHX18 2 (e.g.,-OCF3, -OCCb, -OCBr3, -OCI3,-OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCHF2, - OCHCl2, -OCHBr2, or -OCHI2), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X18 is independently -F, -CI, -Br, or -I. In embodiments, R18 is R19-substituted or unsubstituted C1-C4 alkyl. In embodiments, R18 is unsubstituted C1-C4 alkylene. In embodiments, R18 is independently unsubstituted methyl. In embodiments, R18 is
independently unsubstituted ethyl. [0143] R19 is independently oxo, halogen (e.g., -F, -CI, Br, -I), -CX19 3, -CHX19 2, -CH2X19
(e.g., -CF3, -CHF2, -CH2F, -CCI3, -CHC12, -CH2C1, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, or-CH2I), -OCX19 3, -OCH2X19, -OCHX19 2 (e.g.,-OCF3, -OCCb, -OCBr3, -OCb,-OCH2F, - OCH2Cl, -OCH2Br, -OCH2I, -OCHF2, -OCHC , -OCHBr2, or - OCHI2), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,
-NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(0)H, -NHC(O)- OH, -NHOH, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Cio or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X19 is independently -F, -CI, -Br, or -I. In embodiments, R19 is unsubstituted C1-C4 alkylene. In embodiments, R19 is independently unsubstituted methyl. In embodiments, R19 is
independently unsubstituted ethyl.
[0144] In embodiments, the compound has the formula:
Figure imgf000054_0001
R1, R2, X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000054_0002
R1, R2 X3, X4 are as described herein. In embodiments, the
compound has the formula:
Figure imgf000054_0003
R1 R2, X3, X4 are as described
herein. In embodiments, the compound has the formula:
Figure imgf000054_0004
R1, R2, X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000055_0001
. R1 R2, X3, X4 are as described herein. In embodiments, the
Figure imgf000055_0002
embodiments, the compound has the formula
Figure imgf000055_0003
. R1 R2, X3, X4 are as
described herein. In embodiments, the compound has the formula:
Figure imgf000055_0004
R1 R2, X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000055_0005
. R1, R2 X3, X4 are as described herein. In embodiments, the
compound has the formula:
Figure imgf000055_0006
. R1 R2, X3, X4 are as described
herein. In embodiments, the compound has the formula:
Figure imgf000055_0007
. R1, R2 X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000056_0001
. R1 R2, X3, X4 are as described herein. In embodiments, the
compound has the formula:
Figure imgf000056_0002
. R1, R2, X3, X4 are as described herein. [0145] In embodiments, R1 is -C(0)R1C, -C(0)0R1C, -C(0) R1AR1B (e.g., -C(0)H, - C(0)CH3, -C(0)C6H5, -C(0)OH, -C(0)OCH3, -C(0) H2, or -C(0) HCH3), substituted or unsubstituted Ci-Ci2 alkyl, substituted or unsubstituted 2 to 12 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. In embodiments, R1 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. In embodiments, R1 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. In embodiments, R1 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
from -Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, and -OCH2CH3 [0146] In embodiments, R1 is unsubstituted C1-C12 alkyl. In embodiments, R1 is unsubstituted 2 to 12 membered heteroalkyl. In embodiments, R1 is unsubstituted C3-C8 cycloalkyl. In embodiments, R1 is unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R1 is unsubstituted C6-Ci2 aryl. In embodiments, R1 is unsubstituted 5 to 12 membered heteroaryl. In embodiments, R1 is unsubstituted C1-C10 alkyl. In embodiments, R1 is unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R1 is unsubstituted C5-C6 cycloalkyl. In embodiments, R1 is unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R1 is unsubstituted phenyl. In embodiments, R1 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1 is unsubstituted C4-C10 alkenyl. In embodiments, R1 is unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R1 is unsubstituted biphenyl. In embodiments, R1 is unsubstituted benzodioxyl. In embodiments, R1 is unsubstituted tetramethyl tetrahydronaphthyl. In embodiments, R1 is unsubstituted tetrahydronaphthyl. In embodiments, R1 is unsubstituted dihydroindenyl. In embodiments, R1 is unsubstituted phenyl. In embodiments, R1 is unsubstituted naphthyl. In embodiments, R1 is unsubstituted benzodioxinyl. In embodiments, R1 is unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1 is unsubstituted dioxoborolanyl. In embodiments, R1 is unsubstituted C4-C10 alkenyl. In embodiments, R1 is unsubstituted tetramethyl
dioxoborolanyl. In embodiments, R1 is -C(0)-(unsubstituted phenyl) .
[0147] In embodiments, R1 is independently unsubstituted methyl. In embodiments, R1 is independently unsubstituted ethyl. In embodiments, R1 is independently unsubstituted propyl. In embodiments, R1 is independently unsubstituted isopropyl. In embodiments, R1 is independently unsubstituted n-propyl. In embodiments, R1 is independently unsubstituted butyl. In embodiments, R1 is independently unsubstituted n-butyl. In embodiments, R1 is independently unsubstituted iso-butyl. In embodiments, R1 is independently unsubstituted t- butyl. In embodiments, R1 is independently unsubstituted pentyl. In embodiments, R1 is independently unsubstituted n-pentyl. In embodiments, R1 is independently unsubstituted hexyl. In embodiments, R1 is independently unsubstituted n-hexyl. In embodiments, R1 is independently unsubstituted heptyl. In embodiments, R1 is independently unsubstituted n- heptyl. In embodiments, R1 is independently unsubstituted octyl. In embodiments, R1 is independently unsubstituted n-octyl. In embodiments, R1 is independently unsubstituted nonyl. In embodiments, R1 is independently unsubstituted n-nonyl. In embodiments, R1 is independently unsubstituted decyl. In embodiments, R1 is independently unsubstituted n- decyl. In embodiments, R1 is independently unsubstituted undecyl. In embodiments, R1 is independently unsubstituted n-undecyl. In embodiments, R1 is independently unsubstituted dodecyl. In embodiments, R1 is independently unsubstituted n-dodecyl. In embodiments, R1 is independently unsubstituted benzyl. In embodiments, R1 is independently unsubstituted Ci-Cio alkyl. In embodiments, R1 is independently halo- substituted methyl. In embodiments, R1 is independently halo- substituted ethyl. In embodiments, R1 is independently halo- substituted isopropyl. In embodiments, R1 is independently halo- substituted n-propyl. In embodiments, R1 is independently halo- substituted n-butyl. In embodiments, R1 is independently halo- substituted t-butyl. In embodiments, R1 is independently halo-substituted n-pentyl. In embodiments, R1 is independently halo-substituted benzyl. In embodiments, R1 is independently halo-substituted Ci-Cio alkyl. In embodiments, R1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1 is independently
unsubstituted 2 to 7 membered heteroalkyl. In embodiments, R1 is independently
unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R1 is independently
unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R1 is independently
unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R1 is independently unsubstituted 7 to 9 membered heteroalkyl.
[0148] In embodiments, R1 is independently unsubstituted 5 membered heteroaryl. In embodiments, R1 is independently unsubstituted 6 membered heteroaryl. In embodiments, R1 is independently unsubstituted pyridyl. In embodiments, R1 is independently unsubstituted 2- pyridyl. In embodiments, R1 is independently unsubstituted 3-pyridyl. In embodiments, R1 is independently unsubstituted 4-pyridyl. In embodiments, R1 is independently unsubstituted pyridazinyl. In embodiments, R1 is independently unsubstituted pyrimidinyl. In
embodiments, R1 is independently unsubstituted pyrazinyl. In embodiments, R1 is independently unsubstituted triazinyl. In embodiments, R1 is independently unsubstituted pyrrolyl. In embodiments, R1 is independently unsubstituted 2-pyrrolyl. In embodiments, R1 is independently unsubstituted 3 -pyrrolyl. In embodiments, R1 is independently unsubstituted furanyl. In embodiments, R1 is independently unsubstituted 2-furanyl. In embodiments, R1 is independently unsubstituted 3-furanyl. In embodiments, R1 is independently unsubstituted thienyl. In embodiments, R1 is independently unsubstituted 2-thienyl. In embodiments, R1 is independently unsubstituted 3- thienyl. In embodiments, R1 is independently unsubstituted pyrazolyl. In embodiments, R1 is independently unsubstituted isoxazolyl. In embodiments, R1 is independently unsubstituted isothiazolyl. In embodiments, R1 is independently unsubstituted imidazolyl. In embodiments, R1 is independently unsubstituted oxazolyl. In embodiments, R1 is independently unsubstituted thiazolyl. In embodiments, R1 is
independently unsubstituted phenyl. In embodiments, R1 is independently unsubstituted biphenyl. In embodiments, R1 is independently unsubstituted 2-biphenyl. In embodiments, R1 is independently unsubstituted 3-biphenyl. In embodiments, R1 is independently unsubstituted 4-biphenyl. In embodiments, R1 is unsubstituted pyrrolidinyl. In
embodiments, R1 is unsubstituted tetrahydrofuranyl. In embodiments, R1 is unsubstituted tetrahydrothienyl. In embodiments, R1 is unsubstituted piperidinyl. In embodiments, R1 is unsubstituted piperazinyl. In embodiments, R1 is unsubstituted tetrahydropyranyl. In embodiments, R1 is unsubstituted thianyl. In embodiments, R1 is unsubstituted morpholinyl. In embodiments, R1 is unsubstituted dioxanyl. In embodiments, R1 is unsubstituted oxazinyl. In embodiments, R1 is unsubstituted benzo[d][l,3]dioxol.
[0149] In embodiments, R1 is R20-substituted C1-C12 alkyl. In embodiments, R1 is R20- substituted 2 to 12 membered heteroalkyl. In embodiments, R1 is R20-substituted C3-C8 cycloalkyl. In embodiments, R1 is R20-substituted 3 to 8 membered heterocycloalkyl. In embodiments, R1 is R20-substituted C6-C12 aryl. In embodiments, R1 is R20-substituted 5 to 12 membered heteroaryl. In embodiments, R1 is R20-substituted C1-C10 alkyl. In
embodiments, R1 is R20-substituted 2 to 10 membered heteroalkyl. In embodiments, R1 is R20-substituted C5-C6 cycloalkyl. In embodiments, R1 is R20-substituted 5 to 6 membered heterocycloalkyl. In embodiments, R1 is R20-substituted phenyl. In embodiments, R1 is R20- substituted 5 to 6 membered heteroaryl. In embodiments, R1 is R20-substituted C4-C10 alkenyl. In embodiments, R1 is R20-substituted 5 to 8 membered heteroalkyl. In
embodiments, R1 is R20-substituted biphenyl. In embodiments, R1 is R20-substituted benzodioxyl. In embodiments, R1 is R20-substituted tetramethyl tetrahydronaphthyl. In embodiments, R1 is R20-substituted tetrahydronaphthyl. In embodiments, R1 is R20- substituted dihydroindenyl. In embodiments, R1 is R20-substituted phenyl. In embodiments, R1 is R20-substituted naphthyl. In embodiments, R1 is R20-substituted benzodioxinyl. In embodiments, R1 is R20-substituted 5 to 6 membered heteroaryl. In embodiments, R1 is R20- substituted dioxoborolanyl. In embodiments, R1 is R20-substituted C4-C10 alkenyl. In embodiments, R1 is R20-substituted tetramethyl dioxoborolanyl. In embodiments, R1 is -C(O)-(R20C-substituted phenyl) . In embodiments, R1 is R20- substituted pyrrolidinyl. In embodiments, R1 is R20-substituted tetrahydrofuranyl. In embodiments, R1 is R20- substituted tetrahydrothienyl. In embodiments, R1 is R20-substituted piperidinyl. In embodiments, R1 is R20-substituted piperazinyl. In embodiments, R1 is R20-substituted tetrahydropyranyl. In embodiments, R1 is R20-substituted thianyl. In embodiments, R1 is R20-substituted morpholinyl. In embodiments, R1 is R20-substituted dioxanyl. In embodiments, R1 is R20- substituted oxazinyl. In embodiments, R1 is R20-substituted benzo[d][l,3]dioxol.
[0150] In embodiments, R1 is independently R20-substituted methyl. In embodiments, R1 is independently R20-substituted ethyl. In embodiments, R1 is independently R20-substituted propyl. In embodiments, R1 is independently R20-substituted isopropyl. In embodiments, R1 is independently R20-substituted n-propyl. In embodiments, R1 is independently R20- substituted butyl. In embodiments, R1 is independently R20-substituted n-butyl. In embodiments, R1 is independently R20-substituted iso-butyl. In embodiments, R1 is independently R20-substituted t-butyl. In embodiments, R1 is independently R20-substituted pentyl. In embodiments, R1 is independently R20-substituted n-pentyl. In embodiments, R1 is independently R20-substituted hexyl. In embodiments, R1 is independently R20-substituted n- hexyl. In embodiments, R1 is independently R20-substituted heptyl. In embodiments, R1 is independently R20-substituted n-heptyl. In embodiments, R1 is independently R20-substituted octyl. In embodiments, R1 is independently R20-substituted n-octyl. In embodiments, R1 is independently R20-substituted nonyl. In embodiments, R1 is independently R20-substituted n- nonyl. In embodiments, R1 is independently R20-substituted decyl. In embodiments, R1 is independently R20-substituted n-decyl. In embodiments, R1 is independently R20-substituted undecyl. In embodiments, R1 is independently R20-substituted n-undecyl. In embodiments, R1 is independently R20-substituted dodecyl. In embodiments, R1 is independently R20- substituted n-dodecyl. In embodiments, R1 is independently R20-substituted benzyl. In embodiments, R1 is independently R20-substituted C1-C10 alkyl. [0151] In embodiments, R1 is independently R20-substituted 2 to 6 membered heteroalkyl.
In embodiments, R1 is independently R20-substituted 2 to 7 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 2 to 8 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 2 to 9 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 2 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 3 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 4 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 5 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 6 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 7 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 8 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 6 to 10 membered heteroalkyl. In embodiments, R1 is independently R20-substituted 7 to 9 membered heteroalkyl. [0152] In embodiments, R1 is independently R20-substituted 5 membered heteroaryl. In embodiments, R1 is independently R20-substituted 6 membered heteroaryl. In embodiments, R1 is independently R20-substituted pyridyl. In embodiments, R1 is independently R20- substituted 2-pyridyl. In embodiments, R1 is independently R20-substituted 3-pyridyl. In embodiments, R1 is independently R20-substituted 4-pyridyl. In embodiments, R1 is independently R20-substituted pyridazinyl. In embodiments, R1 is independently R20- substituted pyrimidinyl. In embodiments, R1 is independently R20-substituted pyrazinyl. In embodiments, R1 is independently R20-substituted triazinyl. In embodiments, R1 is independently R20-substituted pyrrolyl. In embodiments, R1 is independently R20-substituted 2-pyrrolyl. In embodiments, R1 is independently R20-substituted 3-pyrrolyl. In
embodiments, R1 is independently R20-substituted furanyl. In embodiments, R1 is independently R20-substituted 2-furanyl. In embodiments, R1 is independently R20- substituted 3-furanyl. In embodiments, R1 is independently R20-substituted thienyl. In embodiments, R1 is independently R20-substituted 2-thienyl. In embodiments, R1 is independently R20-substituted 3- thienyl. In embodiments, R1 is independently R20- substituted pyrazolyl. In embodiments, R1 is independently R20-substituted isoxazolyl. In embodiments, R1 is independently R20-substituted isothiazolyl. In embodiments, R1 is independently R20-substituted imidazolyl. In embodiments, R1 is independently R20- substituted oxazolyl. In embodiments, R1 is independently R20-substituted thiazolyl. In embodiments, R1 is independently R20-substituted phenyl. In embodiments, R1 is independently R20-substituted biphenyl. In embodiments, R1 is independently R20-substituted 2-biphenyl. In embodiments, R1 is independently R20-substituted 3-biphenyl. In
embodiments, R1 is independently R20-substituted 4-biphenyl. [0153] In embodiments, R1 is unsubstituted biphenyl. In embodiments, R1 is
Figure imgf000062_0001
-subsituted biphenyl. In embodiments, R is s,
Figure imgf000062_0002
R iments, R1 In embodiments, R1 is
Figure imgf000062_0003
In embodiments, R1 is
Figure imgf000063_0001
. In embodiments, R1 is
In embodiments, R1 is
Figure imgf000063_0002
In embodiments, R1 is
In embodiments, R is
Figure imgf000063_0003
. In embodiments, R1 is
In embodiments, R1 is odiments, R1 is odiments, R1 is embodiments, R1 is
Figure imgf000063_0004
embodiments, R1 is . In embodiments, R1 is
Figure imgf000063_0005
Figure imgf000064_0001
[0154] In embodiments, R1 is independently -CX^ (e.g., -CF3, -CC13, -CBr3, -CI3). In embodiments, R1 is independently -CHX^ (e.g, -CHF2, CHCl2,-CHBr2, or -CHI2). In embodiments, R1 is independently -CH2X1 (e.g., -CH2F, -CH2CI, -CH2Br, or -CH2I). In embodiments, R1 is independently -OCX^ (e.g., -OCF3, -OCCh, -OCBr3, -OCI3). In embodiments, R1 is independently -OCH2X1 (e.g., -OCH2F, -OCH2CI, -OCH2Br, or - OCH2I). In embodiments, R1 is independently -OCHX^ (e g, -OCHF2, OCHCl2,-OCHBr2, or -OCHI2). In embodiments, R1 is independently -CN. In embodiments, R1 is
independently -SOniR1D (e.g., -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SC(CH3)3. -SOCH3, -SO2H). In embodiments, R1 is independently -SOviNR1AR1B (e.g., -SONH2, - S02NH2,-SONHCH3, or -S02NHCH3). In embodiments, R1 is
independently -NHC(0)NR1AR1B (e.g., -NHC(0)NH2, - NHC(0)NHCH3, or -
NHC(0)N(CH3)2). In embodiments, R1 is independently -N(0)mi (e.g.,. -NO, -NO2). In embodiments, R1 is independently -NR1AR1B (e.g., -NH2, -NHCH3, or -N(CH3)2). In embodiments, R1 is independently -C(0)R1C (e.g., -C(0)H, or -C(0)CH3). In embodiments, R1 is independently -C(0)-0R1C (e.g., -C(0)OH, or -C(0)OCH3). In embodiments, R1 is independently -C(0)NR1AR1B (e.g., -C(0)NH2, or -C(0)NHCH3). In embodiments, R1 is independently -OR1D (e.g., -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 or- OC(CH3)3). In embodiments, R1 is independently - R1AS02R1D (e.g., -NHSO2H). In embodiments, R1 is independently - R1AC(0)Rlc (e.g., - HC(0)H, or- HC(0)CH3). In embodiments, R1 is independently - R1AC(0)0R1C (e.g., - HC(O)OH). In embodiments, R1 is independently - R1A0R1C (e.g., -NHOH). In embodiments, R1 is independently -OH. In embodiments, R1 is independently -NH2. In embodiments, R1 is independently -COOH. In embodiments, R1 is independently -CONH2. In embodiments, R1 is independently -NO2. In embodiments, R1 is independently -SH. In embodiments, R1 is independently halogen. In embodiments, R1 is independently -F. In embodiments, R1 is independently -CI. In embodiments, R1 is independently -Br. In embodiments, R1 is independently -I. In embodiments, R1 is independently -CF3. In embodiments, R1 is independently -CHF2. In embodiments, R1 is independently -CH2F. In embodiments, R1 is independently -OCF3. In embodiments, R1 is independently -OCH2F. In embodiments, R1 is independently -OCHF2. In embodiments, R1 is independently -OCH3. In embodiments, R1 is independently - OCH2CH3. In embodiments, R1 is independently -OCH2CH2CH3. In embodiments, R1 is independently -OCH(CH3)2. In embodiments, R1 is independently -OC(CH3)3. In embodiments, R1 is independently -SCH3. In embodiments, R1 is independently -SCH2CH3. In embodiments, R1 is independently -SCH2CH2CH3. In embodiments, R1 is independently - SCH(CH3)2. In embodiments, R1 is independently -SC(CH3)3. In embodiments, R1 is independently -CH3. In embodiments, R1 is independently -CH2CH3. In embodiments, R1 is independently -CH2CH2CH3. In embodiments, R1 is independently -CH(CH3)2. In embodiments, R1 is independently -C(CH3)3.
[0155] In embodiments, R1 is independently halogen, -CXX 3, -CHXX 2, -
CH2X1, -OCX , -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NHC(0)NR1AR1B, -N
(O)mi, -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0)NR1AR1B, -OR1D, -NR1AS02R1D, -NR1AC(0) R1C, -NR1AC(0)ORlc, -NR1A0R1C (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, - CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, - OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, -OCH2I, -CN, -SH, - S03H, -SO4H, -SO2NH2, -NO2, -NH2, -C(0)H, -C(0)CH3, -C(0)OH, - C(0)OCH3, -CONH2, -OH, -OCH3, -NHSO2H, -NHC(0)H, NHC(0)OH, or -NHOH), substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2), 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), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, G5-C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). ). In embodiments, R1 is independently halogen, -CXS, -CHX^, - CH2X1, -OCX , -OCH2X1, -OCHX1!, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N (O)mi, -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0) Ric -NR1AC(0)ORlc, -NR1AORlc (e.g. -F, -CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, - CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, - OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, -OCH2I, -CN, -SH, - S03H, -SO4H, -SO2NH2, -NO2, -NH2, -C(0)H, -C(0)CH3, -C(0)OH, -
C(0)OCH3, -CONH2, -OH, -OCH3, -NHSO2H, -NHC(0)H, NHC(0)OH, or -NHOH), unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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- C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R1 is independently -F, -CI, -Br, -I, -CF3, -CC13, -CBr3, - CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, - OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, - OCH2I, -CN, -SH, -S03H, -SO4H, -SO2NH2, -NO2, -NH2, -C(0)H, -C(0)CH3, -C(0)OH, - C(0)OCH3, -CONH2, -OH, -OCH3, -NHSO2H, -NHC(0)H, NHC(0)OH, -NHOH, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6, cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or
unsubstituted 5 to 6 membered heteroaryl. In embodiments, R1 is independently -F, -CI, -Br, -I, -CF3, -CCb, -CBr3, -Cb, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHC , -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, -OCH2I, -CN, -SH, -S03H, -S04H, -SO2NH2, -NO2, -NH2, -C(0)H, - C(0)CH3, -C(0)OH, -C(0)OCH3, -CONH2, -OH, -OCH3, -NHSO2H, -NHC(0)H,
NHC(0)OH, -NHOH, unsubstituted Ci-C6 alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C3-C6, cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,
unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0156] In embodiments, R1 is independently substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1 is independently substituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1 is independently unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1 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, R1 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). In embodiments, R1 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). In embodiments, R1 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C6). In embodiments, R1 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C6, or C5-C6). In embodiments, R1 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). In embodiments, R1 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, R1 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, R1 is independently substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1 is independently substituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1 is independently unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1 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, R1 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, R1 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0157] In embodiments, R1A is independently hydrogen. In embodiments, R1A is independently -CX1A 3 (e.g. -CF3, -CC13, -CBr3, or -CI3). In embodiments, R1A is independently -CHX1A 2 (e.g., CHF2, -CHCl2,-CHBr2 or -CHI2). In embodiments, R1A is independently -CH2X1A ,(e.g. -CH2F, -CH2CI, -CH2Br,or -CH2I). In embodiments, R1A is independently -CN. In embodiments, R is independently -COOH. In embodiments, R is independently -CO H2. In embodiments, X1A is independently -F, -CI, -Br, or -I.
[0158] In embodiments, R1A is independently substituted or unsubstituted alkyl (e.g., Ci- C12, Ci-C8, C1-G5, C1-C4, or C1-C2). In embodiments, R1A is independently substituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1A is independently unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1A is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R1A is
independently substituted C1-C4 alkyl. In embodiments, R1A is independently unsubstituted C1-C4 alkyl. In embodiments, R1A is independently unsubstituted methyl. In embodiments, R1A is independently unsubstituted ethyl. In embodiments, R1A is independently
unsubstituted propyl. In embodiments, R1A is independently unsubstituted isopropyl. In embodiments, R1A is independently unsubstituted tert-butyl. In embodiments, R1A 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, R1A 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). In embodiments, R1A 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). In embodiments, R1A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6). In embodiments, R1A is independently substituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6). In embodiments, R1A 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). In embodiments, R1A 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, R1A 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, R1A is independently substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1A is independently substituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1A is independently unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1A 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, R1A 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, R1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0159] In embodiments, R1B is hydrogen. In embodiments, R1B is -CX1B 3 (e.g. -CF3, - CC13, -CBr3, or -CI3). In embodiments, R1B is -CHX1B 2 (e.g., CHF2, -CHCl2,-CHBr2 or - CHI2). In embodiments, R1B is -CH2X1B (e.g. -CH2F, -CH2C1, -CH2Br,or -CH2I). In embodiments, R1B is -CN. In embodiments, R1B is -COOH. In embodiments, R1B is -CO H2. In embodiments, X1B is independently -F, -CI, -Br, or -I.
[0160] In embodiments, R1B is independently substituted or unsubstituted alkyl (e.g., Ci- Ci2, Ci-C8, C1-G5, C1-C4, or Ci-C2). In embodiments, R1B is independently substituted alkyl (e.g., Ci-Ci2, Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R1B is independently unsubstituted alkyl (e.g., Ci-Ci2, Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R1B is substituted or unsubstituted C1-C4 alkyl. In embodiments, R1B is substituted C1-C4 alkyl. In embodiments, R1A is unsubstituted C1-C4 alkyl. In embodiments, R1B is independently unsubstituted methyl. In embodiments, R1B is independently unsubstituted ethyl. In embodiments, R1B is independently unsubstituted propyl. In embodiments, R1B is independently unsubstituted isopropyl. In embodiments, R1B is independently unsubstituted tert-butyl. In embodiments, R1B 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, R1B 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). In embodiments, R1B 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). In embodiments, R1B is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6). In embodiments, R1B is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-G5). In embodiments, R1B 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). In embodiments, R1B 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, R1E 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, R1B is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1B is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1B is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1B 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, R1B 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, R1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered). [0161] In embodiments, R1A and R1B 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). In embodiments, R1A and R1B 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). In embodiments, R1A and R1B 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).
[0162] In embodiments, R1A and R1B 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). In embodiments, R1A and R1B
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). In embodiments, R1A and R1B 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).
[0163] In embodiments, R1C is independently hydrogen. In embodiments, R1C is independently -CX1C 3 (e.g. -CF3, -CC13, -CBr3, or -CI3). In embodiments, R1C is
independently -CHX1C 2 (e.g., CHF2, -CHCl2,-CHBr2 or -CHI2). . In embodiments, R1C is independently -CH2Xlc(e.g. -CH2F, -CH2C1, -CH2Br,or -CH2I). In embodiments, R1C is independently -CN. In embodiments, R1C is independently -COOH. In embodiments, R1C is independently -CO H2. In embodiments, X1C is independently -F, -CI, -Br, or -I. [0164] In embodiments, R is independently substituted or unsubstituted alkyl (e.g., Ci- Ci2, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1C is independently substituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1C is independently unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R1C is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R1C is
independently substituted C1-C4 alkyl. In embodiments, R1A is independently unsubstituted C1-C4 alkyl. In embodiments, R1C is independently unsubstituted methyl. In embodiments, R1C is independently unsubstituted ethyl. In embodiments, R1C is independently
unsubstituted propyl. In embodiments, R1C is independently unsubstituted isopropyl. In embodiments, R1C is independently unsubstituted tert-butyl. In embodiments, R1C 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, R1C 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). In embodiments, R1C 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). In embodiments, R1C is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6). In embodiments, R1C is independently substituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1C 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). In embodiments, R1C 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, R1C 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, R1C is independently substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1C is independently substituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1C is independently unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl). In embodiments, R1C 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, R1C 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, R1C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0165] In embodiments, R1D is independently hydrogen. In embodiments, R1D is independently -CX1D 3 (e.g. -CF3, -CC13, -CBr3, or -CI3). In embodiments, R1D is independently -CHX1D 2 (e.g., CHF2, -CHCl2,-CHBr2 or -CHI2). In embodiments, R1D is independently -CH2X1D (e.g. -CH2F, -CH2C1, -CH2Br, or -CH2I). In embodiments, R1D is independently -CN. In embodiments, R1D is independently -COOH. In embodiments, R1D is independently -CO H2. In embodiments, X1D is independently -F, -CI, -Br, or -I.
[0166] In embodiments, R1D is independently substituted or unsubstituted alkyl (e.g., Ci- Ci2, Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R1D is independently substituted alkyl (e.g., Ci-Ci2, Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R1D is independently unsubstituted alkyl (e.g., Ci-Ci2, Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R1D is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R1D is
independently substituted C1-C4 alkyl. In embodiments, R1D is independently unsubstituted C1-C4 alkyl. In embodiments, R1D is independently unsubstituted methyl. In embodiments, R1D is independently unsubstituted ethyl. In embodiments, R1D is independently
unsubstituted propyl. In embodiments, R1D is independently unsubstituted isopropyl. In embodiments, R1D is independently unsubstituted tert-butyl. In embodiments, R1D 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, R1D 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). In embodiments, R1D 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). In embodiments, R1D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6). In embodiments, R1D is independently substituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6). In embodiments, R1D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6). In embodiments, R1D 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). In embodiments, R1D 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, R1D 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 is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1D is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1D is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R1D 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, R1D 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, R1D 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, R1 is independently
halogen, -CX^, -CHX^, -CH2X1, -OCX^, -OCH2X1, -OCHX^ (e.g. -F, CI, -Br, -I, -CF3, - CC , -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, - OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, - OCH2CI, or -OCH2I), -CN, -OH, - H2, -COOH, -CO H2, -NO2, -SH, -S03H, -SO4H, - SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HSO2H, - HC=(0)H, - HC(0)-OH, - HOH, R20-substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, Ci- C4, or C1-C2), R20-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), R20- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R20-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), R20-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R20-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, R1 is independently halogen, -CX^, -CHX^, -CH2X1, -OCX^, -OCH2X1, -OCHX^, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2,
-NHC=(0)NH2, -NHSO2H, -NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C5, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X1 is independently -F, -CI, -Br, or -I. In embodiments, R1 is independently hydrogen. In embodiments, R1 is independently unsubstituted methyl. In embodiments, R1 is independently unsubstituted ethyl.
[0168] R20 is independently oxo,
halogen, -CX20 3, -CHX20 2, -CH2X20, -OCX20 3, -OCH2X20, -OCHX20 2, (e.g. -F, CI, -Br, -I, - CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, - SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(0)H, - NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, Ci- C4, or C1-C2), R21- 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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21- 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), R21 -substituted or unsubstituted aryl (e.g., C6-Ci2, C6- Cio, or phenyl), or R21- 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, R20 is independently halogen, -CX20 3, -CHX20 2, -CH2X20, -OCX20 3, -OCH2X20, -OCHX20 2, (e.g. -F, CI, -Br, -I, - CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -
SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(0)H, - NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, Ci- C4, or C1-C2), R21- 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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-G5), R21- 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), R21 -substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R21- 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, R20 is independently halogen, -CX20 3, -CHX20 2, -CH2X20, -OCX20 3, -OCH2X20, -OCHX20 2, (e.g. -F, CI, -Br, -I, - CF3, -CCb, -CBr3, -Cb, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -S04H, - SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) NH2, - HSO2H, - HC= (O)H, - HC(0)-OH, - HOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6- C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 is independently -F, -CI, -Br, or -I. In embodiments, R20 is independently unsubstituted methyl. In embodiments, R20 is independently
unsubstituted ethyl. In embodiments, R20 is R21-substituted or unsubstituted C1-C4 alkyl. In embodiments, R20 is R21-substituted C1-C4 alkyl. In embodiments, R20 is independently unsubstituted C1-C4 alkyl.
[0169] In embodiments, R1 is independently substituted with one of R20, two of R20, three of R20, four R20, or five of R20. In embodiments, R1 is independently substituted with (R20)Z2o. 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.
[0170] In embodiments, R20 is independently -Br. In embodiments, R20 is independently - F. In embodiments, R20 is independently -CI. In embodiments, R20 is independently -CN. In embodiments, R20 is independently -CF3. In embodiments, R20 is independently -CH3. In embodiments, R20 is independently -CH2CH3. In embodiments, R20 is independently -C6H5. In embodiments, R20 is independently -OH. In embodiments, R20 is independently -OCH3. In embodiments, R20 is independently -OCH2CH3.
[0171] In embodiments, R20 is independently oxo. In embodiments, R20 is independently halogen. In embodiments, R20 is independently -CX20 3. In embodiments, R20 is
independently -CHX202. In embodiments, R20 is independently -CH2X20. In embodiments, R20 is independently -OCX20 3, . In embodiments, R20 is independently -OCH2X20. In embodiments, R20 is independently -OCHX202. In embodiments, R20 is independently -CN. In embodiments, R20 is independently -OH. In embodiments, R20 is independently -NH2. In embodiments, R is independently -COOH. In embodiments, R is independently -CO H2. In embodiments, R20 is independently -NO2. In embodiments, R20 is independently -SH. In embodiments, R20 is independently -SO3H. In embodiments, R20 is independently -SO4H In embodiments, R20 is independently -SO2 H2. In embodiments, R20 is independently
-NHNH2. In embodiments, R20 is independently -O H2. In embodiments, R20 is independently - HC=(0) HNH2. In embodiments, R20 is independently - HC=(0) H2. In embodiments, R20 is independently -NHSO2H. In embodiments, R20 is independently - HC=(0)H. In embodiments, R20 is independently - HC(0)-OH. In embodiments, R20 is independently - HOH. [0172] R20 1 is independently hydrogen, oxo,
halogen, -CX20 -CHX20 -CH2X20 -OCX20 -OCH2X20 \ -OCHX20 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -
NHC=(0)H, -NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C8, Ci-C6, C1-C4, or C1-C2), R21-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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21-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), R21-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R21-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, R20 1 is independently oxo,
halogen, -CX20,1 3, -CHX20 -CH2X20'1, -OCX20,1 3, -OCH2X20 -OCHX20 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 1 is independently -F, -CI, -Br, or -I. In embodiments, R20 1 is independently unsubstituted methyl. In embodiments, R20 1 is independently unsubstituted ethyl. In embodiments, R20 1 is independently -Br. In embodiments, R20 1 is independently -F. In embodiments, R20 1 is independently -CI. In embodiments, R20 1 is independently -CN. In embodiments, R20 1 is independently -CF3. In embodiments, R20 1 is independently -CH3. In embodiments, R20 1 is independently -CH2CH3. In embodiments, R20 1 is independently -C6H5. In embodiments, R20 1 is independently -OH. In embodiments, R20 1 is independently -OCH3. In
embodiments, R20 1 is independently -OCH2CH3. In embodiments, R20 1 is independently oxo. In embodiments, R20 1 is independently halogen. In embodiments, R20 1 is
independently -CX20 1 3. In embodiments, R20 1 is independently -CHX20 J 2. In embodiments, R20 1 is independently -CH2X20 Λ. In embodiments, R20 1 is independently -OCX20,1 3, . In embodiments, R20 1 is independently -OCH2X20 l . In embodiments, R20 1 is
independently -OCHX20 J 2. In embodiments, R20 1 is independently -CN. In embodiments, R20 1 is independently -OH. In embodiments, R20 1 is independently -NH2. In embodiments, R20 1 is independently -COOH. In embodiments, R20 1 is independently -CONH2. In embodiments, R20 1 is independently -NO2. In embodiments, R20 1 is independently -SH. In embodiments, R20 1 is independently -S03H. In embodiments, R20 1 is independently -SO4H. In embodiments, R20 1 is independently -SO2NH2. In embodiments, R20 1 is independently -NHNH2. In embodiments, R20 1 is independently -ONH2. In embodiments, R20 1 is independently -NHC=(0)NHNH2. In embodiments, R20 1 is independently -NHC=(0)NH2. In embodiments, R20 1 is independently -NHSO2H. In embodiments, R20 1 is independently - NHC=(0)H. In embodiments, R20 1 is independently -NHC(0)-OH. In embodiments, R20 1 is independently -NHOH.
[0173] R20 2 is independently hydrogen, oxo,
halogen, -CX20 2 3, -CHX20 2 2, -CH2X20 2, -OCX20 2 3, -OCH2X20 2, -OCHX20 2 2, (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C8, Ci-C6, C1-C4, or C1-C2), R21-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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21-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), R21-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R21-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, R20 2 is independently oxo,
halogen, -CX20 2 3, -CHX20 2 2, -CH2X20 2, -OCX20 2 3, -OCH2X20 2, -OCHX20 2 2 (e.g. -F, CI, -Br, -I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-
CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 2 is independently -F, -CI, -Br, or -I. In embodiments, R20 2 is independently unsubstituted methyl. In embodiments, R20 2 is independently unsubstituted ethyl. In embodiments, R20 2 is independently -Br. In embodiments, R20 2 is independently -F. In embodiments, R20 2 is independently -CI. In embodiments, R20 2 is independently -CN. In embodiments, R20 2 is independently -CF3. In embodiments, R20 2 is independently -CH3. In embodiments, R20 2 is independently -Ο¾0Η3. In embodiments, R20 2 is independently -C6H5. In embodiments, R20 2 is independently -OH. In embodiments, R20 2 is independently -OCH3. In
embodiments, R20 2 is independently -0Ο¾0Η3. In embodiments, R20 2 is independently oxo. In embodiments, R20 2 is independently halogen. In embodiments, R20 2 is
independently -CX20 2 3. In embodiments, R20 2 is independently -CHX20 22. In embodiments, R20 2 is independently -CH2X20 2. In embodiments, R20 2 is independently -OCX20 2 3, . In embodiments, R20 2 is independently -OCH2X20 2. In embodiments, R20 2 is
independently -OCHX20 22. In embodiments, R20 2 is independently -CN. In embodiments, R20 2 is independently -OH. In embodiments, R20 2 is independently - H2. In embodiments, R20 2 is independently -COOH. In embodiments, R20 2 is independently -CO H2. In embodiments, R20 2 is independently -N02. In embodiments, R20 2 is independently -SH. In embodiments, R20 2 is independently -SO3H. In embodiments, R20 2 is independently -SO4H. In embodiments, R20 2 is independently -SO2 H2. In embodiments, R20 2 is independently -NHNH2. In embodiments, R20 2 is independently -ONH2. In embodiments, R20 2 is independently - HC=(0) HNH2. In embodiments, R20 2 is independently - HC=(0)NH2. In embodiments, R20 2 is independently - HSO2H. In embodiments, R20 2 is independently - HC=(0)H. In embodiments, R20 2 is independently - HC(0)-OH. In embodiments, R20 2 is independently - HOH.
[0174] R20 3 is independently hydrogen, oxo,
halogen, -CX20 3 3, -CHX20 3 2, -CH2X20 3, -OCX20 3 3, -OCH2X20 3, -OCHX20 3 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C8, Ci-C6, C1-C4, or C1-C2), R21-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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21-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), R21-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R21-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, R20 3 is independently oxo,
halogen, -CX20 3 3, -CHX20 3 2, -CH2X20 3, -OCX20 3 3, -OCH2X20 3, -OCHX20 3 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -
NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 3 is independently -F, -CI, -Br, or -I. In embodiments, R20 3 is independently unsubstituted methyl. In embodiments, R20 3 is independently unsubstituted ethyl. In embodiments, R20 3 is independently -Br. In embodiments, R20 3 is independently -F. In embodiments, R20 3 is independently -CI. In embodiments, R20 3 is independently -CN. In embodiments, R20 3 is independently -CF3. In embodiments, R20 3 is independently -CH3. In embodiments, R20 3 is independently -CH2CH3. In embodiments, R20 3 is independently -C5H5. In embodiments, R20 3 is independently -OH. In embodiments, R20 3 is independently -OCH3. In
embodiments, R20 3 is independently -OCH2CH3. In embodiments, R20 3 is independently oxo. In embodiments, R20 3 is independently halogen. In embodiments, R20 3 is
independently -CX20 Y In embodiments, R20 3 is independently -CHX20 3 2. In embodiments, R20 3 is independently -CH2X20 3. In embodiments, R20 3 is independently -OCX20 3 3, . In embodiments, R20 3 is independently -OCH2X20 3. In embodiments, R20 3 is
independently -OCHX20 32. In embodiments, R20 3 is independently -CN. In embodiments, R20 3 is independently -OH. In embodiments, R20 3 is independently -NH2. In embodiments, R20 3 is independently -COOH. In embodiments, R20 3 is independently -CONH2. In embodiments, R20 3 is independently -NO2. In embodiments, R20 3 is independently -SH. In embodiments, R20 3 is independently -SO3H. In embodiments, R20 3 is independently -SO4H. In embodiments, R20 3 is independently -SO2NH2. In embodiments, R20 3 is independently -NHNH2. In embodiments, R20 3 is independently -ONH2. In embodiments, R20 3 is independently -NHC=(0)NHNH2. In embodiments, R20 3 is independently -NHC=(0)NH2. In embodiments, R20 3 is independently -NHSO2H. In embodiments, R20 3 is independently - NHC=(0)H. In embodiments, R20 3 is independently -NHC(0)-OH. In embodiments, R20 3 is independently -NHOH.
[0175] R20 4 is independently hydrogen, oxo,
halogen, -CX20 4 3, -CHX20 4 2, -CH2X20 4, -OCX20 4 3, -OCH2X20 4, -OCHX20 4 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br -
CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - HC=(0)H, - HC(0)-OH, - HOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C8, Ci-C6, C1-C4, or C1-C2), R21-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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21-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), R21-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R21-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, R20 4 is independently oxo,
halogen, -CX20 -CHX20 4 2, -CH2X20 4, -OCX20 4 3, -OCH2X20 4, -OCHX20 4 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 4 is independently -F, -CI, -Br, or -I. In embodiments, R20 4 is independently unsubstituted methyl. In embodiments, R20 4 is independently unsubstituted ethyl. In embodiments, R20 4 is independently -Br. In embodiments, R20 4 is independently -F. In embodiments, R20 4 is independently -CI. In embodiments, R20 4 is independently -CN. In embodiments, R20 4 is independently -CF3. In embodiments, R20 4 is independently -CH3. In embodiments, R20 4 is independently -CH2CH3. In embodiments, R20 4 is independently -C6H5. In embodiments, R20 4 is independently -OH. In embodiments, R20 4 is independently -OCH3. In
embodiments, R20 4 is independently -OCH2CH3. In embodiments, R20 4 is independently oxo. In embodiments, R20 4 is independently halogen. In embodiments, R20 4 is
independently -CX20 4 3. In embodiments, R20 4 is independently -CHX20 . In embodiments, R20 4 is independently -CH2X20 4. In embodiments, R20 4 is independently -OCX20 4 3, . In embodiments, R20 4 is independently -OCH2X20 4. In embodiments, R20 4 is independently -OCHX20 4 2. In embodiments, R20 4 is independently -CN. In embodiments, R20 4 is independently -OH. In embodiments, R20 4 is independently - H2. In embodiments, R20 4 is independently -COOH. In embodiments, R20 4 is independently -CO H2. In embodiments, R20 4 is independently -N02. In embodiments, R20 4 is independently -SH. In embodiments, R20 4 is independently -SO3H. In embodiments, R20 4 is independently -SO4H. In embodiments, R20 4 is independently -S02 H2. In embodiments, R20 4 is independently -NHNH2. In embodiments, R20 4 is independently -ONH2. In embodiments, R20 4 is independently - HC=(0) HNH2. In embodiments, R20 4 is independently - HC=(0)NH2. In embodiments, R20 4 is independently - HS02H. In embodiments, R20 4 is independently - HC=(0)H. In embodiments, R20 4 is independently -NHC(0)-OH. In embodiments, R20 4 is independently - HOH.
[0176] R20 5 is independently hydrogen, oxo,
halogen, -CX20 5 3, -CHX20 5 2, -CH2X20 5, -OCX20 5 3, -OCH2X20 5, -OCHX20 5 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)-OH, -NHOH, R21- substituted or unsubstituted alkyl (e.g., C1-C12, Ci- C8, Ci-C6, C1-C4, or C1-C2), R21-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), R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R21-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), R21-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R21-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, R20 5 is independently oxo,
halogen, -CX20 5 3, -CHX20 5 2, -CH2X20 5, -OCX20 5 3, -OCH2X20 5, -OCHX20 5 2, -CN, -OH, -NH 2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C12, Ci-C8, Ci-C6, 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- C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20 5 is independently -F, -CI, -Br, or -I. In embodiments, R20 5 is independently unsubstituted methyl. In embodiments, R20 5 is independently unsubstituted ethyl. In embodiments, R20 5 is independently -Br. In embodiments, R20 5 is independently -F. In embodiments, R20 5 is independently -CI. In embodiments, R20 5 is independently -CN. In embodiments, R20 5 is independently -CF3. In embodiments, R20 5 is independently -CH3. In embodiments, R20 5 is independently -CH2CH3. In embodiments, R20 5 is independently -C6H5. In embodiments, R20 5 is independently -OH. In embodiments, R20 5 is independently -OCH3. In embodiments, R20 5 is independently -OCH2CH3. In embodiments, R20 5 is independently oxo. In embodiments, R20 5 is independently halogen. In embodiments, R20 5 is independently -CX20 5 3. In embodiments, R20 5 is
independently -CHX20 5 2. In embodiments, R20 5 is independently -CH2X20 5. In
embodiments, R20 5 is independently -OCX20 5 3, . In embodiments, R20 5 is
independently -OCH2X20 5. In embodiments, R20 5 is independently -OCHX20 5 2. In embodiments, R20 5 is independently -CN. In embodiments, R20 5 is independently -OH. In embodiments, R20 5 is independently -NH2. In embodiments, R20 5 is independently -COOH. In embodiments, R20 5 is independently -CONH2. In embodiments, R20 5 is
independently -NO2. In embodiments, R20 5 is independently -SH. In embodiments, R20 5 is independently -S03H. In embodiments, R20 5 is independently -SO4H. In embodiments, R20 5 is independently -SO2NH2. In embodiments, R20 5 is independently -NHNH2. In
embodiments, R20 5 is independently -ONH2. In embodiments, R20 5 is independently -NHC=(0)NHNH2. In embodiments, R20 5 is independently -NHC=(0)NH2. In
embodiments, R20 5 is independently -NHSO2H. In embodiments, R20 5 is independently - NHC=(0)H. In embodiments, R20 5 is independently -NHC(0)-OH. In embodiments, R20 5 is independently -NHOH. diments, R20 is R21- substituted phenyl. In embodiments, R20 is
Figure imgf000083_0001
, z21 is independently an integer from 0 to 5. In embodiments, z21 embodiments, z21 is 1. In embodiments, z21 is 2. In embodiments, z21 is 3. In
embodiments, z21 is 4. In embodiments, z21 is 5. [0178] R is independently oxo,
halogen, -CX21 3, -CHX21 2, -CH2X21, -OCX21 3, -OCH2X21, -OCHX21 2 (e.g. -F, CI, -Br, -I, - CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHb, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -
SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-OH, -NHOH, R22- substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R22-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), R22-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R22-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), R22-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R22-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, R21 is independently oxo, halogen, -CX21 3, -CHX21 2, -CH2X21, -OCX21 3, -OCH2X21, -OCHX21 2 (e.g. -F, CI, -Br, -I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHb, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -S04H, - SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2),
unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X21 is independently -F, -CI, -Br, or -I. In embodiments, R21 is independently unsubstituted methyl. In embodiments, R21 is independently
unsubstituted ethyl.
[0179] R22 is independently oxo,
halogen, -CX22 3, -CHX22 2, -CH2X22, -OCX22 3, -OCH2X22, -OCHX22 2 (e.g. -F, CI, -Br, -I, - CF3, -CCb, -CBr3, -Cb, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, - OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHb, -OCH2F, -OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -S04H, - SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HSO2H, - HC=(0)H, - HC(0)-OH, - HOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2),
unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X22 is independently -F, -CI, -Br, or -I. In embodiments, R22 is independently unsubstituted methyl. In embodiments, R22 is independently
unsub stituted ethyl .
[0180] In embodiments, R1A is independently
hydrogen, -CX1A 3, -CHX1A 2, -CH2X1A, -CN, -COOH, -CO H2, R20A- sub stituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R20A- 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), R20A- sub stituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R20A-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), R20A-sub stituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R20A- sub stituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered). In embodiments, R1A is independently
hydrogen, -CX1A 3, -CHX1A 2, -CH2X1A, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X1A is independently -F, -CI, -Br, or -I. In embodiments, R1A is independently hydrogen. In embodiments, R1A is independently unsubstituted methyl. In embodiments, R1A is independently unsubstituted ethyl.
[0181] In embodiments, R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a R20A-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 R20A- 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, R1A and R1B 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). In embodiments, R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a R20A-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). In embodiments, R1A and R1B 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).
[0182] R20A is independently oxo,
halogen, -CX20A 3, -CHX20A 2, -CH2X20A, -OCX20A 3, -OCH2X20A, -OCHX20A 2 (e.g. -F, CI, -Br, -I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2C1, -CH2Br ,-
CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R21A-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R21A-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), R21A-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R21A-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), R21A-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- Cio, or phenyl), or R21A-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, R20A is
independently oxo,
halogen, -CX20A 3, -CHX20A 2, -CH2X20A, -OCX20A 3, -OCH2X20A, -OCHX20A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20A is independently -F, -CI, -Br, or -I. In embodiments, R20A is independently unsubstituted methyl. In embodiments, R20A is independently unsubstituted ethyl.
[0183] R21A is independently oxo,
halogen, -CX21A 3, -CHX21A 2, -CH2X21A, -OCX21A 3, -OCH2X21A, -OCHX21A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R22A- substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R22A- 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), R22A- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R22A-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), R22A-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R22A- 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, R21A is
independently oxo,
halogen, -CX21A 3, -CHX21A 2, -CH2X21A, -OCX21A 3, -OCH2X21A, -OCHX21A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-
CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X21A is independently -F, -CI, -Br, or -I. In embodiments, R21A is independently unsubstituted methyl. In embodiments, R21A is independently unsubstituted ethyl. [0184] R22A is independently oxo,
halogen, -CX22A 3, -CHX22A 2, -CH2X22A, -OCX22A 3, -OCH2X22A, -OCHX22A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X22A is independently -F, -CI, -Br, or -I. In embodiments, R22A is independently unsubstituted methyl. In embodiments, R22A is independently unsubstituted ethyl. [0185] In embodiments, R1B is independently
hydrogen, -CX1B 3, -CHX1B 2, -CH2X1B, -CN, -COOH, -CONH2, R20B- substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R20B-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), R20B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R20B- 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), R20B-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R20B-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, R1B is independently
hydrogen, -CX1B 3, -CHX1B 2, -CH2X1B, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X1B is independently -F, -CI, -Br, or -I. In embodiments, R1B is independently hydrogen. In embodiments, R1B is independently unsubstituted methyl. In embodiments, R1B is independently unsubstituted ethyl.
[0186] In embodiments, R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a R20B-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 R20B-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, R1A and R1B 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). In embodiments, R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a R20B- 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). In embodiments, R1A and R1B 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).
[0187] R20B is independently oxo,
halogen, -CX20B 3, -CHX20B 2, -CH2X20B, -OCX20B 3, -OCH2X20B, -OCHX20B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -
OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, - SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) NH2, - HS02H, - HC= (O)H, - HC(0)-OH, - HOH, R21B-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or Ci-C2), R21B-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), R21B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6), R21B- 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), R21B-substituted or unsubstituted aryl (e.g., C6-C12, C6- Cio, or phenyl), or R21B-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, R20B is
independently oxo,
halogen, -CX20B 3, -CHX20B 2, -CH2X20B, -OCX20B 3, -OCH2X20B, -OCHX20B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20B is independently -F, -CI, -Br, or -I. In embodiments, R20B is independently unsubstituted methyl. In embodiments, R20B is independently unsubstituted ethyl.
[0188] R21B is independently oxo,
halogen, -CX21B 3, -CHX21B 2, -CH2X21B, -OCX21B 3, -OCH2X21B, -OCHX21B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R22B-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R22B-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), R22B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R22B- 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), R22B-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R22B-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, R21B is
independently oxo, halogen, -CX21B 3, -CHX21B 2, -CH2X21B, -OCX21B 3, -OCH2X21B, -OCHX21B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X21B is independently -F, -CI, -Br, or -I. In embodiments, R21B is independently unsubstituted methyl. In embodiments, R21B is independently unsubstituted ethyl. [0189] R22B is independently oxo,
halogen, -CX22B 3, -CHX22B 2, -CH2X22B, -OCX22B 3, -OCH2X22B, -OCHX22B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X22B is independently -F, -CI, -Br, or -I. In embodiments, R22B is independently unsubstituted methyl. In embodiments, R22B is independently unsubstituted ethyl. [0190] In embodiments, R1C is independently
hydrogen, -CX1C 3, -CHX1C 2, -CH2X1C, -CN, -COOH, -CONH2, R20C-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R20C-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), R20C-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R20C-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), R20C-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R20C-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, R1C is independently
hydrogen, -CX1C 3, -CHX1C 2, -CH2X1C, -CN, -COOH, -CO H2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or Ci-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X1C is independently -F, -CI, -Br, or -I. In embodiments, R1C is independently hydrogen. In embodiments, R1C is independently unsubstituted methyl. In embodiments, R1C is independently unsubstituted ethyl. In embodiments, R1C is independently unsubstituted phenyl. In embodiments, R1C is independently R20C-substituted phenyl.
[0191] R20C is independently oxo,
halogen, -CX20C 3, -CHX20C 2, -CH2X20C, -OCX20C 3, -OCH2X20C, -OCHX20C 2 (e.g. -F, CI, -Br, - I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R2ic-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or Ci-C2), R2ic-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), R2ic-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R2ic-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), R21C- substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R2ic-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, R20C is
independently oxo, halogen, -CX20S, -CHX20L 2, -CH2X20L, -OCX20L 3, -OCH2X20L, -OCHX20L 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20C is independently -F, -CI, -Br, or -I. In embodiments, R20C is independently unsubstituted methyl. In embodiments, R20C is independently unsubstituted ethyl. [0192] In embodiments, R20C is independently -Br. In embodiments, R20C is independently -F. In embodiments, R20C is independently -CI. In embodiments, R20C is independently - CN. In embodiments, R20C is independently -CF3. In embodiments, R20C is
independently -CH3. In embodiments, R20C is independently -CH2CH3. In embodiments, R20C is independently -C6H5. In embodiments, R20C is independently -OH. In embodiments, R20C is independently -OCH3. In embodiments, R20C is independently -OCH2CH3.
[0193] R21C is independently oxo,
halogen, -CX21C 3, -CHX21C 2, -CH2X21C, -0CX21C 3, -0CH2X21C, -0CHX21C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R22C-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R22C-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), R22C-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R22C-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), R22C-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- 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). In embodiments, R21C is
independently oxo,
halogen, -CX21C 3, -CHX21C 2, -CH2X21C, -0CX21C 3, -0CH2X21C, -0CHX21C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X21C is independently -F, -CI, -Br, or -I. In embodiments, R21C is independently unsubstituted methyl. In embodiments, R21C is independently unsubstituted ethyl.
[0194] R22C is independently oxo,
halogen, -CX22C 3, -CHX22C 2, -CH2X22C, -OCX22C 3, -OCH2X22C, -OCHX22C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X22C is independently -F, -CI, -Br, or -I. In embodiments, R22C is independently unsubstituted methyl. In embodiments, R22C is independently unsubstituted ethyl. [0195] In embodiments, R is independently
hydrogen, -CX1D 3, -CHX1D 2, -CH2X1D, -CN, -COOH, -CONH2, R20D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R20D-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), R20D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R20D-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), R20D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R20D-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, R1D is independently
hydrogen, -CX1D 3, -CHX1D 2, -CH2X1D, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X1D is independently -F, -CI, -Br, or -I. In embodiments, R1D is independently hydrogen. In embodiments, R1D is independently unsubstituted methyl. In embodiments, R1D is independently unsubstituted ethyl.
[0196] R20D is independently oxo,
halogen, -CX20D 3, -CHX20D 2, -CH2X20D, -OCX20D 3, -OCH2X20D, -OCHX20D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R21D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R21D-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), R21D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R21D-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), R21D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R21D-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 is independently oxo,
halogen, -CX20D 3, -CHX20D 2, -CH2X20D, -OCX20D 3, -OCH2X20D, -OCHX20D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X20D is independently -F, -CI, -Br, or -I. In embodiments, R20D is independently unsubstituted methyl. In embodiments, R20D is independently unsubstituted ethyl.
[0197] R21D is independently oxo,
halogen, -CX21D 3, -CHX21D 2, -CH2X21D, -OCX21D 3, -OCH2X21D, -OCHX21D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R22D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R22D-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), R22D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R22D-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), R22D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R22D-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, R21D is
independently oxo,
halogen, -CX21D 3, -CHX21D 2, -CH2X21D, -OCX21D 3, -OCH2X21D, -OCHX21D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCb, -CBr3, -Cb, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br - CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X21D is independently -F, -CI, -Br, or -I. In embodiments, R21D is independently unsubstituted methyl. In embodiments, R21D is independently unsubstituted ethyl.
[0198] R22D is independently oxo,
halogen, -CX22D 3, -CHX22D 2, -CH2X22D, -OCX22D 3, -OCH2X22D, -OCHX22D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-
CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X22D is independently -F, -CI, -Br, or -I. In embodiments, R22D is independently unsubstituted methyl. In embodiments, R22D is independently unsubstituted ethyl.
[0199] 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.
[0200] In embodiments, the compound has the formula:
R2
3 N I' /(CrC10 alkyl)-(R20)z20
I YI -L1
Ν Ν
X4 . L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000098_0001
. L1, R2, R20, z20, X3, and X4 are as described herein.
In embodiments, the compound has the formula:
Figure imgf000098_0002
. L1, R2, R20, z20, X3, and X4 are as described
In embodiments, the compound has the formula:
Figure imgf000098_0003
L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000099_0001
, R2U, z20, X3, and X4 are as described herein. Each R may be same or different, and each z20 ma be same or different. In
Α X3 γNΙλΎ
Figure imgf000099_0002
embodiments, the compound has the formula: X4
L1, R2, R20 X3, and X4 are as described herein. In embodiments, the compound has the
formula:
Figure imgf000099_0003
. L1, R2, R20 R20 3, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000099_0004
. L1, R2, R20 2, R20 3, X3, and X4 are as described herein. R20 -1, R20 2, and R20 3 may each independently be an R20 moiety. In embodiments, R20 1 is halogen. In embodiments, R20 1 is -F. In embodiments, R20 1 is -CI. In embodiments, R20 1 is -Br. In embodiments, R20 1 is -I. In embodiments, R20 1 is -CN. In embodiments, R20 1 is -CH3. In embodiments, R20 1 is -CH2CH3. In embodiments, R20 1 is -OCH3. In embodiments, R20 1 is -OCH2CH3. In embodiments, R20 1 is -OCH2CH3. In embodiments, R20 1 is -CF3. In embodiments, R20 1 is -CH2CF3. In embodiments, R20 1 is -OCF3. In embodiments, R20 1 is -OCH2CF3. In embodiments, R20 2 is halogen. In embodiments, R20 2 is -F. In embodiments, R20 2 is -CI. In embodiments, R20 2 is -Br. In embodiments, R20 2 is - I. In embodiments, R20 2 is -CN. In embodiments, R20 2 is -CH3. In embodiments, R20 2 is - CH2CH3. In embodiments, R20 2 is -OCH3. In embodiments, R20 2 is -OCH2CH3. In embodiments, R20 2 is -OCH2CH3. In embodiments, R20 2 is -CF3. In embodiments, R20 2 is - CH2CF3. In embodiments, R20 2 is -OCF3. In embodiments, R20 2 is -OCH2CF3. In embodiments, R20 3 is halogen. In embodiments, R20 3 is -F. In embodiments, R20 3 is -CI. In embodiments, R20 3 is -Br. In embodiments, R20 3 is -I. In embodiments, R20 3 is -CN. In embodiments, R20 3 is -CH3. In embodiments, R20 3 is -CH2CH3. In embodiments, R20 3 is - OCH3. In embodiments, R20 3 is -OCH2CH3. In embodiments, R20 3 is -OCH2CH3. In embodiments, R20 3 is -CF3. In embodiments, R20 3 is -CH2CF3. In embodiments, R20 3 is - OCF3. In embodiments, R20 3 is -OCH2CF3. In embodiments, R20 is halogen. In
embodiments, R20 is -F. In embodiments, R20 is -CI. In embodiments, R20 is -Br. In embodiments, R20 is -I. In embodiments, R20 is -CN. In embodiments, R20 is -CH3. In
embodiments, the compound has the formula:
Figure imgf000100_0001
X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000100_0002
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000101_0001
. L1, R2, R20 z20, X3, and X4 are as described herein.
In embodiments, the compound has the formula:
Figure imgf000101_0002
R20, X3, and X4 are as described herein. In embodiments, R20 is halogen. In embodiments, R20 is -F. In embodiments, R20 is -CI. In embodiments, R20 is -Br. In embodiments, R20 is -I. In embodiments, R20 is -CN. In embodiments, R20 is -CH3. In embodiments, R20 is - CH2CH3. In embodiments, R20 is -OCH3. In embodiments, R20 is -OCH2CH3. In embodiments, R20 is -OCH2CH3. In embodiments, R20 is -CF3. In embodiments, R20 is - CH2CF3. In embodiments, R20 is -OCF3. In embodiments, R20 is -OCH2CF3. In
embodiments, the compound has the formula:
Figure imgf000101_0003
L1, R2, R20, X3, and X4 are as described herein. In embodiments, R20 is halogen. In embodiments, R20 is -F. In embodiments, R20 is -CI. In embodiments, R20 is -Br. In embodiments, R20 is -I. In embodiments, R20 is -CN. In embodiments, R20 is -CH3. In embodiments, R20 is -CH2CH3. In embodiments, R20 is -OCH3. In embodiments, R20 is -OCH2CH3. In embodiments, R20 is -CF3. In embodiments, R20 is -CH2CF3. In embodiments, R20 is -OCF3. In embodiments, R20 is -OCH2CF3. In embodiments, the compound has the formula:
Figure imgf000101_0004
L1, R2, R20 2, R20 3, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000102_0001
. L1, R2, R20 -1,
R20 3, X3, and X4 are as described herein. R20 -1, R20 2, and R20 3 may each independently be an R20 moiety. In embodiments, R20 1 is halogen. In embodiments, R20 1 is -F. In embodiments, R20 1 is -CI. In embodiments, R20 1 is -Br. In embodiments, R20 1 is -I. In embodiments, R20 1 is -CN. In embodiments, R20 1 is -CH3. In embodiments, R20 1 is -CH2CH3. In
embodiments, R20 1 is -OCH3. In embodiments, R20 1 is -OCH2CH3. In embodiments, R20 1 is -OCH2CH3. In embodiments, R20 1 is -CF3. In embodiments, R20 1 is -CH2CF3. In embodiments, R20 1 is -OCF3. In embodiments, R20 1 is -OCH2CF3. In embodiments, R20 2 is halogen. In embodiments, R20 2 is -F. In embodiments, R20 2 is -CI. In embodiments, R20 2 is -Br. In embodiments, R20 2 is -I. In embodiments, R20 2 is -CN. In embodiments, R20 2 is - CH3. In embodiments, R20 2 is -CH2CH3. In embodiments, R20 2 is -OCH3. In embodiments, R20 2 is -OCH2CH3. In embodiments, R20 2 is -OCH2CH3. In embodiments, R20 2 is -CF3. In embodiments, R20 2 is -CH2CF3. In embodiments, R20 2 is -OCF3. In embodiments, R20 2 is - OCH2CF3. In embodiments, R20 3 is halogen. In embodiments, R20 3 is -F. In embodiments, R20 3 is -CI. In embodiments, R20 3 is -Br. In embodiments, R20 3 is -I. In embodiments, R20 3 is -CN. In embodiments, R20 3 is -CH3. In embodiments, R20 3 is -CH2CH3. In
embodiments, R20 3 is -OCH3. In embodiments, R20 3 is -OCH2CH3. In embodiments, R20 3 is -OCH2CH3. In embodiments, R20 3 is -CF3. In embodiments, R20 3 is -CH2CF3. In embodiments, R20 3 is -OCF3. In embodiments R20 3 is -OCH2CF3. In embodiments, the
compound has the formula:
Figure imgf000102_0002
. L1, R2, R20 -1, R20
X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000103_0001
L1, R2, R20 2, R203 X3, and X4 are as described herein.
In embodiments, the compound has the formula:
Figure imgf000103_0002
R20, X3, and X4 are as described herein. In embodiments, R20 is independently halogen. In embodiments, two R20 on adjacent carbons are joined to form an unsubstituted C5 cycloalkyl. In embodiments, two R20 on adjacent carbons are joined to form a substituted C5 cycloalkyl. In embodiments, two R20 on adjacent carbons are joined to form an R21-substituted C5 cycloalkyl. In embodiments, two R20 on adjacent carbons are joined to form an unsubstituted 6 to 7 membered heterocycloalkyl. In embodiments, two R20 on adjacent carbons are joined to form a substituted 6 to 7 membered heterocycloalkyl. In embodiments, two R20 on adjacent carbons are joined to form an R21- substituted 6 to 7 membered heterocycloalkyl.
In embodiments, the compound has the formula:
Figure imgf000103_0003
. R2, R20, 3, and X4 are as described herein. In embodiments, the compound has the
formula:
Figure imgf000103_0004
. R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000104_0001
R , R z20, X , and X are as described herein. In
embodiments, the compound has the formula:
Figure imgf000104_0002
R2 R
X3, and X4 are as described herein. In embodiments, the compound has the formula: R
Figure imgf000104_0003
. R1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, R1 is -OCH3. In embodiments, R1 is unsubstituted C1-C3 alkoxy. In
embodiments, the compound has the formula:
Figure imgf000104_0004
L1, R2, R20 z20, X3, and X4 are as described herein. In embodiments, the compound has the
formula:
Figure imgf000104_0005
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000104_0006
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000105_0001
, R21, z21, X3, and X4 are as described herein. Each R may be same or different, and each z21 may be same or different. In
(R20)z20
2
embodiments, the compound has the formula:
Figure imgf000105_0002
L1, R2,
R , z20, X , and X are as described herein. In embodiments, the compound has the
formula:
Figure imgf000105_0003
, R20, z20, X3, and X4 are as described herein. In embodiments the compound has the formula:
Figure imgf000105_0004
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000105_0005
, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000106_0001
L
R , R , In embodiments, the compound has the
formula
Figure imgf000106_0002
. L1, R2, R20, z20, X3, and X4 are as described herein. Each R20 may be same or different, and each z20 may be same or different. In embodiments, the compound has the formula:
Figure imgf000106_0003
L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments the compound has the formula:
Figure imgf000106_0004
L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments the compound has the formula:
Figure imgf000106_0005
L1, R2, R20, z20, X3, and X4 are as described herein. Each R20 may be same or different and each 20 may be same or different. In embodiments, the compound has the formula:
Figure imgf000107_0001
iA
R , R , z embodiments, the compound has the
formula:
Figure imgf000107_0002
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000107_0003
L1, R2, R21, z21, X3, and X4 are as described herein.
Each R may be same or different, and each z21 may be same or different. In embodiments,
Figure imgf000107_0004
the compound has the formula: L1, R2, R20, z20,
X3 and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000107_0005
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000108_0001
, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000108_0002
L1, R2, R20C, X3, and X4 are as described herein. z20C is independently an integer from 0 to 5. In embodiments, 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:
Figure imgf000108_0003
, R20, z20, X3, and X4 are as described herein. In embodiments, the com ound has the formula:
Figure imgf000108_0004
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula: -C4 alkoxy)-(R20)z20
alkoxy)-(R20)z20
Figure imgf000109_0001
. L1, R2, R20, z20, X3, and X4 are as described herein. Each R20 may be same or different, and each z20 may be same or different.
Figure imgf000109_0002
In embodiments, the compound has the formula: X4 . L1,
R2, R20, z20 X3, and X4 are as described herein. In embodiments, the compound has the
formula:
Figure imgf000109_0003
. L1, R2, R20, z20, X3, and X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000109_0004
, R2, R20, z20, X3, and X4 are as described herein.
[0201] In embodiments, R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, substituted or
unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, unsubstituted Ci-C3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl. In embodiments, R2 is hydrogen.
[0202] In embodiments, R2 is independently -CX2 3. In embodiments, R2 is independently - CHX22. In embodiments, R2 is independently -CH2X2. In embodiments, R2 is
independently -OCX2 3. In embodiments, R2 is independently -OCH2X2. In embodiments, R2 is independently -OCHX22. In embodiments, R2 is independently -C(0)R2C. In embodiments, R2 is independently -C(0)OR2C. In embodiments, R2 is
independently -C(0) R2AR2B. In embodiments, R2 is independently -OR2D. In
embodiments, R2 is independently -OH. In embodiments, R2 is independently -COOH. In embodiments, R2 is independently -CO H2. In embodiments, R2 is independently -CF3. In embodiments, R2 is independently -CHF2. In embodiments, R2 is independently -CH2F. In embodiments, R2 is independently -OCF3. In embodiments, R2 is independently -OCH2F. In embodiments, R2 is independently -OCHF2. In embodiments, R2 is independently -OCH3. In embodiments, R2 is independently -OCH2CH3. In embodiments, R2 is independently - OCH2CH2CH3. In embodiments, R2 is independently -OCH(CH3)2. In embodiments, R2 is independently -OC(CH3)3. In embodiments, R2 is independently -CH3. In embodiments, R2 is independently -CH2CH3. In embodiments, R2 is independently -CH2CH2CH3. In embodiments, R2 is independently -CH(CH3)2. In embodiments, R2 is independently - C(CH3)3. In embodiments, R2 is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R2 is independently substituted C1-C4 alkyl. In embodiments, R2 is
independently unsubstituted C1-C4 alkyl.
[0203] In embodiments, R2 is independently
hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -C(0)R2C, -C(0)OR2C, -C( 0) R2AR2B, -OR2D, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0204] In embodiments, R2 is independently substituted or unsubstituted alkyl (e.g., Ci-C8,
Ci-C6, C1-C4, or C1-C2). In embodiments, R2 is independently substituted alkyl (e.g., Ci-C8,
Ci-C6, C1-C4, or C1-C2). In embodiments, R2 is independently unsubstituted alkyl (e.g., Ci-
C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2 is independently unsubstituted methyl. In embodiments, R2 is independently unsubstituted ethyl. In embodiments, R2 is independently unsubstituted propyl. In embodiments, R2 is independently unsubstituted isopropyl. In embodiments, R2 is independently unsubstituted tert-butyl. In embodiments, R2 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, R2 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). In embodiments, R2 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). In embodiments, R2 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2 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). In embodiments, R2 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, R2 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, R2 is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2 is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2 is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2 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, R2 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, R2 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0205] In embodiments, R2A is independently hydrogen. In embodiments, R2A is independently -CX2A3. In embodiments, R2A is independently -CHX2A 2. In embodiments, R2A is independently -CH2X2A. In embodiments, R2A is independently -CN. In
embodiments, R2A is independently -COOH. In embodiments, R2A is
independently -CO H2. In embodiments, X2A is independently -F, -CI, -Br, or -I.
[0206] In embodiments, R2A is independently substituted or unsubstituted alkyl (e.g., Ci-
C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R2A is independently substituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R2A is independently unsubstituted alkyl
(e.g., Ci-C8, Ci-C6, C1-C4, or Ci-C2). In embodiments, R2A is independently unsubstituted methyl. In embodiments, R2A is independently unsubstituted ethyl. In embodiments, R2A is independently unsubstituted propyl. In embodiments, R2A is independently unsubstituted isopropyl. In embodiments, R is independently unsubstituted tert-butyl. In embodiments, R2A 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, R2A 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). In embodiments, R2A 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). In embodiments, R2A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2A is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2A 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). In embodiments, R2A 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, R2A 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, R2A is
independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2A is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2A is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2A 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, R2A 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, R2A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered).
[0207] In embodiments, R2B is independently hydrogen. In embodiments, R2B is independently -CX2B3. In embodiments, R2B is independently -CHX2B2. In embodiments, R2B is independently -CH2X2B. In embodiments, R2B is independently -CN. In embodiments, R2B is independently -COOH. In embodiments, R2B is independently -CO H2. In
embodiments, X2B is independently -F, -CI, -Br, or -I.
[0208] In embodiments, R2B is independently substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-C6, C1-C4, or C1-C2). In embodiments, R2B is independently substituted alkyl (e.g., Ci-Cs, Ci-C6, C1-C4, or C1-C2). In embodiments, R2B is independently unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R is independently unsubstituted methyl. In embodiments, R2B is independently unsubstituted ethyl. In embodiments, R2B is
independently unsubstituted propyl. In embodiments, R2B is independently unsubstituted isopropyl. In embodiments, R2B is independently unsubstituted tert-butyl. In embodiments, R2B 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, R2B 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). In embodiments, R2B 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). In embodiments, R2B is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2B is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2B 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). In embodiments, R2B 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, R2B 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, R2B is
independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2B is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2B is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2B 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, R2B 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, R2B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered).
[0209] In embodiments, R2A and R2B 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). In embodiments, R2A and R2B 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). In embodiments, 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).
[0210] In embodiments, R2A and R2B 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). In embodiments, R2A and R2B
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). In embodiments, R2A and R2B 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).
[0211] In embodiments, R2C is independently hydrogen. In embodiments, R2C is independently -CX2C 3. In embodiments, R2C is independently -CHX2C2. In embodiments, R2C is independently -CIHhX20. In embodiments, R2C is independently -CN. In embodiments, R2C is independently -COOH. In embodiments, R2C is independently -CO H2. In
embodiments, X2C is independently -F, -CI, -Br, or -I.
[0212] In embodiments, R2C is independently substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2C is independently substituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2C is independently unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2C is independently unsubstituted methyl. In embodiments, R2C is independently unsubstituted ethyl. In embodiments, R2C is
independently unsubstituted propyl. In embodiments, R2C is independently unsubstituted isopropyl. In embodiments, R2C is independently unsubstituted tert-butyl. In embodiments, R2C 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, R2C 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). In embodiments, R2C 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). In embodiments, R2C is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6). In embodiments, R2C is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-G5). In embodiments, 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). In embodiments, R2C 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, R2C 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, R2C is
independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2C is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2C is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2C 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, R2C 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, R2C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered).
[0213] In embodiments, R2D is independently hydrogen. In embodiments, R2D is independently -CX2D 3. In embodiments, R2D is independently -CHX2D2. In embodiments, R2D is independently -CIHhX20. In embodiments, R2D is independently -CN. In
embodiments, R2D is independently -COOH. In embodiments, R2D is
independently -CO H2. In embodiments, X2D is independently -F, -CI, -Br, or -I.
[0214] In embodiments, R2D is independently substituted or unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2D is independently substituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2D is independently unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2). In embodiments, R2D is independently unsubstituted methyl. In embodiments, R2D is independently unsubstituted ethyl. In embodiments, R2D is independently unsubstituted propyl. In embodiments, R2D is independently unsubstituted isopropyl. In embodiments, R2D is independently unsubstituted tert-butyl. In embodiments, R2D 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, R2D 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). In embodiments, R2D 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). In embodiments, R2D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R2D 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). In embodiments, R2D 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, R2D 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, R2D is
independently substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2D is independently substituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2D is independently unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl). In embodiments, R2D 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, R2D 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, R2D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
membered).
[0215] In embodiments, R2 is independently
hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -OH, -COOH, -CO H2, - C(0)R23, R23-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or C1-C2), R23- 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), R23 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R23 -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), R23-substituted or unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or R23-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, R2 is independently hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -OH, -COOH, -CO H2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-G5, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X2 is independently -F, -CI, -Br, or -I. In embodiments, R2 is independently hydrogen. In embodiments, R2 is independently unsubstituted methyl. In embodiments, R2 is
independently unsubstituted ethyl.
[0216] R23 is independently oxo,
halogen, -CX23 3, -CHX23 2, -CH2X23, -OCX23 3, -OCH2X23, -OCHX23 2, -CN, -OH, - H2, -CO OH, -CO H2, -NO2, -SH, -S03H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HSO2H, - HC=(0)H, - HC(0)-OH, -NHOH, R24-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R24-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), R24-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C6), R24-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), R24-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R24-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, R23 is independently oxo,
halogen, -CX23 3, -CHX23 2, -CH2X23, -OCX23 3, -OCH2X23, -OCHX23 2, -CN, -OH, -NH2, -COO H, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X23 is independently - F, -CI, -Br, or -I. In embodiments, R23 is independently unsubstituted methyl. In
embodiments, R23 is independently unsubstituted ethyl.
[0217] R24 is independently oxo,
halogen, -CX24 3, -CHX24 2, -CH2X24, -OCX24 3, -OCH2X24, -OCHX24 2, -CN, -OH, -NH2, -COO H, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-OH, -NHOH, R25 -substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R -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), R25-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C6), R25-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), R25-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R25-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, R24 is independently oxo,
halogen, -CX24 3, -CHX24 2, -CH2X24, -OCX24 3, -OCH2X24, -OCHX24 2, -CN, -OH, - H2, -COO H, -CO H2, -NO2, -SH, -S03H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) NH2, - HSO2H, - HC= (O)H, - HC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X24 is independently - F, -CI, -Br, or -I. In embodiments, R24 is independently unsubstituted methyl. In
embodiments, R24 is independently unsubstituted ethyl. [0218] R25 is independently oxo,
halogen, -CX25 3, -CHX25 2, -CH2X25, -OCX25 3, -OCH2X25, -OCHX25 2, -CN, -OH, -NH2, -COO H, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, -NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X25 is independently - F, -CI, -Br, or -I. In embodiments, R25 is independently unsubstituted methyl. In
embodiments, R25 is independently unsubstituted ethyl. [0219] In embodiments, R is independently
hydrogen, -CX2A 3, -CHX2A 2, -CH2X2A, -CN, -COOH, -CO H2, R23A-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R23A-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), R23A-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R23A-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), R23A-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R23A-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, R2A is independently
hydrogen, -CX2A 3, -CHX2A 2, -CH2X2A, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X2A is independently -F, -CI, -Br, or -I. In embodiments, R2A is independently hydrogen. In embodiments, R2A is independently unsubstituted methyl. In embodiments, R2A is independently unsubstituted ethyl. In embodiments, R2A is R23A-substituted or unsubstituted C1-C4 alkyl. In
embodiments, R2A is R23A-substituted C1-C4 alkyl. In embodiments, R2A is unsubstituted Ci- C4 alkyl.
[0220] In embodiments, R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a R23A-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
R23A-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, R2A and R2B 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). In embodiments, R2A and R2B substituents bonded to the same nitrogen atom may optionally be j oined to form a R23A-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). In embodiments, 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).
[0221] R23A is independently oxo,
halogen, -CX23A 3, -CHX23A 2, -CH2X23A, -OCX23A 3, -OCH2X23A, -OCHX23A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R24A- substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R24A- 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), R24A- substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R24A-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), R24A-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R24A- 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, R23A is
independently oxo,
halogen, -CX23A 3, -CHX23A 2, -CH2X23A, -OCX23A 3, -OCH2X23A, -OCHX23A 2 (e.g. -F, CI, -Br, -I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-
CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X23A is independently -F, -CI, -Br, or -I. In embodiments, R23A is independently unsubstituted methyl. In embodiments, R23A is independently unsubstituted ethyl. [0222] R24A is independently oxo,
halogen, -CX24A 3, -CHX24A 2, -CH2X24A, -OCX24A 3, -OCH2X24A, -OCHX24A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - S04H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R25A-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or Ci-C2), R25A-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), R25A-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R25A-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), R25A-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R25A-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, R24A is
independently oxo,
halogen, -CX24A 3, -CHX24A 2, -CH2X24A, -OCX24A 3, -OCH2X24A, -OCHX24A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X24A is independently -F, -CI, -Br, or -I. In embodiments, R24A is independently unsubstituted methyl. In embodiments, R24A is independently unsubstituted ethyl. [0223] R25A is independently oxo,
halogen, -CX25A 3, -CHX25A 2, -CH2X25A, -OCX25A 3, -OCH2X25A, -OCHX25A 2 (e.g. -F, CI, -Br, -I, -CF3, -CCb, -CBr3, -Cb, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHC , -OCHBr2, -OCHI2, -OCH2F, - OCH2B1-, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X25A is independently -F, -CI, -Br, or -I. In embodiments, R25A is independently unsubstituted methyl. In embodiments, R25A is independently unsubstituted ethyl.
[0224] In embodiments, R2B is independently
hydrogen, -CX2B 3, -CHX2B 2, -CH2X2B, -CN, -COOH, -CONH2, R23B-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R23B-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), R23B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R23B- 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), R23B-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R23B-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, R2B is independently
hydrogen, -CX2B 3, -CHX2B 2, -CH2X2B, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X2B is independently -F, -CI, -Br, or -I. In embodiments, R2B is independently hydrogen. In embodiments, R2B is independently unsubstituted methyl. In embodiments, R2B is independently unsubstituted ethyl. [0225] In embodiments, R and R substituents bonded to the same nitrogen atom may optionally be joined to form a R23B-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 R23B-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, R2A and R2B 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). In embodiments, R2A and R2B substituents bonded to the same nitrogen atom may optionally be j oined to form a R23B- 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). In embodiments, R2A and R2B 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). [0226] R23B is independently oxo,
halogen, -CX23B 3, -CHX23B 2, -CH2X23B, -OCX23B 3, -OCH2X23B, -OCHX23B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -
NHC= (O)H, -NHC(0)-OH, -NHOH, R24B-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R24B-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), R24B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R24B- 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), R24B-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R24B-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, R23B is
independently oxo,
halogen, -CX23B 3, -CHX23B 2, -CH2X23B, -OCX23B 3, -OCH2X23B, -OCHX23B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCb, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - S04H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X23B is independently -F, -CI, -Br, or -I. In embodiments, R23B is independently unsubstituted methyl. In embodiments, R23B is independently unsub stituted ethyl .
[0227] R24B is independently oxo,
halogen, -CX24B 3, -CHX24B 2, -CH2X24B, -OCX24B 3, -OCH2X24B, -OCHX24B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R25B-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R25B-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), R25B-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R25B-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), R25B-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R25B-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, R24B is
independently oxo,
halogen, -CX24B 3, -CHX24B 2, -CH2X24B, -OCX24B 3, -OCH2X24B, -OCHX24B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X24B is independently -F, -CI, -Br, or -I. In embodiments, R24B is independently unsubstituted methyl. In embodiments, R24B is independently unsubstituted ethyl.
[0228] R25B is independently oxo,
halogen, -CX25B 3, -CHX25B 2, -CH2X25B, -OCX25B 3, -OCH2X25B, -OCHX25B 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -
OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X25B is independently -F, -CI, -Br, or -I. In embodiments, R25B is independently unsubstituted methyl. In embodiments, R25B is independently unsubstituted ethyl. In embodiments, R25B is unsubstituted C1-C4 alkyl.
[0229] In embodiments, R2C is independently
hydrogen, -CX2C 3, -CHX2C 2, -CH2X2C, -CN, -COOH, -CONH2, R23C-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R23C-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), R23C-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R23C-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), R23C-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R23C-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, R2C is independently
hydrogen, -CX2C 3, -CHX2C 2, -CH2X2C, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X2C is independently -F, -CI, -Br, or -I. In embodiments, R2C is independently hydrogen. In embodiments, R2C is independently unsubstituted methyl. In embodiments, R2C is independently unsubstituted ethyl. In embodiments, R2C is R23C-substituted or unsubstituted C1-C4 alkyl. In
embodiments, R2C is R23C-substituted C1-C4 alkyl. In embodiments, R2C is unsubstituted Ci- C4 alkyl.
[0230] R23C is independently oxo,
halogen, -CX23C 3, -CHX23C 2, -CH2X23C, -OCX23C 3, -OCH2X23C, -OCHX23C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, -
OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R24C-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R24C-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), R24C-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R24C-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), R24C-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R24C-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, R23C is
independently oxo,
halogen, -CX23C 3, -CHX23C 2, -CH2X23C, -OCX23C 3, -OCH2X23C, -OCHX23C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCb,-CHBr2,-CHl2,-CH2F, -CH2CI, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X23C is independently -F, -CI, -Br, or -I. In embodiments, R23C is independently unsubstituted methyl. In embodiments, R23C is independently unsubstituted ethyl.
[0231] R24C is independently oxo,
halogen, -CX24C 3, -CHX24C 2, -CH2X24C, -OCX24C 3, -OCH2X24C, -OCHX24C 2 (e.g. -F, CI, -Br, - I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R25C-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or Ci-C2), R25C-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), R25C-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R25C-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), R25C-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- Cio, or phenyl), or R25C-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, R24C is
independently oxo,
halogen, -CX24C 3, -CHX24C 2, -CH2X24C, -OCX24C 3, -OCH2X24C, -OCHX24C 2 (e.g. -F, CI, -Br, - I, -CF3, -CCI3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCI3, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, -
OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X is independently -F, -CI, -Br, or -I. In embodiments, R24C is independently unsubstituted methyl. In embodiments, R24C is independently unsubstituted ethyl.
[0232] R25C is independently oxo,
halogen, -CX25C 3, -CHX25C 2, -CH2X25C, -OCX25C 3, -OCH2X25C, -OCHX25C 2 (e.g. -F, CI, -Br, - I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br ,-CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCb, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X25C is independently -F, -CI, -Br, or -I. In embodiments, R25C is independently unsubstituted methyl. In embodiments, R25C is independently unsubstituted ethyl.
[0233] In embodiments, R2D is independently
hydrogen, -CX2D 3, -CHX2D 2, -CH2X2D, -CN, -COOH, -CONH2, R23D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), R23D-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), R23D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R23D-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), R23D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or R23D-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, R2D is independently
hydrogen, -CX2D 3, -CHX2D 2, -CH2X2D, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X2D is independently -F, -CI, -Br, or -I. In embodiments, R2D is independently hydrogen. In embodiments, R2D is independently unsubstituted methyl. In embodiments, R2D is independently unsubstituted ethyl. In embodiments, R2D is R23D-substituted or unsubstituted C1-C4 alkyl. In
embodiments, R2D is R23D-substituted C1-C4 alkyl. In embodiments, R2D is unsubstituted Ci- C4 alkyl.
[0234] R23D is independently oxo,
halogen, -CX23D 3, -CHX23D 2, -CH2X23D, -OCX23D 3, -OCH2X23D, -OCHX23D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, R24D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or C1-C2), R24D-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), R24D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R24D-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), R24D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R24D-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, R23D is
independently oxo,
halogen, -CX23D 3, -CHX23D 2, -CH2X23D, -OCX23D 3, -OCH2X23D, -OCHX23D 2 (e.g. -F, CI, -Br, -I, -CF3, -CC13, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHI2 -CH2F, -CH2CI, -CH2Br ,-
CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X23D is independently -F, -CI, -Br, or -I. In embodiments, R23D is independently unsubstituted methyl. In embodiments, R23D is independently unsubstituted ethyl. [0235] R24D is independently oxo,
halogen, -CX24D 3, -CHX24D 2, -CH2X24D, -OCX24D 3, -OCH2X24D, -OCHX24D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - S04H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, -
NHC= (O)H, -NHC(0)-OH, -NHOH, R25D-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci- C6, C1-C4, or Ci-C2), R25D-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), R25D-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C5, or C5-C6), R25D-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), R25D-substituted or unsubstituted aryl (e.g., C6-Ci2, C6- C10, or phenyl), or R25D-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, R24D is
independently oxo,
halogen, -CX24D 3, -CHX24D 2, -CH2X24D, -OCX24D 3, -OCH2X24D, -OCHX24D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2 ,-CHI2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2Cl, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X24D is independently -F, -CI, -Br, or -I. In embodiments, R24D is independently unsubstituted methyl. In embodiments, R24D is independently unsubstituted ethyl. [0236] R25D is independently oxo,
halogen, -CX25D 3, -CHX25D 2, -CH2X25D, -OCX25D 3, -OCH2X25D, -OCHX25D 2 (e.g. -F, CI, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2,-CHBr2,-CHl2,-CH2F, -CH2C1, -CH2Br - CH2I, -OCF3, -OCCb, -OCBr3, -OCI3, -OCHF2, -OCHCI2, -OCHBr2, -OCHI2, -OCH2F, - OCH2Br, -OCH2CI, or -OCH2I), -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHSO2H, - NHC=(0)H, -NHC(0)-OH, -NHOH, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci- C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, C6-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X25D is independently -F, -CI, -Br, or -I. In embodiments, R25D is independently unsubstituted methyl. In embodiments, R25D is independently unsub stituted ethyl .
[0237] In embodiments, the compound has the formula:
Figure imgf000131_0001
. R1, X3, X4 are as described herein. In embodiments, R1 is independently R20-sub stituted 5 membered heteroaryl. In embodiments, R1 is independently R20-sub stituted 6 membered heteroaryl. In embodiments, R1 is independently R20-substituted pyridyl. In embodiments, R1 is independently R20-sub stituted 2-pyridyl. In embodiments, R1 is independently R20- substituted 3-pyridyl. In embodiments, R1 is independently R20-substituted 4-pyridyl. In embodiments, R1 is independently R20-substituted pyridazinyl. In embodiments, R1 is independently R20-sub stituted pyrimidinyl. In embodiments, R1 is independently R20- substituted pyrazinyl. In embodiments, R1 is independently R20-substituted triazinyl. In embodiments, R1 is independently R20-substituted pyrrolyl. In embodiments, R1 is independently R20-sub stituted 2-pyrrolyl. In embodiments, R1 is independently R20- substituted 3-pyrrolyl. In embodiments, R1 is independently R20-substituted furanyl. In embodiments, R1 is independently R20-substituted 2-furanyl. In embodiments, R1 is independently R20-sub stituted 3-furanyl. In embodiments, R1 is independently R20- substituted thienyl. In embodiments, R1 is independently R20-substituted 2-thienyl. In embodiments, R1 is independently R20-substituted 3- thienyl. In embodiments, R1 is independently R20-substituted pyrazolyl. In embodiments, R1 is independently R20- substituted isoxazolyl. In embodiments, R1 is independently R20-substituted isothiazolyl. In embodiments, R1 is independently R20-substituted imidazolyl. In embodiments, R1 is independently R20-substituted oxazolyl. In embodiments, R1 is independently R20-substituted thiazolyl. In embodiments, R1 is independently R20-substituted phenyl. In embodiments, R1 is independently R20-substituted biphenyl. In embodiments, R1 is independently R20- substituted 2-biphenyl. In embodiments, R1 is independently R20-substituted 3-biphenyl. In embodiments, R1 is independently R20-substituted 4-biphenyl. In embodiments, the
compound has the formula:
Figure imgf000132_0001
. R1 X3, X4 are as described herein. In
embodiments, the compound has the formula:
Figure imgf000132_0002
R1, X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000132_0003
R1, X3, X4 are as described herein. In embodiments, the
compound has the formula:
Figure imgf000132_0004
. R1, X3, X4 are as described herein. In
embodiments, the compound has the formula
Figure imgf000132_0005
. R1, X3, X4 are as described herein. In embodiments, the compound has the
Figure imgf000133_0001
R1 X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000133_0002
R X , X are as described herein. In embodiments, the compound
has the formula:
Figure imgf000133_0003
R1, X3, X4 are as described herein. In
embodiments, the compound has the formula:
Figure imgf000133_0004
R1, X3, X4 are as described herein. In embodiments, the compound has the formula:
Figure imgf000133_0005
. R , X , X are as described herein. In embodiments, the
compound has the formula:
Figure imgf000133_0006
R1 X3, X4 are as described
herein. In embodiments, the compound has the formula:
Figure imgf000133_0007
R X3, X4 are as described herein.
[0238] In embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X1 is -F. In embodiments, X1 is -CI. In embodiments, X1 is -Br. In embodiments, X1 is -I. In embodiments, X2 is -F. In embodiments, X2 is -CI. In embodiments, X2 is -Br. In embodiments, X2 is -I. In embodiments, X3 is -F. In embodiments, X3 is -CI. In embodiments, X3 is -Br. In embodiments, X3 is -I. In embodiments, X4 is -F. In embodiments, X4 is -CI. In embodiments, X4 is -Br. In embodiments, X4 is -I. In embodiments, X3 and X4 are independently -CI or -Br. In embodiments, X3 and X4 are -CI. In embodiments, X4 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.
[0239] In embodiments, X3 and X4 are independently halogen, -CCI3, -CBr3, -CF3, -CI3, CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, - H2,
-COOH, -CO H2, -NO2, -SH, -OCCb, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, or -OCH2F. In embodiments, X3 and X4 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). In embodiments, X3 and X4 are independently -CH3.
[0240] In embodiments, the compound has the formula:
Figure imgf000134_0001
R1 and R2 are
as described herein. In embodiments, the compound has the formula:
Figure imgf000134_0002
. R1 and R2 are as described herein. In embodiments, the compound has the formula:
Figure imgf000134_0003
R1 and R2 are as described herein. In embodiments, the compound has the formula:
Figure imgf000135_0001
R1 and R2 are as described herein.
In embodiments, the compound has the formula:
Figure imgf000135_0002
R1 and R2 are as
R2
0Ι ^ Νγ Ν γ ρ1 N^ N R17 described herein. In embodiments, the compound has the formula CI
R1 and R2 are as described herein. In embodiments, the compound has the formula
R2
Figure imgf000135_0003
. R1 and R2 are as described herein. In embodiments, the compound
R2
CI ΝγNYΝ "Y R17"R1 has the formula: CI . R1 and R2 are as described herein. In
embodiments, the compound has the formula:
Figure imgf000135_0004
R1 and R2 are as described herein. In embodiments, the compound has the formula:
Figure imgf000135_0005
. R1 and R2 are as described herein. In embodiments, the γ Ν compound has the formula: CI R1 and R2 are as described
herein. In embodiments, the compound has the formula:
Figure imgf000136_0001
and R2 are as described herein. In embodiments, the compound has the formula:
Figure imgf000136_0002
. R1 and R2 are as described herein. [0241] In embodiments, 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.
[0242] In embodiments, the compound has the formula:
Figure imgf000136_0003
R2, X3, X4, L1, R20 and z20 are as described herein.
[0243] In embodiments, L1 is a bond. In embodiments, L1 is a unsubstituted C1-C2 alkylene. In embodiments, L1 is a unsubstituted phenylene.
[0244] In embodiments, the compound has a formula:
as described herein.
Figure imgf000136_0004
[0245] In embodiments, R2 is hydrogen.
[0246] In embodiments, the compound has a formula:
Figure imgf000137_0001
(IV). R2, X3, X4, R20 and z20 are as described herein. 0247] In embodiments, the compound has a formula:
Figure imgf000137_0002
)z20 (V). R2, X3, X4, R20 and z20 are as described herein.
[0248] In embodiments, X3 and X4 are each independently -Br, -F, or -CI. In
embodiments, z20 is 0, 1, 2 or 3. In embodiments, R20
is -Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, or -OCH2CH3
[0249] In embodiments, z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 1 and R20 is halogen. In embodiments, z20 is 1 and R20 is -F. In embodiments, z20 is 1 and R20 is -CI. In embodiments, z20 is 1 and R20 is -Br. In embodiments, z20 is 1 and R20 is -I. In embodiments, z20 is 1 and R20 is -CN. In embodiments, z20 is 1 and R20 is -N02. In embodiments, z20 is 1 and R20 is -CF3. In embodiments, z20 is 1 and R20 is -CH3. In embodiments, z20 is 1 and R20 is -CH2CH3. In embodiments, z20 is 1 and R20 is OH, -OCH3. In embodiments, z20 is 1 and R20 is and -OCH2CH3.
[0250] In formula (II) and (III), X3 and X4 are independently -CI or -Br. In embodiments, X3 and X4 are-Cl. In embodiments, X3 and X4 are independently -Br. In embodiments, X3 is -CI and X4 is -Br. In embodiments, X3 is -Br and X4 is -CI.
[0251] In embodiments, the compound is
Figure imgf000137_0003
Figure imgf000138_0001
In embodiments, the compound is
in embodiments, the compound is
Figure imgf000138_0002
[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
KEA1-48. In embodiments, the compound is KEAl-50. In embodiments, the compound is
KEA1-88. In embodiments, the compound is KEAl-62. In embodiments, the compound is
KEA1-94. In embodiments, the compound is KEAl-69. In embodiments, the compound is
KEA1-46. In embodiments, the compound is KEAl-90. In embodiments, the compound is
KEA1-55. In embodiments, the compound is KEAl-37. In embodiments, the compound is
KEA1-91. In embodiments, the compound is KEAl-64. In embodiments, the compound is
KEA1-75. In embodiments, the compound is KEAl-72. In embodiments, the compound is
KEA1-61. In embodiments, the compound is KEAl-59. In embodiments, the compound is
KEA1-76. In embodiments, the compound is KEAl-80. In embodiments, the compound is
KEA1-77. In embodiments, the compound is KEAl-57. In embodiments, the compound is
KEA1-49. In embodiments, the compound is KEAl-43. In embodiments, the compound is
KEA1-95. In embodiments, the compound is KEAl-78. In embodiments, the compound is
KEA1-54. In embodiments, the compound is KEAl-73. In embodiments, the compound is
KEA1-23. In embodiments, the compound is KEAl-70. In embodiments, the compound is
KEA1-36. In embodiments, the compound is KEAl-67. In embodiments, the compound is
KEA1-42. In embodiments, the compound is KEAl-79. In embodiments, the compound is
KEA1-39. In embodiments, the compound is KEAl-38. In embodiments, the compound is
KEA1-22. In embodiments, the compound is KEAl-56. In embodiments, the compound is
KEA1-32. In embodiments, the compound is KEAl-40. In embodiments, the compound is
KEA1-58. In embodiments, the compound is KEAl-85. In embodiments, the compound is
KEA1-68. In embodiments, the compound is KEAl-45. In embodiments, the compound is
KEAl-53. In embodiments, the compound is KEAl-63. In embodiments, the compound is
KEA1-47. In embodiments, the compound is KEAl-74. In embodiments, the compound is
KEA1-41. In embodiments, the compound is KEAl-30. In embodiments, the compound is
KEA1-98. In embodiments, the compound is KEAl-60. In embodiments, the compound is
KEA1-31. In embodiments, the compound is KEAl-71. In embodiments, the compound is
KEA1-84. In embodiments, the compound is KEAl-93. In embodiments, the compound is KEA1-81.
[0253] In some embodiments, a compound as described herein may include multiple instances of R20 or R23, and/or other variables. In such embodiments, each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each R and/or R , is different, they may be referred to, for example, as R20 1, R20 2, R20 3, R20 4, R20 5, R23 R23 2, R23 3, R23 4, or R23 5, respectively, wherein the definition of R20 is assumed by R20 1, R20 2, R20 3, R20 4, R20 5; and/or R23 is assumed by R23 R23 2, R23 3, R23 4, R23 5. The variables used within a definition of R20 and/or R23, and/or other variables that appear at multiple instances and are different may similarly be appropriately labeled to distinguish each group for greater clarity. In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure).
[0254] In embodiments, unless otherwise indicated, 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).
[0255] In an aspect is provided a Caspase 3 inhibitor. In embodiments, the Thioredoxin inhibitor is a compound described herein. In embodiments, 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). In embodiments, the Caspase 3 inhibitor contacts one or more amino acids corresponding to K72 of human thioredoxin. In embodiments, the Caspase 3 inhibitor covalently binds an amino acid corresponding to K72 in human thioredoxin. In embodiments, 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. In embodiments, modulation of the contact between thioredoxin and Caspase 3 reduces inhibition of Caspase 3 activity by thioredoxin. In embodiments, 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).
[0256] In embodiments, the compound is a compound described herein, including in an aspect, embodiment, claim, figure, table, example, or scheme.
[0257] In embodiments, -I^-R1 is not unsubstituted unsaturated alkyl. In embodiments, - I^-R1 is not unsubstituted C2-C6 unsaturated alkyl. In embodiments, -I^-R1 is not
unsubstituted C2-C5 unsaturated alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C4 unsaturated alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C3 unsaturated alkyl. In embodiments, -L -R is not embodiments, -L -R is not
Figure imgf000141_0001
. In em o ments, -L -R s not embodiments, -I^-R1 is not ^ 4 . In embodiments, -I^-R1 is not-(CH2)4CCH. In embodiments, -I^-R1 is not -(CH2)3CCH. In embodiments, -I^-R1 is not -(CH2)2CCH. In embodiments, -I^-R1 is not -CH2CCH. In embodiments, -I^-R1 is not -CCH. In
embodiments, -I^-R1 is not ethynyl.In embodiments, -I^-R1 is not 1-propynyl. In
embodiments, -I^-R1 is not 3-propynyl. In embodiments, -I^-R1 is not 3-butynyl. In
CI
N^N embodiment, the compound is not H . In embodiment, the compound is not
CI CI
N^N N^N
N ΛNΑ.C.I ^ [NλNλCI
H . In embodiment, the compound is not H In
embodiment, the compound is not
Figure imgf000141_0002
In embodiment, the compound is not
CI
N^N
N^^N^^CI
4 H . In embodiments, -I^-R1 is not-(CH2)4CCR20. In embodiments, -I^-R1 is not -(CH2)3CCR20. In embodiments, -I^-R1 is not -(CH2)2CCR20. In embodiments, -I^-R1 is not -CH2CCR20. In embodiments, -I^-R1 is not -CCR20. In embodiments, -R1 is not - CCR20. In embodiments, -I^-R1 is not unsubstituted alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C6 alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C5 alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C4 alkyl. In embodiments, -I^-R1 is not unsubstituted C2-C3 alkyl.
[0258] In embodiments, 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
embodiments, 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
embodiments, 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
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 KEA1-36. In
embodiments, 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
embodiments, 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.
III. Pharmaceutical compositions
[0259] In an aspect is provided a pharmaceutical composition including a thioredoxin inhibitor and a pharmaceutically acceptable excipient. In embodiments, the thioredoxin inhibitor is a compound described herein. In embodiments, 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). In embodiments, the thioredoxin inhibitor is included in a therapeutically effective amount.
[0260] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0261] In embodiments of the pharmaceutical compositions, the compound, or
pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount.
[0262] In embodiments of the pharmaceutical compositions, 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
pharmaceutical compositions, the second agent is an agent for treating cancer. In
embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-cancer agent for treating breast cancer. In embodiments, 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 everolimus. IV. Methods of Treatment
[0263] In an aspect is provided a method of treating cancer, the method 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. In embodiments, 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). In embodiments, the thioredoxin inhibitor is included in a therapeutically effective amount. [0264] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein. In
embodiments, 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. In embodiments, 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. In embodiments, 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. In embodiments, 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. In embodiments, 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). In embodiments, the disease is associated with aberrant thioredoxin activity.
[0266] In embodiments, 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.
[0267] In embodiments, 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. In embodiments, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In
embodiments, the second agent is a chemotherapeutic. In embodiments, 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.
V. Methods of Inhibition
[0268] In an aspect is provided a method of inhibiting thioredoxin activity including contacting the thioredoxin with a thioredoxin inhibitor. In embodiments, the thioredoxin is a human thioredoxin. In embodiments, the thioredoxin inhibitor is a compound described herein. In embodiments, 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). In embodiments, the thioredoxin inhibitor is provided in a therapeutically effective amount. In embodiments, the thioredoxin inhibitor contacts an amino acid corresponding to K72 of SEQ ID NO: 1.
[0269] In embodiments, 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. In embodiments, 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.
[0270] In embodiments, 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). In embodiments, 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. [0271] In an aspect is provided a method of inhibiting thioredoxin activity including contacting the thioredoxin with a compound described herein. In embodiments, the thioredoxin is a human thioredoxin. In embodiments, the compound is provided in an effective amount. In embodiments, the compound is provided in a therapeutically effective amount. In embodiments, the method includes contacting the thioredoxin protein with an effective amount of a compound described herein. In embodiments, compound is covalently bonded to the amino acid corresponding to K72 of human thioredoxin (e.g., SEQ ID NO: l). In embodiments, the compound contacts an amino acid corresponding to K72 of human thioredoxin (e.g., SEQ ID NO: l).
[0272] In as aspect is provided a method of increasing Caspase 3 protein activity, the method including contacting a thioredoxin protein with a compound described herein. In embodiments, the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1. In embodiments, the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1. In embodiments, the method does not include inhibiting (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, each at about 1, 2, 3, 4, 5,6 7, 8, 9, 10, 20, 30, 40, 50 , 60, 70, 80, 90, or 100 micromolar compound) thioredoxin associated reduction of a protein activity or function (e.g., compared to control such as absence of the compound).
[0273] In as aspect is provided a method of increasing apoptosis of a cell, the method including contacting the cell with a compound described herein. In embodiments, the compound contacts a thioredoxin in the cell. In embodiments, the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1. In embodiments, the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1. In embodiments, the method includes increasing Caspase 3 protein activity in the cell (e.g., compared to control such as absence of the compound). In embodiments, the method does not include inhibiting (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, each at about 1, 2, 3, 4, 5,6 7, 8, 9, 10, 20, 30, 40, 50 , 60, 70, 80, 90, or 100 micromolar compound) thioredoxin associated reduction of a protein activity or function (e.g., compared to control such as absence of the compound).
[0274] In embodiments, the inhibition is competitive inhibition. In embodiments, the inhibition is irreversible. In embodiments, the inhibition is reversible.
[0275] Where the compound covalently binds to the thioredoxin protein, a thioredoxin protein (e.g., SEQ ID NO: 1) covalently bonded to a thioredoxin inhibitor is formed (also referred to herein as a "thioredoxin -compound adduct"), as described below. In
embodiments, the resulting covalent bond is reversible. Where the resulting covalent bond is reversible, the bonding reverses upon denaturation of the protein. Thus, in embodiments, the reversibility of a covalent bond between the compound and the thioredoxin upon denaturation of the thioredoxin avoids or decreases autoimmune response in a subject subsequent to administration of the compound (relative to irreversibility). Moreover, in embodiments, the reversibility of a covalent bond between the compound and the thioredoxin upon denaturation of the thioredoxin avoids or decreases the toxicity (e.g. liver toxicity) of the compound in a subject (relative to irreversibility). VI. Thioredoxin protein
[0276] In an aspect is provided a thioredoxin protein covalently bonded to a thioredoxin inhibitor (a thioredoxin protein-thioredoxin inhibitor complex). In embodiments, the thioredoxin is a human thioredoxin. In embodiments, the thioredoxin inhibitor is a compound described herein. In embodiments, 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). In embodiments, the thioredoxin inhibitor is provided in a therapeutically effective amount. In embodiments, the thioredoxin inhibitor contacts an amino acid of SEQ ID NO: 1. In embodiments, the thioredoxin inhibitor contacts an amino acid corresponding to K72 of SEQ ID NO: 1. In embodiments, the
Thioredoxin inhibitor covalently binds an amino acid corresponding to K72 in SEQ ID NO: l . [0277] In an aspect is provided a thioredoxin protein covalently bonded to a compound described herein. In embodiments, compound is covalently bonded an amino acid of SEQ ID NO: 1. In embodiments, compound is covalently bonded to the amino acid corresponding to K72 of SEQ ID NO: 1.
[0278] In embodiments, the compound is bonded to a lysine residue of the thioredoxin protein. In embodiments, the compound is covalently bonded to a lysine residue of the thioredoxin protein. In embodiments, the compound is reversibly covalently bonded to a lysine residue of the thioredoxin protein. In embodiments, the compound is irreversibly covalently bonded to a lysine residue of the thioredoxin protein. In embodiments, the lysine residue corresponds to K72 of SEQ ID NO: 1. [0279] In an embodiment, the thioredoxin protein is covalently bonded (e.g., reversibly or irreversibly) to a portion of a compound described herein (e.g., portion of a thioredoxin inhibitor or portion of a compound described herein).
[0280] In an aspect is provided a thioredoxin protein (e.g., SEQ ID NO: 1) covalently bonded to a thioredoxin inhibitor (e.g., thioredoxin inhibitor, compound described herein, or a portion of a compound described herein).
[0281] In embodiments, the thioredoxin protein covalently bonded to a thioredoxin inhibitor or compound described herein is the product of a reaction between the thioredoxin protein and a thioredoxin inhibitor or compound described herein. In embodiments, X3 is a leaving group. In embodiments, X3 participates in the chemical reaction between the thioredoxin protein and a thioredoxin inhibitor or compound described herein. In
embodiments, X4 is a leaving group. In embodiments, X4 participates in the chemical reaction between the thioredoxin protein and a thioredoxin inhibitor or compound described herein. It will be understood that the covalently bonded thioredoxin protein and thioredoxin inhibitor (e.g., compound described herein) are the remnants of the reactant thioredoxin protein and thioredoxin inhibitor or compound, wherein each reactant now participates in the covalent bond between the thioredoxin protein and thioredoxin inhibitor or compound. In
embodiments of the covalently bonded thioredoxin protein and compound described herein, the remnant of the substituted triazinyl is a linker including a covalent bond between the thioredoxin protein and the remainder of the compound described herein. It will be understood by a person of ordinary skill in the art that when a thioredoxin protein is covalently bonded to a thioredoxin inhibitor (e.g., compound described herein), the thioredoxin inhibitor (e.g., compound described herein) forms a remnant of the pre-reacted thioredoxin inhibitor (e.g., compound described herein) wherein a bond connects the remnant of the thioredoxin inhibitor (e.g., compound described herein) to the remnant of the thioredoxin protein (e.g., amino acid corresponding to K72 of SEQ ID NO: 1). The remnant of the thioredoxin inhibitor (compound described herein) may also be called a portion of the thioredoxin inhibitor. As a non-limiting example, the thioredoxin protein covalently bonded to a thioredoxin inhibitor may have the formula:
Figure imgf000149_0001
, wherein -NH-C4- is the sidechain amino group of a thioredoxin protein lysine (e.g., corresponding to K72 of SEQ ID NO: 1), which is bonded to the remainder of the thioredoxin protein and wherein R1, R2, L1, and X3 are as described herein. As a non-limiting example, the thioredoxin protein covalently bonded to a thioredoxin inhibitor may have the formula:
Figure imgf000149_0002
, wherein -NH-C4- is the sidechain amino group of a thioredoxin protein lysine (e.g., corresponding to K72 of SEQ ID NO: 1), which is bonded to the remainder of the thioredoxin protein and wherein R1, R2, L1, and X4 are as described herein. As a non-limiting example, the thioredoxin protein covalently bonded to a thioredoxin inhibitor may have the formula:
Figure imgf000150_0001
wherein -NH-C4- is the sidechain amino group of a thioredoxin protein lysine (e.g., corresponding to K72 of SEQ ID NO: 1), which is bonded to the remainder of the thioredoxin protein and wherein R2 and X4 are as described herein. As a non-limiting example, the thioredoxin protein covalently bonded to a thioredoxin inhibitor may have the formula:
Figure imgf000150_0002
, wherein -NH-C4- is the sidechain amino group of a thioredoxin protein lysine (e.g., corresponding to K72 of SEQ ID NO: 1), which is bonded to the remainder of the thioredoxin protein.
VII. Embodiments [0282] Embodiment PI . A compound having the formula:
Figure imgf000150_0003
wherein,
L1 is a bond, -C(O)-, -C(0)NH-, -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;
R1 is halogen, -CX^, -CHX^, -CH2X1, -OCX^, - OCH2X1, -OCHX1!, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0 R1C, - R1A0R1C, 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;
R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX22, -C(0)R2A, -C(0)OR2A, -C(0) R2AR2B, -OR2A, 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;
Each R1A, R1B, R1C, R1D, R2A, and R2B is independently
hydrogen, -CX3, -CHX2, -CH2X, -COOH, -CO H2, 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; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B 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;
ml and vl are independently an integer from 1 to 2; and
X, X1, X2, X3, and X4 are independently -F, -CI, -Br, or -I.
[0283] Embodiment P2. The compound of Embodiment PI, wherein L1 is a bond.
[0284] Embodiment P3. The compound of Embodiments PI, wherein L1 is an
unsubstituted alkylene.
[0285] Embodiment P4. The compound of Embodiment PI, wherein L1 is an unsubstituted C1-C4 alkylene.
[0286] Embodiment P5. The compound of Embodiment PI, wherein L1 is an unsubstituted methylene. [0287] Embodiment P6. The compound of Embodiment PI, wherein L1 is an unsubstituted heteroalkylene.
[0288] Embodiment P7. The compound of Embodiment PI, wherein L1 is an unsubstituted 2 to 4 membered heteroalkylene. [0289] Embodiment P8. The compound of Embodiment PI, wherein L1 is - CH2CH2O-, -OCH2CH2-, -OCH2-, or -CH2O-.
[0290] Embodiment P9. The compound of Embodiment PI, wherein L1 is an unsubstituted arylene.
[0291] Embodiment PI 0. The compound of Embodiment PI, wherein L1 is an
unsubstituted phenyl ene.
[0292] Embodiment PI 1. The compound of one of Embodiments PI to P10, wherein R1 is -C(0)R1C, -C(0)ORlc, -C(0) R1AR1B, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted 2 to 12 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
[0293] Embodiment P12. The compound of one of Embodiments PI to P10, wherein R1 is -C(0)-(unsubstituted phenyl), substituted or unsubstituted C1-C10 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.
[0294] Embodiment P13. The compound of one of Embodiments PI to P10, wherein R1 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 dihydroindene, unsubstituted phenyl, unsubstituted naphthyl, unsubstituted benzodioxinyl, unsubstituted 5 to 6 membered heteroaryl, unsubstituted dioxoborolanyl, substituted phenyl, substituted biphenyl.
[0295] Embodiment P14. The compound of one of Embodiments PI to P10, wherein R1 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 dihydroindene, unsubstituted naphthyl, unsubstituted benzodioxinyl, unsubstituted 5 to 6 membered heteroaiyl, unsubstituted tetram ethyl dioxoborolanyl,; or
Ci-Cio alkyl, phenyl, or biphenyl; each optionally substituted with from 1 to 3 substituents selected from:
-Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, and -OCH2CH3.
[0296] Embodiment PI 5. The compound of one of Embodiments PI to P14, wherein R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0297] Embodiment PI 6. The compound of one of Embodiments PI to PI 4, wherein R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, unsubstituted Ci-C3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl.
[0298] Embodiment PI 7. The compound of one of Embodiments PI to P14, wherein R2 is hydrogen. [0299] Embodiment PI 8. The compound of one of Embodiments PI to PI 7, wherein wherein X3 and X4 are independently -CI or -Br.
[0300] Embodiment PI 9. The compound of one of Embodiments PI to PI 7, wherein wherein X3 and X4 are -CI. 0301] Embodiment P20. The compound of Embodiment PI, wherein the compound is:
Figure imgf000153_0001
[0302] Embodiment P21. The compound of any one of Embodiments PI to P20, wherein
the compound is not
Figure imgf000154_0001
[0303] Embodiment P22. A pharmaceutical composition comprising the compound of any one of Embodiments PI to P20 and a pharmaceutically acceptable excipient. [0304] Embodiment P23. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
[0305] Embodiment P24. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of one of Embodiments PI to PI 9. [0306] Embodiment P25. The method of one of Embodiments P23 to P24, wherein the cancer is breast cancer.
[0307] Embodiment P26. The method of one of Embodiments P23 to P24, wherein the cancer is triple negative breast cancer.
[0308] Embodiment P27. A method of increasing Caspase 3 protein activity, said method comprising contacting a Thioredoxin protein with a compound of one of Embodiments PI to P20.
[0309] Embodiment P28. The method of Embodiment P27, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of human thioredoxin.
[0310] Embodiment P29. The method of Embodiment P27, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of human thioredoxin.
[0311] Embodiment P30. A method of increasing apoptosis of a cell, said method comprising contacting the cell with a compound of one of Embodiment PI to P20.
[0312] Embodiment P31. The method of Embodiment P30, wherein the compound contacts a thioredoxin in the cell.
[0313] Embodiment P32. The method of Embodiment P31, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of human thioredoxin. [0314] Embodiment P33. The method of Embodiment P31, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of human thioredoxin.
[0315] Embodiment Ql . A compound having the formula:
Figure imgf000155_0001
wherein,
L1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
R1 is halogen, -CX^, -CHX^, -CH2X\ -OCX^, - OCH2X1, -OCHX^, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0 R1C, - R1AORlc, 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;
R1 is halogen, -CX^, -CHX^, -CH2X1, -OCX^, - OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NHC(0)NR1AR1B, -N(0)mi, -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0)NR1AR1B, -OR1D, -NR1AS02R1D, -NR1AC(0)R1C, -NR1AC(0)0 R1C, -NR1AORlc, 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;
R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX22, -C(0)R2C, -C(0)OR2C, -C(0)NR2AR2B, -OR2D, 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;
Each R1A, R1B, R1C, R1D, R2A, R2B, R2C and R2D is independently hydrogen, -CX3, -CHX2, -CH2X, -COOH, -CONH2, 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; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B 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;
ml and vl are independently an integer from 1 to 2; and
X, X1, X2, X3, and X4 are independently -F, -CI, -Br, or -I.
[0316] Embodiment Q2. The compound of Embodiment Ql, wherein L1 is a bond.
[0317] Embodiment Q3. The compound of Embodiment Ql, wherein L1 is an unsubstituted alkylene.
[0318] Embodiment Q4. The compound of claim 1, wherein L1 is an unsubstituted C1-C4 alkylene.
[0319] Embodiment Q5. The compound of Embodiment Ql, wherein L1 is an unsubstituted methylene.
[0320] Embodiment Q6. The compound of Embodiment Ql, wherein L1 is an unsubstituted heteroalkylene. [0321] Embodiment Q7. The compound of Embodiment Ql, wherein L1 is an unsubstituted 2 to 4 membered heteroalkylene.
[0322] Embodiment Q8. The compound of Embodiment Ql, wherein L1 is - CH2CH2O-, -OCH2CH2-, -OCH2-, or -CH2O-.
[0323] Embodiment Q9. The compound of Embodiment Ql, wherein L1 is an unsubstituted arylene.
[0324] Embodiment Q10. The compound of Embodiment Ql, wherein L1 is an
unsubstituted phenylene.
[0325] Embodiment Ql 1. The compound of any one of Embodiments Ql to Q10, wherein R1 is -C(0)R1C, -C(0)ORlc, -C(0) R1AR1B, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted 2 to 12 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
[0326] Embodiment Q12. The compound of any one of Embodiments Ql to Q10, wherein R1 is -C(0)-(unsubstituted phenyl), substituted or unsubstituted C1-C10 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.
[0327] Embodiment Q13. The compound of any one of Embodiments Ql to Q10, wherein R1 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.
[0328] Embodiment Q14. The compound of one of Embodiments Ql to Q10, wherein R1 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 from: -Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, and -OCH2CH3. [0329] Embodiment Q15. The compound of any one of Embodiments Ql to Q14, wherein R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0330] Embodiment Q16. The compound of any one of Embodiments Ql to Q14, wherein R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, unsubstituted Ci-C3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl. [0331] Embodiment Q17. The compound of any one of Embodiments Ql to Q14, wherein R2 is hydrogen.
[0332] Embodiment Q18. The compound of any one of Embodiments Ql to Q17, wherein X3 and X4 are independently -CI or -Br.
[0333] Embodiment Q19. The compound of any one of Embodiments Ql to Q17, wherein X3 and X4 are -CI.
[0334] Embodiment Q20. The compound of Embodiment Ql, wherein the compound has a formula:
Figure imgf000158_0001
z20 is an integer from 0 to 5;
R20 is independently
halogen, -CX20 3, -CHX20 2, -CH2X20, -OCX20 3, -OCH2X20, -OCHX20 2, -CN, -OH, - H2, -COO H, -CO H2, -NO2, -SH, -S03H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HSO2H, - HC=(0)H, - HC(0)-OH, - HOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and X20 are independently -F, -CI, -Br, or -I.
[0335] Embodiment Q21. The compound of Embodiment Q20, wherein L1 is a bond, unsubstituted C1-C2 alkylene, or unsubstituted phenylene.
[0336] Embodiment Q22. The compound of Embodiment Q20, wherein the compound has a formula:
Figure imgf000158_0002
[0337] Embodiment Q23. The compound of Embodiment Q20, wherein the compound has a formula:
Figure imgf000159_0001
[0338] Embodiment Q24. The compound of Embodiment Q20, wherein the compound has a formula:
Figure imgf000159_0002
[0339] Embodiment Q25. The compound of any one of Embodiments Q21 to Q24, wherein R2 is hydrogen.
[0340] Embodiment Q26. The compound of any one of Embodiments Q21 to Q25, wherein X3 and X4 are each independently -Br, -F, or -CI.
[0341] Embodiment Q27. The compound of any one of Embodiments Q21 to Q26, wherein z20 is 0, 1, or 2; and R20 is -Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, or -OCH2CH3
[0342] Embodiment Q28. The compound of Embodiment Ql, wherein the compound is:
Figure imgf000159_0003
Figure imgf000160_0001
[0343] Embodiment Q29. The compound of any one of Embodiments Ql to Q28, wherein
CI
N^N the compound is not H [0344] Embodiment Q30. The compound of any one of Embodiments Ql to Q28, wherein -I^-R1 is not an unsubstituted unsaturated Ci to C4 alkyl.
[0345] Embodiment Q31. The compound of any one of Embodiments Ql to Q28, wherein -I^-R1 is not an unsubstituted Ci to C4 alkyl.
[0346] Embodiment Q32. A pharmaceutical composition comprising the compound of any one of Embodiments Ql to Q31 and a pharmaceutically acceptable excipient.
[0347] Embodiment Q33. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
[0348] Embodiment Q34. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of one of Embodiments Q 1 to Q31.
[0349] Embodiment Q35. The method of one of Embodiments Q33 to Q34, wherein the cancer is breast cancer.
[0350] Embodiment Q36. The method of one of Embodiments Q31 to Q34, wherein the cancer is triple negative breast cancer. [0351] Embodiment Q37. The method of one of Embodiment Q31 to Q34, wherein the effective amount of the thioredoxin inhibitor is administered by intraperitoneal injection.
[0352] Embodiment Q38. A method of increasing Caspase 3 protein activity, said method comprising contacting a Thioredoxin protein with a compound of one of Embodiments Ql to Q31.
[0353] Embodiment Q39. The method of Embodiment Q38, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
[0354] Embodiment Q40. The method of Embodiment Q38, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
[0355] Embodiment Q41. A method of increasing apoptosis of a cell, said method comprising contacting the cell with a compound of one of Embodiments Ql to Q31.
[0356] Embodiment Q42. The method of Embodiment Q41, wherein the compound contacts a thioredoxin in the cell. [0357] Embodiment Q43. The method of Embodiment Q42, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
[0358] Embodiment Q44. The method of Embodiment Q42, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1. [0359] Embodiment Q45. The method of Embodiment Q41, comprising increasing Caspase 3 protein activity in the cell.
Examples
A. Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Protein Interaction Disruptor that Impairs Breast Cancer Pathogenicity
[0360] Traditional strategies for cancer target discovery oftentimes involve searching for proteins or genes that may be dysregulated or mutated in tumors, which may miss promising therapeutic targets that do not necessarily exhibit altered expression or activity. Screening chemical libraries for anti-cancer small-molecules using chemical genetics strategies has arisen as a powerful complementary approach to traditional target discovery approaches for mining druggable nodes that can be pharmacologically interrogated in cancer [1,2].
However, a major challenge with chemical genetics is identifying the targets of leads that arise from screens. Oftentimes, lead compounds must be derivatized to either bear biorthogonal and/or photoaffinity handles or conjugated to beads to facilitate
chemoproteomic target identification. However, these approaches oftentimes require additional synthetic efforts to make analogs of lead molecules and alter the structure of the molecule, which hinders or may prevent target identification [3].
[0361] Isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) is one such chemoproteomic strategy to overcome many of these challenges [4-6]. IsoTOP-ABPP uses reactivity-based chemical probes to map reactive, functional, and ligandable hotspots directly in complex proteomes. This platform can be used in a competitive manner to compete covalently-acting small-molecules against the binding of reactivity-based probes to ligandable sites in the proteome to enable both rapid target discovery as well as the identification of druggable hotspots targeted by covalent ligands.
Recent studies have shown the promise of coupling covalent ligand discovery using cysteine- reactive ligand libraries with competitive isoTOP-ABPP platforms to facilitate the discovery of small-molecules that target functional and druggable hotspots directly in complex proteomes [5-7]. Studies using this coupled approach have primarily focused thus far on cysteine-reactivity. However, various studies have shown other reactive scaffolds that can potentially be used for coupling covalent ligand discovery with isoTOP-ABPP for discovering ligands against unique druggable hotspots [8,9]. Dichlorotriazines have recently been demonstrated to show preference for lysines and this scaffold can be used as reactivity- based probes for chemoproteomic studies [9]. [0362] In this study, we coupled the screening of a dichlorotriazine-based covalent ligand library with isoTOP-ABPP platforms to identify compounds and druggable hotspots that impair the pathogenicity of triple-negative breast cancer (TNBC) cells, a subset of breast cancer devoid of estrogen, progesterone, and HER2 receptors. This subset of breast cancer shows the worst prognosis due to the lack of targeted therapies available. We synthesized 58 dichlorotriazine-based covalent ligands to screen this library for compounds that impaired
231MFP TNBC serum-free cell survival and serum-containing cell proliferation (FIGS. 1A-
1C; FIG. 4A-4B; Tables S1A-S1B). We then counterscreened any hits that showed >50 % reductions in either survival or proliferation against MCF10A non-transformed epithelial cells to ensure that any lead hits did not cause non-specific cytotoxicity (FIG. ID; FIG. 4A- 4B). Through this screening effort, we identified a hit KEAl-97 that impaired 23 IMFP cell survival and proliferation and does not affect viability in MCF10A cells (FIGS. 1A-1C; FIG. 2A). [0363] We next performed competitive isoTOP-ABPP with KEAl-97 in vitro against a dichlorotriazine-alkyne probe (DCT-alkyne) in 23 IMFP proteomes to identify specific targets of KEAl-97. We pre-incubated KEAl-97 or vehicle with 23 IMFP proteomes prior to labeling of proteomes with DCT-alkyne, followed by copper-catalyzed alkyne azide cycloaddition (CuAAC)-mediated appendage of a biotin-azide tag bearing an isotopically light (for vehicle-treated) or heavy (for KEAl-97-treated) mass tag with a TEV protease recognition site. Control and treated proteomes were then combined in a 1 : 1 ratio, probe- labeled proteins were avidin-enriched and digested with trypsin, and probe-modified tryptic peptides were isolated and eluted by TEV protease for subsequent quantitative proteomic analysis. We then quantified isotopic light to heavy probe-modified peptide ratios, where a ratio of ~1 indicates no binding by KEAl-97 whereas a ratio >10 indicates a target of KEAl- 97. Through this study, we identified lysine 72 (K72) of thioredoxin (TXN) as the primary target of KEAl-97 showing a light to heavy isotopic peptide ratio of 38 (FIG. 2A). We validated this interaction between KEAl-97 and TXN through fluorescent gel-based ABPP detection showing competition of KEAl-97 against DCT-alkyne labeling of pure human TXN with a 50 % inhibitory concentration of 9 μΜ (FIG. 2B).
[0364] Interestingly, a previous study showed that this K72 is a critical residue for interaction of thioredoxin with procaspase 3. Upon interaction, thioredoxin nitrosylates the active-site cysteine of procaspase 3 to inhibit its activity and suppress apoptosis [10]. We find that KEAl-97 does not inhibit TXN activity— an expected result because KEAl-97 is not binding to the active site (FIG. 2C). Consistent with the role of K72 in protein interactions, we show that TXN pulldown of caspase 3 using pure proteins is impaired by KEAl-97 treatment (FIG. 2D). We further demonstrate that KEAl-97 treatment in 23 IMFP cells leads to caspase 3/7 activation and apoptotic cell death (FIGS. 3A-3B). We also show that KEAl-97 daily treatments in vivo impair 23 IMFP breast tumor xenograft growth in immune-deficient mice (FIG. 3 C).
[0365] We show here an anti-cancer compound KEAl-97 that reacts with K72 of TXN to displace TXN/caspase 3 interactions to activate apoptosis and impair breast cancer pathogenicity. While we cannot exclude other potential targets, which may contribute to the anti-cancer activity of KEA1-97, we show that KEA1-97 selectively modulates certain
functions of TXN through protein interactions with caspase 3 without affecting its catalytic activity. Targeting this unique druggable hotspot may therefore be a safer approach for
targeting thioredoxin for cancer rather than inhibiting all of its activities in repairing oxidized cysteines or disulfides in proteins. Taken more broadly, we show the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP to identify unique anti-cancer
agents and druggable hotspots.
[0366] Table 1. Screening of dichlorotriazine libraries in 231MFP breast cancer cells.
231MFP breast cancer cells were screened for cell survival or proliferation
impairments.
Avg.
Normalized % cell % Cell
Survival" Fragment Fluorescence sem viability % sem Death p value
* KEA1-97 0.237669752 0.01651007 23.76697521 1.65100655 76.2 7.37E-07
* KEAl-100 0.252819193 0.02583414 25.28191935 2.58341371 74.7 1.40E-06
* KEA1-83 0.306130306 0.03853571 30.61303059 3.85357093 69.4 5.36E-06
* KEA1-48 0.315442181 0.02224417 31.54421810 2.22441660 68.5 2.32E-05
* KEA1-50 0.32488761 0.09374192 32.48876096 9.37419183 67.5 4.52E-04
* KEA1-88 0.325065186 0.01622328 32.50651855 1.62232826 67.5 1.67E-06
* KEA1-62 0.345731051 0.04061015 34.57310508 4.06101527 65.4 5.75E-05
* KEA1-94 0.349289538 0.05658318 34.92895378 5.65831835 65.1 7.56E-05
* KEA1-69 0.378763128 0.02051518 37.87631285 2.05151778 62.1 1.99E-06
* KEA1-46 0.384151 197 0.06213249 38.4151 1965 6.21324868 61.6 2.07E-04
* KEA1-90 0.458456872 0.04330338 45.84568719 4.33033775 54.2 2.92E-03
* KEA1-55 0.475575355 0.12997072 47.55753551 12.99707162 52.4 4.59E-03
KEA1-37 0.508519542 0.05942569 50.85195416 5.94256905 49.1 7.28E-04
KEA1-91 0.51 1038242 0.05001916 51.10382415 5.00191638 48.9 5.46E-03
KEA1-64 0.515512238 0.03638820 51.55122375 3.63882040 48.4 3.27E-04
KEA1-75 0.541578203 0.10429047 54.15782035 10.42904658 45.8 3.45E-03
KEA1-72 0.551 136001 0.06273056 55.1 1360015 6.27305591 44.9 1.40E-03
KEA1-61 0.558452844 0.04677201 55.84528443 4.67720074 44.2 8.3 1E-04
KEA1-59 0.58307928 0.06610304 58.30792801 6.61030372 41.7 2.41E-03
KEA1-76 0.59431 1434 0.03684296 59.431 14344 3.68429650 40.6 5.74E-04
KEA1-80 0.601854194 0.07635810 60.18541935 7.63580972 39.8 2.1 1E-02
KEA1-77 0.619137544 0.00724735 61.91375435 0.72473491 38.1 2.86E-05
KEA1-57 0.621885384 0.09254320 62.18853842 9.25432049 37.8 3.32E-02
KEA1-49 0.639075418 0.021 14611 63.90754178 2.11461 137 36.1 1.21E-03
KEA1-43 0.682346959 0.06783465 68.23469589 6.78346529 31.8 4.28E-03 KEA1-95 0.736540885 0.07458921 73.65408850 7.45892080 26.3 1.45E-02
KEA1-78 0.757370206 0.17808034 75.73702057 17.80803434 24.3 2.09E-01
KEA1-54 0.763548267 0.10333523 76.35482669 10.33352284 23.6 1.57E-01
KEA1-73 0.769374619 0.09314903 76.93746187 9.31490252 23.1 4.52E-02
KEA1-23 0.778657918 0.03003266 77.86579183 3.00326606 22.1 1.02E-01
KEA1-70 0.785681851 0.17043504 78.56818509 17.04350362 21.4 2.29E-01
KEA1-36 0.785894841 0.04650077 78.58948408 4.65007723 21.4 7.91E-03
KEA1-67 0.792471549 0.04838839 79.24715495 4.83883872 20.8 1.02E-02
KEA1-42 0.795578942 0.08628044 79.55789416 8.62804438 20.4 1.86E-01
KEA1-79 0.844140401 0.06656461 84.41404007 6.65646076 15.6 7.03E-02
KEA1-39 0.844816111 0.00938335 84.48161114 0.93833533 15.5 2.18E-01
KEA1-38 0.854344665 0.03002201 85.43446648 3.00220115 14.6 1.91E-02
KEA1-22 0.868432512 0.05120951 86.84325121 5.12095107 13.2 1.26E-01
KEA1-56 0.874630947 0.05236559 87.46309466 5.23655911 12.5 3.47E-01
KEA1-32 0.896665064 0.02709740 89.66650644 2.70974049 10.3 6.20E-02
KEA1-40 0.900428135 0.01890376 90.04281347 1.89037592 10.0 4.18E-01
KEA1-58 0.907529725 0.02326508 90.75297254 2.32650790 9.2 7.77E-02
KEA1-85 0.90947257 0.06242816 90.94725696 6.24281602 9.1 3.10E-01
KEA1-68 0.910987956 0.06057357 91.09879558 6.05735740 8.9 2.35E-01
KEA1-45 0.915065073 0.04320550 91.50650731 4.32054957 8.5 5.06E-01
KEA1-53 0.918793327 0.01460178 91.87933273 1.46017800 8.1 5.04E-01
KEA1-63 0.942462554 0.03582060 94.24625541 3.58206049 5.8 6.44E-01
KEA1-47 0.953467608 0.03004695 95.34676080 3.00469500 4.7 5.38E-01
KEA1-74 0.95953641 0.08932347 95.95364102 8.93234684 4.0 7.02E-01
KEA1-41 0.964091779 0.01896208 96.40917787 1.89620754 3.6 4.70E-01
KEA1-30 0.968714431 0.02396985 96.87144313 2.39698496 3.1 6.36E-01
KEA1-98 0.969143561 0.02581361 96.91435607 2.58136140 3.1 6.74E-01
KEA1-60 0.995130499 0.02309990 99.51304985 2.30998991 0.5 9.16E-01
KEA1-31 0.997361545 0.08935832 99.73615452 8.93583188 0.3 9.86E-01
KEA1-71 0.999210645 0.02994306 99.92106451 2.99430562 0.1 9.91E-01
KEA1-84 1.007678869 0.04840444 100.76788685 4.84044433 -0.8 9.20E-01
KEA1-93 1.0585356 0.02004698 105.85356000 2.00469783 -5.9 3.76E-01
KEA1-81 1.148278348 0.04147027 114.82783479 4.14702686 -14.8 7.35E-02 a: * indicates counter screen in MCFIOA 367] Table 1. Screening of dichlorotriazine libraries in 231MFP breast cancer cells.
1MFP breast cancer cells were screened for cell survival or proliferation impairments.
Avg. %
Normalized % cell Cell
Proliferation Fragment Fluorescence sem viability % sem Death p value
* KEA1-83 0.342593205 0.024061 16 34.2593205 2.40611568 65.7 4.88E-07 * KEAl-100 0.4187633 0.08022519 41.87633 8.02251859 58.1 1.70E-04
* KEA1-97 0.490256633 0.03243467 49.0256633 3.24346677 51.0 6.49E-06
KEA1-46 0.519940486 0.0521114 51.9940486 5.21114035 48.0 8.23E-05
KEA1-77 0.541966692 0.02836075 54.1966692 2.83607515 45.8 1.03E-04
KEA1-73 0.561323643 0.07112835 56.1323643 7.11283516 43.9 1.22E-03
KEA1-85 0.562772734 0.03400153 56.2772734 3.40015254 43.7 3.87E-05
KEA1-75 0.568861007 0.04621993 56.8861007 4.62199331 43.1 7.61E-05
KEA1-72 0.575098591 0.01388278 57.5098591 1.38827808 42.5 7.67E-06
KEA1-62 0.5837334 0.01210387 58.37334 1.21038712 41.6 7.95E-06
KEA1-47 0.620956897 0.01367326 62.0956897 1.36732605 37.9 1.62E-05
KEA1-88 0.63135716 0.0306403 63.135716 3.06402962 36.9 4.61E-05
KEA1-63 0.632196344 0.10500991 63.2196344 10.5009907 36.8 1.47E-02
KEA1-79 0.672638045 0.0185102 67.2638045 1.85102041 32.7 5.62E-04
KEA1-37 0.67666721 0.01575959 67.666721 1.57595905 32.3 5.22E-05
KEA1-67 0.683926257 0.0535596 68.3926257 5.35595952 31.6 3.19E-03
KEA1-49 0.689166071 0.01042351 68.9166071 1.0423513 31.1 5.01E-05
KEA1-55 0.690331402 0.058646 69.0331402 5.86459957 31.0 1.60E-03
KEA1-76 0.695218373 0.02245922 69.5218373 2.24592184 30.5 1.59E-04
KEA1-98 0.71221407 0.02256172 71.221407 2.25617181 28.8 1.77E-04
KEA1-50 0.716125748 0.04215717 71.6125748 4.21571673 28.4 9.26E-04
KEA1-48 0.721477561 0.07040282 72.1477561 7.04028195 27.9 6.83E-03
KEA1-94 0.723715519 0.03784922 72.3715519 3.78492239 27.6 9.10E-04
KEA1-84 0.742145917 0.00738428 74.2145917 0.73842831 25.8 2.06E-04
KEA1-64 0.742476828 0.03932721 74.2476828 3.93272085 25.8 1.30E-03
KEA1-32 0.749427807 0.06496991 74.9427807 6.49699109 25.1 1.62E-02
KEA1-95 0.7556465 0.010611 12 75.56465 1.06111156 24.4 1.17E-04
KEA1-61 0.759612563 0.02839764 75.9612563 2.83976404 24.0 8.28E-04
KEA1-70 0.772614907 0.01478485 77.2614907 1.47848457 22.7 3.95E-03
KEA1-23 0.78151 1458 0.02668286 78.1511458 2.66828574 21.8 1.20E-02
KEA1-78 0.782741763 0.01586468 78.2741763 1.58646766 21.7 3.53E-03
KEA1-42 0.795235447 0.03927423 79.5235447 3.92742276 20.5 2.25E-02
KEA1-58 0.795601843 0.01524268 79.5601843 1.52426789 20.4 6.86E-03
KEA1-30 0.811100242 0.00663067 81.1100242 0.66306688 18.9 1.30E-03
KEA1-56 0.819462248 0.01622848 81.9462248 1.62284805 18.1 2.25E-02
KEA1-43 0.828719112 0.02961224 82.87191 12 2.96122389 17.1 4.05E-03
KEA1-41 0.835271549 0.0094011 83.5271549 0.94011012 16.5 1.20E-03
KEA1-60 0.838468071 0.02635439 83.8468071 2.6354394 16.2 2.63E-02
KEA1-74 0.866699426 0.01670567 86.6699426 1.67056695 13.3 1.15E-02
KEA1-53 0.86696 0.02748158 86.696 2.74815771 13.3 8.08E-02
KEA1-54 0.872646636 0.01366872 87.2646636 1.36687165 12.7 7.67E-02
KEA1-90 0.87560788 0.03191808 87.560788 3.19180751 12.4 1.05E-01
KEA1-68 0.877671808 0.03291487 87.7671808 3.29148748 12.2 8.25E-02
KEA1-31 0.884283059 0.03431887 88.4283059 3.43188724 11.6 1.32E-01 KEA1-38 0.886846949 0.02356549 88.6846949 2.35654888 11.3 8.54E-02
KEA1-69 0.888878255 0.01548622 88.8878255 1.54862156 11.1 7.90E-02
KEA1-59 0.890374795 0.01399351 89.0374795 1.39935076 11.0 1.97E-02
KEA1-71 0.894800019 0.00895214 89.4800019 0.89521381 10.5 2.49E-02
KEA1-57 0.899743778 0.02208171 89.9743778 2.20817067 10.0 1.58E-01
KEA1-39 0.901401631 0.02843237 90.1401631 2.843237 9.9 1.76E-01
KEA1-40 0.912506413 0.05003601 91.2506413 5.00360053 8.7 2.87E-01
KEA1-22 0.915769728 0.00608939 91.5769728 0.60893898 8.4 5.43E-02
KEA1-80 0.927682655 0.05282341 92.7682655 5.28234069 7.2 3.82E-01
KEA1-36 0.936024144 0.0233408 93.6024144 2.33407965 6.4 2.94E-01
KEA1-93 0.958149666 0.0101528 95.8149666 1.01527975 4.2 2.98E-01
KEA1-45 0.970710501 0.04644046 97.0710501 4.64404645 2.9 7.04E-01
KEA1-91 0.97744893 0.01544796 97.744893 1.54479565 2.3 7.26E-01
KEA1-81 0.992000982 0.03344327 99.2000982 3.344327 0.8 8.71E-01 a: * * indicates counter screen in MCF10A
[0368] Materials. DCT-alkyne was synthesized as previously reported.
[0369] Cell Culture. 231MFP cells were obtained from Professor Benjamin Cravatt's
group. 231MFP cells were cultured in L15 media with 10% fetal bovine serum (FBS),
supplemented with 1% glutamine (200 mM stock) and grown at 37°C in 0% CO2. MCF10A cells were from a previous study. MCF10A cells were cultured in DMEM/F12K media with
5% horse serum (HS), supplemented with 1% glutamine (200 mM stock), 20 ng/mL EGF
(Santa Cruz Biotechnology), 100 ng/mL cholera toxin (Sigma), 10 ng/mL insulin (Santa Cruz Biotechnology), and 500 ng/mL hydrocortisone (Sigma) and grown at 37°C in 5% CO2.
[0370] Survival and Proliferation Assays. Cells were plated the evening before the
experiment, and allowed to adhere overnight. For serum-free cell survival assays, cells were plated in media not containing FBS. For cell proliferation assays, cells were plated in
complete media. For the chemical genetics screen, cells were treated with either ACN or the lysine-reactive fragment for 48 h at 10 μΜ and cell viability was assessed by Hoescht stain using our previously described methods [22].
[0371] Tumor Xenograft Growth Studies. C.B17 SCID male mice (6-8 weeks old) were injected subcutaneously into the flank with 2,000,000 cells in serum-free media. For
pharmacological treatments, mice were exposed by intraperitoneal (ip) injection with either vehicle (18: 1 : 1 PBS/ethanol/PEG40) or 10 mg/kg KEA1-97 once per day starting 16 days after the initiation of the xenograft experiment and until the completion of the study. Tumors were measured roughly every 7 days by caliper measurements. Animal experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of California, Berkeley.
[0372] IsoTOP-ABPP Analysis. IsoTOP-ABPP analyses were performed as previously described [5-7]. For competitive IsoTOP-ABPP, 231MFP cell lysates were pre-incubated with acetonitrile (ACN) vehicle or KEA1-97 (10 μΜ) for 30 min at 37°C in phosphate- buffered saline (PBS), and then labeled with DCT-alkyne (100 μΜ) for 1 h at room temperature. Lysate was then treated with isotopically light (control) or heavy (treated) TEV- biotin (100 μΜ) and CuAAC was performed as previously described [5,6]. Protein precipitation was performed over one hour and pellets were collected by centrifugation at 6500 x g. Proteins were washed 3 times with cold methanol then denatured and resolubilized by heating in 1.2% SDS/PBS to 85° C for 5 min. Insoluble components were precipitated by centrifugation at 6500 x g and soluble proteome was collected and diluted in 5 ml PBS, for a final concentration of 0.2% SDS. Probe labeled proteins were bound to avidin-agarose beads (170 μΙ_, resuspended beads/sample, Thermo Pierce) while rotating overnight at 4°C. Bead- linked proteins were enriched by washing three times each in PBS and water, then resuspended in 6 M urea/PBS (Sigma-Aldrich) and reduced in dithiothreitol (1 mM, Sigma- Aldrich), alkylated with iodoacetamide (18 mM, Sigma-Aldrich), then washed and resuspended in 2 M urea/PBS with 1 mM calcium chloride. Bead-linked proteins were trypsinized overnight with 0.5 μg/μl sequencing grade trypsin (Promega). Tryptic peptides were discarded, beads were washed three times each in PBS and water, and then washed with one wash of TEV buffer containing 1 μΜ DTT. TEV-biotin tag was digested overnight in TEV buffer containing 1 μΜ DTT and 5 μΙ_, Ac-TEV protease at 29°C. Peptides were diluted in water and acidified with final concentration of 5% formic acid (1.2 M, Spectrum).
[0373] Peptides from all proteomic experiments were pressure-loaded onto a 250 μπι inner diameter fused silica capillary tubing packed with 4 cm of Aqua CI 8 reverse-phase resin
(Phenomenex # 04A-4299). Resin-packed capillary tubing was previously equilibrated on an Agilent 600 series HPLC using gradient from 100% buffer A to 100% buffer B over 10 min, followed by a 5 min wash with 100% buffer B and a 5 min wash with 100% buffer A. The samples were then attached using a MicroTee PEEK 360 μπι fitting (Thermo Fisher
Scientific #p-888) to a 13 cm laser pulled column packed with 10 cm Aqua C18 reverse- phase resin and 3 cm of strong-cation exchange resin for isoTOP-ABPP studies. Samples were analyzed using a Q Exactive Plus mass spectrometer (Thermo Fisher Scientific) using a 5-step Multidimensional Protein Identification Technology (MudPIT) program, using 0 %, 25 %, 50 %, 80 %, and 100 % salt bumps of 500 mM aqeous ammonium acetate and using a gradient of 5-55 % buffer B in buffer A (buffer A: 95:5 water: acetonitrile, 0.1 % formic acid; buffer B 80:20 acetonitrile:water, 0.1 % formic acid). Data was collected in data-dependent acquisition mode with dynamic exclusion enabled (60 s). One full MS (MSI) scan (400-1800 m/z) was followed by 15 MS2 scans of the most abundant ions. Heated capillary temperature was set to 200° C and the nanospray voltage was set to 2.75 kV.
[0374] Data was extracted in the form of MS 1 and MS2 files using Raw Extractor 1.9.9.2 (Scripps Research Institute) and searched against the Uniprot mouse database using
ProLuCID search methodology in IP2 v.3 (Integrated Proteomics Applications, Inc) [23]. Residues were searched with a static modification for cysteine carboxyaminomethylation (+57.02146) and up to two differential modifications for methionine oxidation and lysine probe modifications with either the light or heavy TEV tags (+550.22797 or +556.24178, respectively). Peptides were required to have at least one tryptic end and to contain the TEV modification. ProLUCID data was filtered through DTASelect to achieve a peptide false- positive rate below 1%.
[0375] Gel-Based ABPP. Gel-based ABPP methods were performed as previously described [24]. Recombinant Thioredoxin (0.04 μg) protein were pre-treated with ACN or KEAl-97, respectively, for 30 min at 37°C in an incubation volume of 50 μΐ. PBS, and were subsequently treated with DCT-alkyne (100 μΜ final concentration) for 30 min at 37°C.
CuAAC was performed to append rhodamine-azide onto DCT-alkyne probe-labeled proteins. The samples were separated by SDS/PAGE and scanned using a ChemiDoc MP (Bio-Rad Laboratories, Inc). Inhibition of target labeling was assessed by densitometry using
ImageStudio Light software. [0376] Ni-NTA Magnetocapture Assay. Recombinant his-tagged thioredoxin (Enzo Life Sciences Inc, ADI-SPP-892-200) was used as bait to precipitate pure recombinant caspase-3 (Origene Technologies Inc, TP304444) using Ni-NTA magnetic agarose beads (Qiagen, 220002-020). One microgram of His-txn was added to 50 μΕ of binding buffer (25 mM NaH2PO4/250 mM NaCl/10 mM imidazole/5% vol/vol glycerol/0.05% wt/wt CHAPS, pH 8.0), followed by addition of KEAl-97 (100 μΜ final concentration) or equivalent volume of acetonitrile. Samples were incubated at 37°C for 30 minutes with shaking. One microgram of pure caspase 3 was added to each sample and samples were incubated at 37°C for 30 minutes with shaking. Twenty microliters of Ni-NTA magnetic agarose beads were added to each sample and samples rotated at 4°C for 2 hours. Washes (3 times, 1 mL binding buffer) were performed as quickly as possible using a New England BioLabs magnetic separation rack. The proteins were eluted using 20 μΙ_, binding buffer supplemented with imidazole to a final concentration of 0.5 M. After addition of Laemmli's reducing agent, samples were boiled at 95°C for five minutes and allowed to cool. Samples were separated by SDS/PAGE on a 10% TGX gel, transferred to nitrocellulose membrane and blocked for one hour (5% milk in PBS/Tween). Blots were probed with a rabbit polyclonal anti-caspase-3 antibody (Cell Signaling Technologies, 9662S, 1 : 1000 in 5% milk in PBS/Tween) overnight and goat anti- rabbit-antibody (Li-Cor Inc, 926-3221, 1 : 10,000 in 5% BSA in PBS/Tween) for one hour.
[0377] Thioredoxin Activity Assay. A thioredoxin activity assay kit was purchased from Cayman Chemical Co. (20039). Samples were prepared in a 96-well black-walled plate. To each sample well, 54 μΙ_, assay buffer, human thioredoxin (10 μΙ_, of 0.2 μΜ solution), human thioredoxin reductase (10 μΙ_, of 1.0 μΜ solution), KEA1-97 (1 μΙ_, yielding final
concentrations of 100 μΜ, 30 μΜ, 10 μΜ, 3 μΜ, 1 μΜ, 0.3 μΜ, 0.1 μΜ KEA1-97 or equivalent volume of acetonitnle) and 5 μΙ_, of NADPH (diluted according to kit instructions) were added. The plate was incubated at 37°C for 30 minutes. After incubation, 20 μΙ_, of fluorescent substrate (diluted according to kit instructions) was added to each sample as quickly as possible. The plate was immediately placed in a SpectraMax i3 plate reader (Molecular Devices) and fluorescence was monitored over one hour after 480 nm excitation and 520 nm emission. Reaction rates were plotted and compared.
[0378] Flow cytometry analysis of cell viability and apoptosis. For the analysis of early and late stage apoptosis, cells were isolated and stained according to the manufacturer's instructions. Briefly, media and trypsinized cells were pelleted by centrifugation at 500x g for 5 min, washed once in PBS, and resuspended in Binding Buffer (10 mM HEPES/NaOH pH 7.4, 140 mM NaCl, 2.5 mM CaCl2) containing propidium iodide (BD Biosciences) and FITC- conjugated Annexin V (BD Biosciences). Following a 15 min incubation, the cells were diluted with Binding Buffer to a final volume of 0.5mL and the fluorescence measured using a BD Biosciences LSR Fortessa cytometer. FlowJo Software was used for all data analysis. The percentage of early apoptotic (Annexin V positive, propidium iodide negative) and late apoptotic (Annexin V positive, propidium iodide positive) cells was quantified (n=3). [0379] For the measurement of caspase-3/7 activity, 2 μΜ CellEvent™ Caspase-3/7 Green Detection Reagent (Invitrogen) was added to the media during the final 30 min of the treatment. Media and trypsinized cells were pelleted by centrifugation at 500x g for 5 min, washed once in PBS, and resuspended in PBS. The fluorescence was measured using a BD Biosciences LSR Fortessa flow cytometer. FlowJo Software was for data analysis and the percentage of cells exhibiting active caspase-3/7 was quantified (n=3). T-test was employed for all statistical analyses.
B. Synthesis of Dichlorotriazine library
Figure imgf000171_0001
[0380] 4,6-dichloro-N-decyl-l,3,5-triazin-2-amine (KEA1-22) A solution of 2,4,6- trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N-diisopropylethylamine (20 μ , 0.1 mmol, Sigma, 387649) was added. Decylamine (10 \L, 0.5 mmol, Sigma, D2404) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding off-white crystals (0.06 g,
40% yield). 1H MR (400MHz, CDCb): 0.87 (t, J= 6.6Hz, 3H), 1.28 (d, J= 23.6 Hz, 14H), 1.74 - 1.48 (m, 2H), 3.47 (q, J= 6.8Hz, 2H), 6.15 (t, J= 5.9 Hz, 1H)13C MR: (100MHz, CDCb): δ 14.21, 22.77, 26.75, 29.13, 29.26, 29.38, 29.58, 29.60, 31.97, 41.67, 165.85, 169.96, 171.07. HRMS (-ESI): Calculated: 303.1222 (C13H22CI2N4). Observed: 303.1148.
Figure imgf000171_0002
[0381] 4,6-dichloro-N-(cyclohexylmethyl)-l,3,5-triazin-2-amine (KEA1-23). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N-diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. Cyclohexanemethylamine (70 \L, 0.5 mmol, Sigma, 101842) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding off white crystals (0.01 g, 8% yield). ¾ NMR (400MHz, CDCb): 1.05 - 0.91 (m, 2H), 1.21 (tq, J = 24.3, 12.3 Hz, 3H), 1.81 - 1.43 (m, 6H)), 3.33 (t, J= 6.5 Hz, 2H), 5.89 (t, J= 4.5 Hz, 1H). 13C MR: (100MHz, CDCb): δ 25.80, 26.34, 30.73, 37.76, 100.11, 166.17, 169.91, 171.08. HRMS (-ESI): Calculated: 259.0596 (C10H14CI2N4). Observed: 259.0521.
Figure imgf000172_0001
[0382] N-([l,r-biphenyl]-4-ylmethyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-30). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in
tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N- diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. 4-phenylbenzylamine (0.11 g, 0.6 mmol, Sigma, 552313) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white powder (0.07 g, 35% yield). ¾ NMR (400MHz, CDCb): 4.72 (d, J= 6.1 Hz, 2H), 6.47 (t, J= 5.5 Hz, 1H), 7.37 (d, J= 8.1 Hz, 3H), 7.44 (t, J= 7.5 Hz, 2H), 7.58 (dd, J= 7.6, 5.6 Hz, 4H). 13C NMR: (100MHz, CDCb): δ 45.28, 127.22, 127.69, 127.82, 128.32, 128.99, 135.31, 140.53, 141.32, 166.01, 170.19. HRMS (-ESI): Calculated: 329.0439 (C16H12CI2N4). Observed: 329.0362.
Figure imgf000173_0001
[0383] N-(benzo[(/J[l,3]dioxol-5-ylmethyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-31). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in
tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N- diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. Piperonylamine (50\L, 0.5 mmol, Sigma, P49503) was then added to the solution. The reaction stirred at 0°C for 3.5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white powder (0.4 g, 27% yield). ¾ NMR (400MHz, CDCb): 4.56 (d, J= 6.0Hz, 2H), 5.97 (s, 2H), 6.10 (t, J = 3.4 Hz, 1H), 6.78 (d, J= 1.8 Hz, 3H). 13C NMR: (100MHz, CDCb): δ 45.48, 100.10, 101.43, 108.45, 108.71, 121.48, 130.02, 147.70, 148.28, 165.82, 170.22, 171.27. HRMS (-ESI): Calculated: 297.0024 (C11H8CI2N4O2). Observed: 296.9949
Figure imgf000173_0002
[0384] N-(3,5-bis(trifluoromethyl)benzyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEAl-32). A solution of 2,4,6-trichloro-l,3,5-triazine (0.11 g, 0.6 mmol, Sigma, C95501) in
tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N- diisopropylethylamine (20 μΕ, 0.1 mmol, Sigma, 387649) was added. 3,5- bis(trifluorom ethyl) benzylamine (0.14 g, 0.6 mmol, Sigma, 263389) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding white crystals (0.12 g, 49% yield). ¾ NMR (400MHz, CDCb): 4.83 (d, J= 6.4Hz, 2H), 7.18 (t, J= 5.2 Hz, 1H), 7.83 (d, J= 13.7 Hz, 2H). 13C MR: (100MHz, CDCb): δ 44.60, 119.11, 121.83, 122.18, 122.22, 122.26, 124.54, 128.09, 131.87, 132.20, 132.54, 132.87, 139.20, 166.29, 170.28, 171.59. HRMS (-ESI): Calculate .9795.
Figure imgf000174_0001
[0385] (£)-4,6-dichloro-N-(3,7-dimethylocta-2,6-dien-l-yl)-l,3,5-triazin-2-amine (KEA1- 36). A solution of 2,4,6-trichloro-l,3,5-triazine (0.11 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N- diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. Geranylamine (90 \L, 0.5 mmol, Sigma, 412643) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.07 g, 47% yield). ¾ NMR (400MHz, CDCb): 1.60 (s, 3H), 1.70 (d, J= 15.3 Hz, 6H), 2.08 (dt, J= 17.4, 7.1 Hz, 4H), 4.06 (t, J= 6.3 Hz, 2H), 5.14 (dt, J= 66.7, 6.8 Hz, 2H), 5.94 (t, J= 5.6 Hz, 1H). 13C NMR: (100MHz, CDCb): δ 16.61, 17.86, 25.83, 26.41, 39.58, 39.62, 117.98, 123.67, 132.16, 142.17, 165.62, 169.91, 171.07. HRMS (-ESI): Calculated: 299.0909 (C13H18CI2N4). Observed: 299.0834.
Figure imgf000174_0002
[0386] 4-(2-((4,6-dichloro-l,3,5-triazin-2-yl)amino)ethyl)phenol (KEA1-37). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in a bath of dry ice in acetone. To the solution N-N-diisopropylethylamine (20 μί, 0.1 mmol, Sigma, 387649) was added. Tyramine (0.09 g, 0.7 mmol, Sigma, T90344) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (30% to 70% ethyl acetate in hexanes) yielding white crystals (0.01 g, 9% yield). ¾ NMR (400MHz, CD3OD): 2.78 (t, J= 7.3Hz, 2H), 3.57 (t, J= 7.3Hz, 2H), 6.87 (dd, J= 132.4, 8.4 Hz, 1H). 4.87 (s) is water in solvent. 13C NMR: (100MHz, CD3OD): δ 35.24, 44.04, 116.25, 130.62, 130.87, 157.06, 167.20, 170.47, 171.40. HRMS (-ESI):
Calculated: 283.0232 (C11H10CI2N4O). Observed: 283.0158.
Figure imgf000175_0001
[0387] 4,6-dichloro-N-(2-(2-methoxyphenoxy)ethyl)-l,3,5-triazin-2-amine (KEA1-38). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in
tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. 2-(2-methoxyphenoxy) ethylamine (90 \L, 0.5 mmol, Sigma, CDS003691) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (40% to 60% ethyl acetate in hexanes) yielding a white solid (0.03 g, 15% yield). ¾ NMR (400MHz, CDCb): 3.90 - 3.38 (m, 5H), 4.16 (t, J= 5.0 Hz, 2H), 6.80 (t, J= 5.3 Hz, 1H), 7.05 - 6.87 (m, 4H). * 1.80 (s) - negligible grease. 13C NMR: (100MHz, CDCb): δ 41.17, 55.85, 68.45, 112.07, 115.95, 121.14, 123.03, 147.60, 150.16, 165.99. HRMS (-ESI): Calculated: 313.0337 (C12H12CI2N4O2). Observed: 313.0262.
Figure imgf000176_0001
[0388] 4,6-dichloro-N-(l-phenylethyl)-l,3,5-triazin-2-amine (KEA1-39). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (20 \L, 0.1 mmol, Sigma, 387649) was added. Alpha-Methylbenzylamine (70 \L, 0.5 mmol, Sigma, M31104) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding yellow oil (0.02 g, 16% yield). 1H MR (400MHz, CDCb): 1.60 (d, J= 6.8 Hz, 3H), 5.43 - 4.78 (m, 1H), 6.07 (d, J= 8.1 Hz, 1H), 7.40 - 7.28 (m, 5H). 13C MR: (100MHz, CDCb): δ 21.85, 51.21, 126.22, 128.17, 129.08, 141.53, 165.13, 170.12, 171.18. HRMS (-ESI): Calculated:
267.0283 (C11H10CI2N4). Observed: 267.0207.
Figure imgf000176_0002
[0389] 4,6-dichloro-N-(3-methoxybenzyl)-l,3,5-triazin-2-amine (KEA1-40). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (20 μΕ, 0.1 mmol, Sigma, 387649) was added. 3-methoxybenzylamine (70 μΕ, 0.5 mmol, Sigma, 159891) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding an off-white solid (0.02 g, 11% yield). ¾ NMR (400MHz, CDCb): 3.81 (s, 3H), 4.64 (d, J= 6.0 Hz, 2H), 6.22 (t, J= 4.1 Hz, 1H), 6.92 - 6.82 (m, 1H), 7.29 (d, J= 7.7 Hz, 1H). 13C NMR: (100MHz, CDCb): δ 45.46, 55.43, 113.59, 113.61, 119.99, 130.22, 137.84, 160.15, 165.97, 171.28. HRMS (-ESI): Calculated: 283.0232 (C11H10CI2N4O). Observed: 283.0159.
Figure imgf000177_0001
[0390] 4,6-dichloro-N-(2-methylbenzyl)-l,3,5-triazin-2-amine (KEA1-41). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2-methylbenzylamine (70 \L, 0.5 mmol, Sigma, 127132) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding white crystals (0.01 g, 5% yield). ¾ NMR (400MHz, CDCb): 2.35 (s, 3H), 4.65 (d, J= 5.7Hz, 2H), 5.93 (t, J= 3.7 Hz, 1H), 7.26 - 7.15 (m, 4H). * 1.56 (s) is negligible water, 1.25 (s) is negligible grease. 13C NMR: (100MHz, CDCb): δ 19.24, 43.83, 100.11, 126.65, 128.62, 128.65, 130.97, 134.05, 136.52. HRMS (-ESI): Calculated: 267.0283 (C11H10CI2N4). Observed: 267.0208.
Figure imgf000177_0002
[0391] 4,6-dichloro-N-(2-phenoxyethyl)-l,3,5-triazin-2-amine (KEA1-42). A solution of 2,4,6-trichloro-l,3,5-triazine (0.10 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (20 μΐ., 0.1 mmol, Sigma, 387649) was added. 2-phenoxyethylamine (70 \L, 0.5 mmol, Sigma, 448400) was then added to the solution. The reaction stirred at 0°C for 8 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (30% to 70% ethyl acetate in hexanes) yielding an off-white solid (0.03 g, 19% yield). 1H MR (400MHz, CDCb): 3.91 (q, J= 5.5 Hz, 2H), 4.13 (t, J= 5.1 Hz, 2H), 6.41 (t, J= 6.1 Hz, 1H), 6.89 (d, J= 7.9 Hz, 2H), 6.99 (t, J= 7.4 Hz, 1H), 7.33 - 7.27 (m, 2H). 13C MR: (100MHz, CDCb): δ 41.05, 65.66, 114.49, 121.67, 129.79, 158.13, 166.03, 170.26, 171.17. HRMS (-ESI): Calculated: 283.0232 (C11H10CI2N4O). Observed: 283.0159.
Figure imgf000178_0001
[0392] 4,6-dichloro-N-(2,3-dihydrobenzo[*][l,4]dioxin-6-yl)-l,3,5-triazin-2-amine (KEA1-43). A solution of 2,4,6-trichloro-l,3,5-triazine (0.11 g, 0.6 mmol, Sigma, C95501) in tetrahydrofuran (12.5 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (20 \L, 0.1 mmol, Sigma, 387649) was added. l-4-benzodioxan-6- amine (70 \L, 0.5 mmol, Sigma, 193232) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (25% to 75% ethyl acetate in hexanes) yielding a white solid (0.04 g, 24% yield). ¾ MR (400MHz, CDCb): 4.27 (d, J= 0.8, 4H), 6.95 - 6.84 (m, 2H), 7.14 (d, J= 2.3 Hz, 1H), 7.43 (s, 1H). * 1.60 (s) is negligible water, 1.25 (s) is negligible grease. 13C NMR: (100MHz, CDCb): δ 64.43, 64.57, 111.36, 115.16, 117.74, 129.17, 143.78. HRMS (-ESI): Calculated: 297.0024
(C11H8CI2N4O2). Observed: 296.9948.
Figure imgf000179_0001
[0393] N-(sec-butyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-45). A solution of 2,4,6- trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. sec-Butylamine (110 \L, 1.1 mmol, Sigma, B89000) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (30% to 70% ethyl acetate in hexanes) yielding a white solid (0.01 g, 4% yield). ¾ NMR (400MHz, CDCb): 0.93 (t, J= 6.5Hz, 3H), 1.17 (m, J= 12.9, 6.5 Hz, 3H), 1.52 (m, J= 13.3, 6.6 Hz, 2H), 4.14 - 3.75 (m, 1H), 5.22 - 4.92 (m, 1H). 13C NMR:
(100MHz, CDCh): δ 10.40, 20.22, 29.60, 48.34, 100.11, 165.42. HRMS (-ESI): Calculated: 219.0283 (C7H10CI2N4). Observed: 219.0210.
Figure imgf000179_0002
[0394] 4,6-dichloro-N-pentyl-l,3,5-triazin-2-amine (KEA1-46). A solution of 2,4,6- trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Pentylamine (130 \L, 1.1 mmol, Sigma, 171409) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding off-white crystals (0.05 g, 20%). ¾ NMR (100MHz, CDCb): 0.89 (t, J= 6.9Hz, 3H), 1.40 - 1.27 (m, 4H), 1.60 (p, J = 7.3Hz, 2H), 3.47 (q, J= 6.8Hz, 2H), 6.48 (t, J= 6.2 Hz, 1H). 13C NMR: (100MHz, CDCb): δ 14.03, 22.36, 28.82, 28.88, 41.67, 77.36, 165.87, 169.72, 171.08. HRMS
(-ESI): Calculated: 233.0439 (C8H12CI2N4). Observed: 233.0367.
Figure imgf000180_0001
[0395] N-benzhydryl-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-47). A solution of 2,4,6- trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Benzhydrylamine (190 \L, 1.1 mmol, Sigma, A53605) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (5% to 95% ethyl acetate in hexanes) yielding a white powder (0.17 g, 46% yield). ¾ NMR (400MHz, CDCb): 6.39 (d, J= 8.6Hz, 1H), 6.57 (d, J= 8.5Hz, 1H), 7.27 - 7.22 (m, 4H), 7.41 - 7.29 (m, 6H). 13C NMR: (100MHz, CDCb): δ 58.92, 127.40, 128.16, 128.99, 139.96, 165.23, 170.21, 171.27. HRMS (-ESI): Calculated: 329.0439 (C16H12CI2N4) Observed: 329.0363.
Figure imgf000180_0002
[0396] N-benzyl-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-48). A solution of 2,4,6- trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. Benzylamine (120 μΐ., 1.1 mmol, Sigma, 185701) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (5% to 95% ethyl acetate in hexanes) yielding a white powder (0.11 g, 39% yield). ¾ NMR (400MHz, CDCb): 4.69 (d, J= 6.1Hz, 2H), 6.69 (t, J= 5.3 Hz, 1H), 7.51- 7.10 (m, 5H). 13C NMR: (100MHz, CDCb): δ 45.52, 100.08, 127.82, 128.26, 129.07, 136.39, 165.95, 170.07, 171.27. HRMS (-ESI): Calculated: 253.0126 (CioH8Cl2N4).
Observed: 253.0051.
Figure imgf000181_0001
[0397] 0-benzyl-N-(4,6-dichloro-l,3,5-triazin-2-yl)hydroxylamine (KEA1-49). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 \L, 0.2 mmol, Sigma, 387649) was added. o-Benzylhydroxylamine (160 \L, 1.1 mmol, Sigma, CDS001502) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white solid (0.13 g, 45% yield). ¾ NMR (400MHz, CDCb): 4.99 (s, 2H), 7.44 - 7.35 (m, 5H), 8.87 (s, 1H). 13C MR: (100MHz, CDCb): δ 79.05, 128.79, 129.34, 129.67, 134.09, 166.78. HRMS (-ESI): Calculated: 269.0075 (CioH8Cl2N40). Observed: 269.0000.
Figure imgf000181_0002
[0398] N-(4-bromobenzyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-50). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-Bromobenzylamine (160 \L, 1.1 mmol, Sigma, 479152) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white powder (0.11 g, 31% yield). ¾ NMR (400MHz, CDCb): 4.64 (d, J= 6.2Hz, 2H), 6.64 (t, J= 6.4 Hz, 1H), 7.18 (d, J= 8.3Hz, 2H), 7.48 (d, J= 8.4Hz, 2H). 13C NMR: (100MHz, CDCb): δ 44.87, 77.36, 122.25, 129.50, 132.20, 135.44, 166.04, 170.19, 171.36. HRMS (-ESI): Calculated: 330.9231 (CioH7BrCl2N4). Observed: 330.9156.
Figure imgf000182_0001
[0399] 4,6-dichloro-N-cyclopentyl-l,3,5-triazin-2-amine (KEA1-53). A solution of 2,4,6- trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Cyclopentylamine (1 10 \L, 1.1 mmol, Sigma, CI 15002) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding colorless oil (0.02 g, 7% yield). ¾ NMR (400MHz, CDCb): 1.54 - 1.41 (m, 2H), 1.81 - 1.60 (m, 4H), 2.16 - 1.99 (m, 2H), 4.35 (q, J= 7.0Hz, 1H), 5.74 (d, J= 6.4 Hz, 1H). 13C NMR: (100MHz, CDCb): δ 23.65, 33.02, 53.38, 165.39, 169.87, 171.04. HRMS (-ESI): Calculated: 330.9231
(C8HioCl2N4). Observed: 330.9156.
Figure imgf000183_0001
[0400] 4,6-dichloro-N-(2,4-dimethoxybenzyl)-l,3,5-triazin-2-amine (KEA1-54). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2,4- dimethoxybenzylamine (160 \L, 1.1 mmol, Sigma, 432725) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding an off-white solid (0.04 g, 12% yield). ¾ MR (400MHz, CDCh): 3.82 (d, J= 10.5Hz, 6H), 4.56 (d, J= 6.1Hz, 2H), 6.39 (t, J= 5.7Hz, 1H), 6.49 - 6.41 (m, 2H), 7.21 (d, J= 8.1Hz, 1H). 13C NMR: (100MHz, CDCh): δ 41.49, 55.53, 55.57, 98.80, 104.07, 116.92, 130.90, 158.77, 161.25, 165.52, 169.91, 170.93. HRMS (- ESI): Calculated: 313.0337 (C12H12CI2N4O2). Observed: 313.0261.
Figure imgf000183_0002
[0401] 4,6-dichloro-N-(3,4-difluorobenzyl)-l,3,5-triazin-2-amine (KEA1-55). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 3,4,-difluorobenzylamine (130 μΕ, 1.1 mmol, Sigma, 264407) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding an off-white solid (0.16 g, 50% yield). ¾ NMR (400MHz, CDCb): 4.64 (d, J= 6.3Hz, 2H), 6.37 (t, J = 5.6Hz, 1H), 7.03-7.06 (m, 1H), 7.20 - 7.10 (m, 2H). * 1.60 (s) is negligible water, 1.25 (s) is negligible grease. 13C MR: (100MHz, CDCb): δ 44.48, 44.50, 117.03, 117.85, 118.02, 122.72, 123.83, 123.86, 123.93, 133.44, 166.09, 170.33, 171.42. HRMS (-ESI): Calculated: 288.9938 (C10H6CI2F2N4). Observed: 288.9862.
Figure imgf000184_0001
[0402] 4,6-dichloro-N-(3,4-dimethoxybenzyl)-l,3,5-triazin-2-amine (KEA1-56). A solution of 2,4,6-trichloro-l,3,5-triazine (0.23 g, 1.3 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3,4- dimethoxybenzylamine (160 \L, 1.1 mmol, Sigma, V1309) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.04 g, 10% yield). ¾ NMR (400MHz, CDCb): 3.87 (s, 6H), 4.59 (d, J= 5.9Hz, 2H), 6.29 (t, J= 6.3Hz, 1H), 6.84 (s, 3H). 13C NMR: (100MHz, CDCb): δ 45.53, 56.05, 56.08, 1 11.29, 111.43, 120.43, 128.71, 149.09, 149.38, 265.77, 170.14, 171.20. HRMS (-ESI): Calculated: 313.0337 (C12H12CI2N4O2). Observed: 313.0262.
Figure imgf000185_0001
[0403] 4,6-dichloro-N-(3,5-difluorobenzyl)-l,3,5-triazin-2-amine (KEA1-57). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3,5-difluorobenzylamine (130 \L, 1.1 mmol, Sigma, 469351) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white powder (0.03 g, 9% yield). 1H MR (400MHz, CDCb): 4.69 (d, J= 6.4Hz, 2H), 6.61 (t, J= 5.6Hz, 1H), 6.80 - 6.71 (m, 1H), 6.83 (d, J= 6.0Hz, 2H). * 1.60 (s) is negligible water, 1.25 (s) is negligible grease. 13C MR: (100MHz, CDCb): δ 44.59, 103.46, 103.71, 103.96, 110.34, 110.41, 110.52, 110.59, 140.44, 164.58, 166.24, 170.34, 171.50. HRMS (-ESI): Calculated: 288.9938 (C10H6CI2F2N4). Observed: 288.9663.
Figure imgf000185_0002
[0404] 4,6-dichloro-N-(4-fluorobenzyl)-l,3,5-triazin-2-amine (KEA1-58). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 4-fluorobenzylamine (120 μΐ., 1.1 mmol, Sigma, 162493) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white powder (0.11 g, 36% yield). ¾ NMR (400MHz, CDCb): 4.66 (d, J= 6.2Hz, 2H), 6.83 (t, J= 5.8Hz, 1H), 7.04 (t, J= 8.6Hz, 2H), 7.32 - 7.27 (m, 2H). C NMR: (100MHz, CDCb): δ 44.77, 77.36, 115.86, 116.08, 129.61, 129.69, 132.24, 132.28, 161.37, 163.82, 165.94, 170.07, 171.30. HRMS (- ESI): Calculated: 271.0032 (C10H7CI2FN4). Observed: 270.9957.
Figure imgf000186_0001
[0405] 4,6-dichloro-N-(2,4-dimethylbenzyl)-l,3,5-triazin-2-amine (KEA1-59). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 μΐ., 0.2 mmol, Sigma, 387649) was added. 3,5-dimethylbenzylamine (160 μΐ., 1.1 mmol, Sigma, CDS003079) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding an off-white solid (0.16 g, 53% yield). ¾ NMR (400MHz, CDCb): 2.31 (s, 6H), 4.61 (d, J= 6.0Hz, 2H), 6.90 (s, 3H), 6.94 (s, 1H). 13C NMR: (100MHz, CDCb): δ 21.33, 45.36, 125.52, 129.74,
136.19, 138.61, 165.76, 169.87, 171.13. HRMS (-ESI): Calculated: 281.0439 (C12H12CI2N4). Observed: 281.0364.
Figure imgf000186_0002
[0406] 4,6-dichloro-N-(furan-2-ylmethyl)-l,3,5-triazin-2-amine (KEA1-60). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 μΐ., 0.2 mmol, Sigma, 387649) was added. Furfurylamine (90 \L, 1.1 mmol, Sigma, F20009) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding an off-white solid (0.04 g, 14% yield). 1H MR (400MHz, CDCb): 4.68 (d, J= 5.9Hz, 2H), 6.40 - 6.26 (m, 2H), 6.51 (t, J= 5.2Hz, 1H), 7.38 (s, 1H). * 1.64 (s) is negligible water. 13C NMR: (100MHz, CDCb): δ 38.49, 108.66, 110.73, 142.96, 149.36, 165.81, 170.24, 171.20. HRMS (-ESI): Calculated: 242.9919 (C8H6C12N40). Observed: 242.9848.
Figure imgf000187_0001
[0407] 4,6-dichloro-N-(4-phenylbutan-2-yl)-l,3,5-triazin-2-amine (KEA1-61). A solution of 2,4,6-trichloro-l,3,5-triazine (0.23 g, 1.3 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 \L, 0.2 mmol, Sigma, 387649) was added, l-methyl-3-phenylpropylamine (170 \L, 1.1 mmol, Sigma, M70533) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding an off-white powder (0.27 g, 86% yield). ¾ NMR (400MHz, CDCb): 1.27 (d, J= 6.5Hz, 3H), 1.88 (q, J = 6.7Hz, 2H), 2.70 - 2.60 (m, 2H), 4.19 (m, J= 7.4Hz, 1H), 6.07 (d, J= 8.5Hz, 1H), 7.36 - 7.07 (m, 5H). 13C NMR: (100MHz, CDCb): δ 20.52, 32.27, 37.93, 47.56, 126.15, 128.23, 128.50, 140.82, 165.31, 169.73, 170.85.
[0408] HRMS (-ESI): Calculated: 295.0596 (Ci3Hi4Cl2N4). Observed: 295.0524.
Figure imgf000188_0001
[0409] 4,6-dichloro-N-(3-methoxypropyl)-l,3,5-triazin-2-amine (KEA1-62). A solution of 2,4,6-trichloro-l,3,5-triazine (0.25 g, 1.3 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3-methoxypropylamine (110 \L, 1.1 mmol, Sigma, M25007) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding colorless crystals (0.11 g, 41% yield). ¾ NMR (400MHz, CDCh): 1.85 (p, J= 5.6 Hz, 2H), 3.31 (s, 3H), 3.48 (t, J= 5.5Hz, 2H), 3.57 (q, J= 5.9Hz, 2H), 6.87 (t, J= 6.8Hz, 1H). 13C NMR: (100MHz, CDCh): δ 28.53, 40.51, 59.00, 71.54, 165.53, 169.69, 170.87. HRMS (-ESI): Calculated: 235.0232 (C7H10CI2N4O). Observed: 235.0160.
Figure imgf000188_0002
[0410] 4,6-dichloro-N-(2-chlorobenzyl)-l,3,5-triazin-2-amine (KEA1-63). A solution of 2,4,6-trichloro-l,3,5-triazine (0.25 g, 1.3 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2-chlorobenzylamine (130 \L, 1.1 mmol, Sigma, C27204) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.02 g, 6% yield). ¾ NMR (400MHz, CDCb): 4.75 (d, J= 6.3Hz, 2H), 6.34 (t, J= 5.6Hz, 1H), 7.32 - 7.27 (m, 2H), 7.47 - 7.38 (m, 2H). * 1.58 (s) is negligible water, 1.25 (s) is negligible grease. 13C MR: (100MHz, CDCb): δ 43.62, 127.40, 129.89, 129.97, 130.65, 133.92, 166.05, 170.30, 171.22. HRMS (-ESI): Calculated: 288.5440 (C10H7CI3N4). Observed: 288.9631.
Figure imgf000189_0001
[0411] 4,6-dichloro-N-(4-methoxybenzyl)-l,3,5-triazin-2-amine (KEA1-64). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.2 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-methoxybenzylamine (140 \L, 1.1 mmol, Sigma, Ml 1103) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white solid (0.21 g, 69% yield). ¾ NMR (400MHz, CDCb): 3.78 (s, 3H), 4.59 (d, J= 6.1 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 7.08 (t, J= 5.6 Hz, 1H), 7.21 (d, J= 8.7 Hz, 2H). 13C NMR: (100MHz, CDCb): δ 44.88, 55.36, 114.27, 128.44, 129.22, 159.42, 165.66, 169.77, 171.06. HRMS (- ESI): Calculated: 283.0232 (C11H10CI2N4O). Observed: 283.0156.
Figure imgf000189_0002
[0412] N-([l,r-biphenyl]-2-ylmethyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-67). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 2-phenylbenzylamine (190 μΐ., 1.1 mmol, Sigma, CDS004024) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white solid (0.18 g, 50% yield). ¾ NMR (400MHz, CDCb): 4.63 (d, J= 6.1Hz, 2H), 6.62 (t, J= 5.7Hz, 1H), 7.45 - 7.15 (m, 9H). *2.15 is negligible acetone solvent. 13C NMR: (100MHz, CDCb): δ 43.51,127.48, 127.91, 128.20, 128.49, 128.94, 128.96, 128.97, 130.57, 133.89, 140.36, 142.17, 165.51, 169.62, 170.89. HRMS (- ESI): Calculated: 329.0439 (C16H12CI2N4). Observed: 329.0364.
Figure imgf000190_0001
[0413] N-([l,r-biphenyl]-3-ylmethyl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-68). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3-phenylbenzylamine (0.19 g, 1.0 mmol, Sigma, CDS003128) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.13 g, 37% yield). ¾ NMR (400MHz, CDCb): 4.73 (d, J= 6.1Hz, 2H), 6.73 (t, J= 5.2Hz, 1H), 7.30 - 7.23 (m, 1H), 7.36 (t, J= 7.3Hz, 1H), 7.43 (q, J= 7.5Hz, 3H), 7.54 (t, J= 10.0Hz, 4H). 13C NMR: (100MHz, CDCb): δ 45.46, 126.60, 126.64, 126.97, 127.19, 127.70, 128.95, 129.43, 136.95, 140.60, 142.00, 165.92, 169.94, 171.21. HRMS (-ESI): Calculated: 329.0439 (C16H12CI2N4). Observed: 329.0367.
Figure imgf000191_0001
[0414] 4,6-dichloro-N-(3-phenylpropyl)-l,3,5-triazin-2-amine (KEA1-69). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3-phenylpropylamine (150 \L, 1.1 mmol, Sigma, 8.41119) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a white, fluffy solid (0.15 g, 51% yield). ¾ MR (400MHz, CDCb): 1.97 (p, J= 7.4Hz, 2H), 2.70 (t, J = 7.6Hz, 2H), 3.52 (q, J= 6.7Hz, 2H), 6.56 (t, J= 5.4Hz, 1H), 7.22 - 7.17 (m, 3H), 7.29 (t, J = 7.3 Hz, 2H). 13C MR: (100MHz, CDCb): δ 30.51, 32.99, 41.14, 76.84, 126.35, 128.41, 128.66, 140.74, 165.92, 169.74, 171.10. HRMS (-ESI): Calculated: 281.0439 (C12H12CI2N4). Observed: 281.0367.
Figure imgf000191_0002
[0415] 4,6-dichloro-N-(4-phenylbutyl)-l,3,5-triazin-2-amine (KEA1-70). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 4-phenylbutylamine (170 μΐ., 1.1 mmol, Sigma, 145394) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding white crystals (0.22 g, 68% yield). ¾ NMR (400MHz, CDCb): 1.73 - 1.61 (m, 4H), 2.65 (t, J= 7.0Hz, 2H), 3.50 (q, J = 6.4Hz, 2H), 6.64 (t, J= 5.0Hz, 1H), 7.21 - 7.11 (m, 3H), 7.27 (t, J= 7.4Hz, 2H). 13C NMR: (100MHz, CDCb): δ 28.40, 28.60, 35.38, 41.44, 126.05, 128.44, 128.48, 141.72, 165.83, 169.65, 171.05. HRMS (-ESI): Calculated: 295.0596 (C13H14CI2N4). Observed: 295.0524.
Figure imgf000192_0001
[0416] 4,6-dichloro-N-phenethyl-l,3,5-triazin-2-amine (KEA1-71). A solution of 2,4,6- trichloro-l,3,5-triazine (0.22 g, 1.2 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Phenyl ethyl amine (140 μί, 1.1 mmol, Sigma, 241008) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding white crystals (0.20 g, 69% yield). ¾ NMR (400MHz, CDCb): 2.90 (t, J= 6.9Hz, 2H), 3.76 (q, J= 6.8Hz, 2H), 6.74 (t, J= 5.5Hz, 1H), 7.34 - 7.09 (m, 5H). 13C NMR: (100MHz, CDCb): δ 35.24, 42.71, 126.96, 128.84, 128.85, 137.77, 165.72, 169.64, 171.07. HRMS (-ESI): Calculated: 267.0283
(C11H10CI2N4). Observed: 267.0210.
Figure imgf000192_0002
[0417] 4,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)-l,3,5-triazin-2-amine (KEA1-72). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΐ., 0.2 mmol, Sigma, 387649) was added.
Tetrahydrofurfurylamine (110 μΐ., 1.1 mmol, Sigma, 131911) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (35% to
65% ethyl acetate in hexanes) yielding a white solid (0.12 g, 44% yield). ¾ NMR (400MHz, CDCb): 1.62 - 1.50 (m, 1H), 1.92 (p, J = 6.8 Hz, 2H), 2.03 (m, J= 13.0, 6.8 Hz, 1H), 3.40 (m, 1H), 3.76 (m, 2H), 3.81 - 3.67 (m, 2H), 3.87 (q, J= 6.8 Hz, 1H), 4.05 (m, J= 7.1, 3.3 Hz, 1H), 6.51 (t, J= 4.4Hz, 1H). 13C NMR: (100MHz, CDCb): δ 25.90, 28.75, 45.19, 68.36, 166.05, 170.05, 170.97. HRMS (-ESI): Calculated: 247.0232 (C8Hi0Cl2N4O). Observed: 247.0160.
Figure imgf000193_0001
[0418] 4,6-dichloro-N-(5,6,7,8-tetrahydronaphthalen-l-yl)-l,3,5-triazin-2-amine (KEA1- 73). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 5,6,7,8-tetrahydro-l- naphthylamine (150 \L, 1.1 mmol, Sigma, A80009) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a pale-pink solid (0.12 g, 38% yield). ¾ NMR (400MHz, CDCb): 1.81 (m, 4H), 2.71 (dt, J= 78.4, 5.8 Hz, 6H), 7.04 (d, J= 7.5Hz, 1H), 7.18 (t, J = 7.7Hz, 1H), 7.37 (s, 1H), 7.46 (d, J= 7.8Hz, 1H). 13C NMR: (100MHz, CDCb): δ 22.52, 22.75, 24.99, 29.74, 12.24, 125.93, 128.33, 131.02, 133.35, 138.85, 165.01, 170.22, 171.52. HRMS (-ESI): Calculated: 293.0439 (C13H12CI2N4). Observed: 293.0364.
Figure imgf000194_0001
[0419] 4,6-dichloro-N-(3-(trifluoromethyl)benzyl)-l,3,5-triazin-2-amine (KEA1-74). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 3-
(trifluoromethyl)benzylamine (150 \L, 1.1 mmol, Sigma, 263494) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.17 g, 48% yield). ¾ MR (400MHz, CDCb): 4.76 (d, J= 6.3Hz, 2H), 7.14 (t, J= 5.4Hz, 1H), 7.53 - 7.49 (m, 2H), 7.57 (s, 2H). 13C NMR: (100MHz, CDCb): δ 44.94, 124.58, 124.61, 125.04, 125.08, 129.57, 131.11, 131.13, 137.55, 166.14, 170.12, 171.42. HRMS (-ESI): Calculated: 320.0000 (C11H7CI2F3N4). Observed: 320.9924.
Figure imgf000194_0002
[0420] 4,6-dichloro-N-(4-(trifluoromethyl)benzyl)-l,3,5-triazin-2-amine (KEA1-75). A solution of 2,4,6-trichloro-l,3,5-triazine (0.23 g, 1.2 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 4- (trifluoromethyl)benzylamine (150 μΐ., 1.1 mmol, Sigma, 263508) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.04 g, 11% yield). ¾ NMR (400MHz, CDCb): 4.76 (d, J= 6.2Hz, 2H), 6.40 (t, J= 7.0Hz, 1H), 7.53 (dd, J= 79.8, 8.0 Hz, 4H). * 1.58 (s) is negligible water. C NMR: (100MHz, CDCb): δ 44.95, 126.04, 126.08, 128.01, 166.22, 170.33, 171.45. HRMS (-ESI): Calculated: 321.0000 (C11H7CI2F3N4). Observed: 320.9925.
Figure imgf000195_0001
[0421] 4,6-dichloro-N-trityl-l,3,5-triazin-2-amine (KEA1-76). A solution of 2,4,6- trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Triphenylmethylamine (0.31 g, 1.2 mmol, Sigma, 325430) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding a white solid (0.22 g, 49% yield). ¾ NMR (400MHz, CDCb): 7.09 (s, 1H), 7.32 - 7.20 (m, 15H). 13C NMR:
(100MHz, CDCb): δ 71.92, 127.57, 128.24, 128.79, 143.24, 165.67, 169.58, 170.03. HRMS (-ESI): Calculated: 405.0752 (C22H16CI2N4). Observed: 405.0676.
Figure imgf000195_0002
[0422] 4,6-dichloro-N-(naphthalen-l-yl)-l,3,5-triazin-2-amine (KEA1-77). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.2 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2-naphthylamine (0.15 g, 1.1 mmol, Sigma, N8381) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a tan solid (0.17 g, 54% yield). ¾ NMR (400MHz, CDCb): 7.53 - 7.45 (m, J= 11.6 Hz 3H), 7.90 - 7.76 (m, 4H), 8.06 (s, 1H). 13C MR: (100MHz, CDCb): δ 118.94, 120.67, 126.11, 127.09, 127.82, 127.91, 129.34, 131.37, 133.22, 133.58, 153.69, 164.29, 170.32, 171.55. HRMS (-ESI): Calculated: 289.0126 (Ci3H8Cl2N4). Observed: 289.0050.
Figure imgf000196_0001
[0423] 4,6-dichloro-N-(2,2,2-trifluoroethyl)-l,3,5-triazin-2-amine (KEA1-78). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2,2,2-fluoroethylamine (80 \L, 1.1 mmol, Sigma, 269042) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding white crystals (0.16 g, 60% yield). ¾ NMR (400MHz, CDCb): 4.23 (p, J= 8.5 Hz, 1H), 6.92 (t, J= 6.4Hz, 1H). 13C MR: (100MHz, CDCb): δ 42.48, 42.83, 166.73, 170.69, 171.65. HRMS (-ESI): Calculated: 244.9687 (C5H3C12F3N4). Observed: 244.9614.
Figure imgf000197_0001
[0424] 4,6-dichloro-N-(2,3-dihydro-lH-inden-l-yl)-l,3,5-triazin-2-amine (KEA1-79). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- dnsopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 1-aminoindan (140 \L, 1.1 mmol, Sigma, A59506) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding yellow solid (0.19 g, 62% yield). ¾ NMR (400MHz, CDCb): 1.96 - 1.87 (m, J= 5.3 Hz 1H), 2.74 - 2.66 (m, J= 4.4 Hz, 1H), 2.97 - 2.89 (m, J= 7.9 Hz, 1H), 3.09 - 3.00 (m, J = 3.9 Hz 1H), 5.63 (q, J= 7.7 Hz, 1H), 6.10 (d, J= 7.9 Hz, 1H), 7.29 - 7.20 (m, 4H). 13C NMR: (100MHz, CDCb): δ 30.25, 33.82, 56.91, 123.97, 125.25, 127.16, 128.79, 141.34, 143.46, 165.74,
170.20, 171.24. HRMS (-ESI): Calculated: 279.0283 (C12H10CI2N4). Observed: 279.0212.
Figure imgf000197_0002
[0425] 4,6-dichloro-N-(2,3-dihydro-lH-inden-2-yl)-l,3,5-triazin-2-amine (KEA1-80). A solution of 2,4,6-trichloro-l,3,5-triazine (0.26 g, 1.4 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 2-aminoindan (140 \L, 1.1 mmol, Sigma, 479128) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a dull- yellow solid (0.18 g, 57% yield). ¾ NMR (400MHz, CDCb): 2.86 (dd, J= 16.1, 4.2 Hz, 2H), 3.37 (dd, J= 16.1, 6.8 Hz, 2H), 5.05 - 4.63 (m, 1H), 6.21 (d, J= 7.3 Hz, 1H), 7.35 - 7.06 (m, 4H). 13C NMR: (100MHz, CDCb): δ 39.80, 52.93, 124.97, 127.26, 140.05, 165.42, 170.00, 171.08. HRMS (-ESI): Calculated: 279.0283 (C12H10CI2N4). Observed: 279.0216.
Figure imgf000198_0001
[0426] (3-((4,6-dichloro-l,3,5-triazin-2-yl)amino)phenyl)(phenyl)methanone (KEA1-81). A solution of 2,4,6-trichloro-l,3,5-triazine (0.22 g, 1.2 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΐ., 0.2 mmol, Sigma, 387649) was added. 3-aminobenzophenone (0.23 g, 1.1 mmol, Sigma, 255254) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (50% ethyl acetate in hexanes) yielding an off-white solid (0.28 g, 73% yield). ¾ NMR (400MHz, (CD3)2CO): 7.73 - 7.55 (m, 6H), 7.87 (d, J= 7.9 Hz, 2H), 7.99 (d, J= 7.3 Hz, 1H), 8.20 (s, 1H). *2.82, 2.79 (s) is residual solvent water. 13C MR: (150MHz, (CD3)2CO): δ 124.04, 124.14, 126.19, 126.29, 127.19, 19.41, 130.11, 130.69, 133.44, 138.03, 138.22, 139.11, 195.73. HRMS (-ESI): Calculated: 343.0232 (C16H10CI2N4O). Observed: 343.0155.
Figure imgf000198_0002
[0427] 4'-((4,6-dichloro-l,3,5-triazin-2-yl)amino)-[l,r-biphenyl]-4-carbonitrile (KEAl- 83). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΐ., 0.2 mmol, Sigma, 387649) was added. 4-(4- aminophenyl)benzonitrile (0.22 g, 1.1 mmol, Sigma, 644048) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a pale yellow solid (0.08 g, 21% yield). ¾ NMR (400MHz, CDCh): 7.57 (s, 1H), 7.78 - 7.62 (m, 8H). * 1.55 (s) is residual water in deuterated solvent. 13C MR: (150MHz, (CD3)2CO): δ 111.71, 119.38, 122.71, 122.81, 128.37, 128.66, 133.61, 145.37. HRMS (-ESI): Calculated: 340.0235 (Ci6H9Cl2N5).
Observed: 340.0160.
Figure imgf000199_0001
[0428] 4,6-dichloro-N-(3',5'-dichloro-[l, r-biphenyl]-4-yl)-l,3,5-triazin-2-amine (KEA1- 84). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-amino-3',5'- dichlorobiphenyl (0.26 g, 1.1 mmol, Sigma, BML00042)) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (20% to 80% ethyl acetate in hexanes) yielding a pale yellow solid (0.08 g, 21% yield). ¾ NMR (400MHz,
(CD3)2CO): 7.47 (t, J= 1.8 Hz, 1H), 7.71 (d, J= 1.8 Hz, 2H), 7.81 (d, J= 8.7 Hz, 2H), 7.90 (dd, J= 8.9, 2.3 Hz, 2H). 13C NMR: (100MHz, (CD3)2CO): δ 122.62, 126.17, 127.64, 128.56, 136.06. HRMS (-ESI): Calculated: 382.9503 (C15H8CI4N4). Observed: 382.9427.
Figure imgf000200_0001
[0429] 4,6-dichloro-N-(4'-ethyl-[l,r-biphenyl]-4-yl)-l,3,5-triazin-2-amine (KEA1-85). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-amino-4'- ethylbiphenyl (0.22 g, 1.1 mmol, Sigma, 772240) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding white crystals (0.19 g, 50% yield). ¾ NMR (400MHz, CDCb): 1.28 (t, J= 7.6 Hz, 3H), 2.70 (q, J= 7.6 Hz, 2H), 7.39 (dd, J= 88.4, 8.0 Hz, 4H), 7.65 - 7.55 (m, 4H), 7.73 (s, 1H). 13C NMR: (100MHz, CDCb): δ .13, 15.70, 28.64, 121.71, 126.94, 127.79, 128.54, 134.71, 137.46, 138.85, 143.86, 164.13. HRMS (-ESI): Calculated:
343.0596 (C17H14CI2N4). Observed: 343.0525.
Figure imgf000200_0002
[0430] N-([l,r-biphenyl]-4-yl)-4,6-dichloro-l,3,5-triazin-2-amine (KEA1-88). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-aminobiphenyl (0.19 g, 1.1 mmol, Sigma, A2898) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (10% to 90% ethyl acetate in hexanes) yielding a white solid (0.01 g, 3% yield). ¾ NMR (400MHz, CDCb): 7.36 (t, J= 7.3 Hz, 1H), 7.46 (t, J= 7.5 Hz, 2H), 7.67 - 7.55 (m, 7H). * 1.56 (s) is negligible water. 13C NMR: (100MHz, CDCb): δ 121.64, 127.06, 128.06, 129.04, 133.33, 158.96, 203.04. HRMS (-ESI): Calculated: 315.0283 (C15H10CI2N4). Observed: 315.0212.
Figure imgf000201_0001
[0431] 4,6-dichloro-N-(2,3-dihydro-lH-inden-4-yl)-l,3,5-triazin-2-amine (KEA1-90). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-aminoindan (130 \L, 1.1 mmol, Sigma, 162108) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding off- white crystals (0.15 g, 42% yield). ¾ NMR (400MHz, CDCb): 2.14 (p, J= 7.4 Hz, 2H), 2.92 (dt, J= 56.2, 7.4 Hz, 4H), 7.17 (dd, J= 32.7, 7.6 Hz, 2H), 7.41 (s, 1H), 7.64 (d, J= 8.0 Hz, 1H). 13C NMR: (100MHz, CDCb): δ 25.02, 30.51, 33.33, 77.36, 120.09, 122.58, 127.54, 131.86, 136.18, 146.13, 164.38, 165.12. HRMS (-ESI): Calculated: 279.0283 (C12H10CI2N4). Observed: 279.0211.
Figure imgf000201_0002
[0432] 4,6-dichloro-N-(2,3-dihydro-lH-inden-5-yl)-l,3,5-triazin-2-amine (KEA1-91). A solution of 2,4,6-trichloro-l,3,5-triazine (0.23 g, 1.2 mmol, Sigma, C95501) in
tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N- diisopropylethylamine (40 μΕ, 0.2 mmol, Sigma, 387649) was added. 5-aminoindan (0.14 g, 1.1 mmol, Sigma, 130877) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white powder (0.19 g, 54% yield). ¾ NMR (400MHz, CDCb): 2.10 (p, J= 7.5 Hz, 2H), 2.91 (dt, J= 14.3, 7.4 Hz, 4H), 7.22 (s, 2H), 7.36 (s, 1H), 7.72 (s, 1H). 13C NMR: (100MHz, CDCb): δ 25.38, 32.24, 32.81, 117.80, 119.69, 124.59, 133.37, 142.18, 145.37, 163.96, 169.81, 170.08. HRMS (-ESI): Calculated: 279.0283 (C12H10CI2N4). Observed: 279.0211.
Figure imgf000202_0001
[0433] 4,6-dichloro-N-(2,2-diethoxyethyl)-l,3,5-triazin-2-amine (KEA1-93). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. Aminoacetaldehydediethylacetal (160 \L, 1.1 mmol, Sigma, A37200) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.19 g, 61% yield). ¾ NMR (400MHz, CD3OD): 1.21 (t, J= 7.1 Hz, 6H), 3.53 (d, J= 5.2 Hz, 2H), 3.64 - 3.55 (m, 2H), 3.79 - 3.69 (m, H), 4.66 (t, J= 5.2 Hz, 1H). 13C NMR:
(100MHz, CD3OD): δ 15.60, 44.71, 63.80, 101.49, 167.47, 170.70, 171.43. HRMS (-ESI): Calculated: 279.0494 (C9H14CI2N4O2). Observed: 279.0420.
Figure imgf000203_0001
[0434] 4,6-dichloro-N-(4-methoxyphenyl)-l,3,5-triazin-2-amine (KEA1-94). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. ^-Anisidine (0.13 g, 1.1 mmol, Sigma, A88255) was then added to the solution. The reaction stirred at 0°C for 4 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (30% to 70% ethyl acetate in hexanes) yielding yellow-grey crystals (0.20 g, 66% yield). 1H MR (400MHz, (CD3)2CO): 3.82 (s, 3H), 6.99 (d, J= 9.0 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 9.76 (s, 1H). 2.80, 2.83 (s) is residual water in deuterated solvent. 13C NMR: (100MHz, (CD3)2CO): δ 55.74, 100.87, 114.90, 124.31, 124.41, 130.55, 158.33, 165.36, 170.33, 171.32. HRMS (-ESI): Calculated: 269.0075 (CioH8Cl2N40). Observed: 269.0004.
Figure imgf000203_0002
[0435] 4-((4,6-dichloro-l,3,5-triazin-2-yl)amino)cyclohexan-l-ol (KEA1-95). A solution of 2,4,6-trichloro-l,3,5-triazine (0.23 g, 1.2 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropyl ethyl amine (120 μΕ, 0.7 mmol, Sigma, 387649) was added. tra«5-4-aminocyclohexanol hydrochloride (0.18 g, 1.2 mmol, Sigma, 263761) was then added to the solution. The reaction stirred at 0°C for 5 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding an off- white, fluffy solid (0.13 g, 40% yield). ¾ NMR (400MHz, (CD3)2CO): 1.57 - 1.32 (m, 4H), 2.20 - 1.90 (m, 4H), 3.63 - 3.53 (m, 1H), 3.76 (d, J= 4.5 Hz, 1H), 3.92 - 3.81 (m, 1H), 7.89 (d, J= 5.7 Hz, 1H). *2.96 (s) is water in the solvent. 13C NMR: (100MHz, (CD3)2CO): δ 34.61, 50.80, 69.45, 166.21, 170.10, 171.09, 206.22. HRMS (-ESI): Calculated: 261.0388 (C9Hi2Cl2N40). Observed: 261.0317.
Figure imgf000204_0001
[0436] 4,6-dichloro-N-(4'-fluoro-[l,r-biphenyl]-4-yl)-l,3,5-triazin-2-amine (KEA1-97). A solution of 2,4,6-trichloro-l,3,5-triazine (0.11 g, 0.6 mmol, Sigma, C95501) in
tetrahydrofuran (12 mL) was cooled to 0°C. To the solution N-N-diisopropylethylamine (20\L, 0.1 mmol, Sigma, 387649) was added. 4-amino-4'-fluorobiphenyl (0.08 g, 0.4 mmol, Sigma, CDS014140) was dissolved in 5 mL of methanol and added to the solution. The reaction stirred at 0°C for 2 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary-evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary- evaporation. The compound was purified by silica gel chromatography (30% to 70% ethyl acetate in hexanes) yielding an off-white solid (0.02 g, 17% yield). ¾ NMR (400MHz, CDC13): 7.14 (t, J = 8.7Hz, 2H), 7.64 - 7.47 (m, 6H), 7.71 (s, 1H). * 1.26 (t), 2.06 (s), 4.13 (m) is residual ethyl acetate; 1.66 (s) is residual solvent water. 13C NMR: (100MHz, CDC13): δ 100.09, 115.82, 116.04, 121.77, 127.89, 128.57, 128.66, 135.05, 136.25, 136.29, 137.89, 163.92, 164.19, 170.42. HRMS (-ESI): Calculated: 333.0188 (Ci5H9Cl2FN4). Observed: 333.0113.
Figure imgf000204_0002
[0437] 4,6-dichloro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,3,5- triazin-2-amine (KEA1-98). A solution of 2,4,6-trichloro-l,3,5-triazine (0.20 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 μΐ., 0.2 mmol, Sigma, 387649) was added. 3- aminophenylboronic acid pinacol ester (0.23 g, 1.1 mmol, Sigma, 574686) was then added to the solution. The reaction stirred at 0°C for 2 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding a white solid (0.21 g, 53% yield). ¾ NMR (400MHz, CD3OD): 1.35 (s, 12H), 7.42 (t, J= 7.7 Hz, 1H), 7.65 (d, J= 7.3 Hz, 1H), 7.69 (s, 1H), 7.77 (s, 1H), 7.86 (d, J= 8.1 Hz, 1H). 13C NMR: (100MHz, CD3OD): δ 24.99, 84.29, 124.67, 127.67, 128.94, 132.34, 135.30, 164.34, 170.32. HRMS (-ESI):
Calculated: 365.0822 (C15H17BCI2N4O2). Observed: 365.0750.
Figure imgf000205_0001
[0438] 4,6-dichloro-N-(4-chlorophenyl)-l,3,5-triazin-2-amine (KEAl-100). A solution of 2,4,6-trichloro-l,3,5-triazine (0.21 g, 1.1 mmol, Sigma, C95501) in tetrahydrofuran (25 mL) was cooled in an ice bath to 0°C. To the solution N-N-diisopropylethylamine (40 \L, 0.2 mmol, Sigma, 387649) was added. 4-chloroaniline (0.14 g, 1.1 mmol, Sigma, C22415) was then added to the solution. The reaction stirred at 0°C for 3 hours and was monitored by TLC. Upon completion, the reaction was gravity filtered and the solvent was removed by rotary- evaporation. The resulting slurry was dissolved in DCM (50 mL) and washed with 5% citric acid solution (3x, lOOmL). The organic phase was collected and dried with MgS04. The solvent was removed by rotary-evaporation. The compound was purified by silica gel chromatography (15% to 85% ethyl acetate in hexanes) yielding white crystals (0.14 g, 47% yield). ¾ NMR (400MHz, CDCb): 7.44 (dd, J= 49.2, 8.9 Hz, 4H), 7.53 (s, 1H). 13C NMR: (100MHz, CDCh): δ 122.68, 129.56, 131.30, 134.42, 164.21. HRMS (-ESI): Calculated: 272.9580 (C9H5CI3N4). Observed: 272.9510.
[0439] References: [1] Gangadhar, N. M.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2007, 11 (1), 83; [2] Dixon, S. L; Stockwell, B. R. Curr. Opin. Chem. Biol. 2009, 13 (5-6), 549; [3] Smukste, I; Stockwell, B. R. Annu. Rev. Ge-nomics Hum. Genet. 2005, 6, 261; [4] Roberts, A. M; Ward, C. C; Nomura, D. K. Curr. Opin. Biotechnol. 2016, 43, 25; [5] Weerapana, E.; Simon, G. M; Cravatt, B. F. Nat. Chem. Biol. 2008, 4 (7), 405; [6] Backus, K. M; Correia,
B. E.; Lum, K. M.; Forli, S.; Horning, B. D.; Gonzalez-Paez, G. E.; Chat-terjee, S.; Lanning, B. R.; Teijaro, J. R.; Olson, A. J.; Wolan, D. W.; Cravatt, B. F. Nature 2016, 534 (7608), 570;
[7] Roberts, A. M.; Miyamoto, D. K.; Huffman, T. R.; Bateman, L. A.; Ives, A. N.; Heslin, M. J.; Akopian, D.; Contreras, C. M.; Rape, M.; Ski-bola, C. F.; Nomura, D. K. ACS Chem. Biol. 2017; [8] Shannon, D. A.; Weerapana, E. Curr. Opin. Chem. Biol. 2015, 24, 18; [9] Shannon, D. A.; Banerjee, R.; Webster, E. R.; Bak, D. W.; Wang, C; Weerapana, E. J. Am. Chem. Soc. 2014, 136 (9), 3330; [10] Mitchell, D. A.; Morton, S. U.; Fernhoff, N. B.;
Marietta, M. A. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (28), 11609.
[0440] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS: 1. A compound having the formula:
Figure imgf000207_0001
wherein,
L1 is a bond, -C(O)-, -C(0) H-, -C(0)0-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R1 is halogen, -CX^, -CHX^, -CH2X1, -OCX^, - OCH2X1, -OCHX1!, -CN, -SOniR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0 R1C, - R1A0R1C, 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;
R2 is hydrogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX22, -C(0)R2C, -C(0)OR2C, -C(0) R2AR2B, -OR2D, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or sub stituted or unsub stituted heteroaryl ;
Each R1A, R1B, R1C, R1D, R2A, R2B, R2C and R2D is independently hydrogen, -CX3, -CHX2, -CH2X, -COOH, -CO H2, 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; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B 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; ml and vl are independently an integer from 1 to 2; and
X, X1, X2, X3, and X4 are independently -F, -CI, -Br, or -I;
CI
N^N wherein the compound is not H
2. The compound of claim 1, wherein L1 is a bond.
3. The compound of claim 1, wherein L1 is an unsubstituted alkylene.
4. The compound of claim 1, wherein L1 is an unsubstituted C1-C4 alkylene.
5. The compound of claim 1, wherein L1 is an unsubstituted methylene.
6. The compound of claim 1, wherein L1 is an unsubstituted heteroalkylene.
7. The compound of claim 1, wherein L1 is an unsubstituted 2 to 4 membered heteroalkylene.
8. The compound of claim 1, wherein L1 is - CH2CH2O-, -OCH2CH2-, -OCH2-, or -CH2O-.
9. The compound of claim 1, wherein L1 is an unsubstituted arylene.
10. The compound of claim 1, wherein L1 is an unsubstituted phenylene.
11. The compound of claim 1, wherein R1
is -C(0)R1C, -C(0)ORlc, -C(0) R1AR1B, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted 2 to 12 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
12. The compound of claim 1, wherein R1 is -C(0)-(unsubstituted phenyl), substituted or unsubstituted C1-C10 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.
13. The compound of claim 1, wherein R1 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, substituted or unsubstituted phenyl, unsubstituted naphthyl, unsubstituted benzodioxinyl, unsubstituted 5 to 6 membered heteroaryl, unsubstituted dioxoborolanyl, substituted phenyl, substituted biphenyl.
14. The compound of claim 1, wherein R1 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 substituted C1-C10 alkyl, substituted phenyl, or substituted biphenyl; each optionally substituted with 1 to 3 substituents selected from:
-Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, and -OCH2CH3.
15. The compound of claim 1, wherein R2 is hydrogen, -CX2 3, -CHX2 2, - CH2X2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
16. The compound of claim 1, wherein R2 is hydrogen, -CX2 3, -CHX2 2, - CH2X2, unsubstituted Ci-C3 alkyl, or unsubstituted 2 to 3 membered heteroalkyl.
17. The compound of claim 1, wherein R2 is hydrogen.
18. The compound of claim 1, wherein X3 and X4 are independently -CI or -Br.
19. The compound of claim 1, wherein X3 and X4 are -CI.
20. The compound of claim 1, wherein the compound has a formula:
Figure imgf000210_0001
z20 is an integer from 0 to 5;
R20 is independently
halogen, -CX20 3, -CHX20 2, -CH2X20, -OCX20 3, -OCH2X20, -OCHX20 2, -CN, -OH, - H2, -COO H, -CO H2, -NO2, -SH, -S03H, -SO4H, -SO2 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HSO2H, - HC=(0)H, - HC(0)-OH, - HOH, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and
X20 are independently -F, -CI, -Br, or -I.
21. The compound of claim 20, wherein L1 is a bond, unsubstituted C1-C2 alkylene, or unsubstituted phenylene.
22. The compound of claim 20, wherein the compound has a formula:
Figure imgf000210_0002
23. The compound of claim 20, wherein the compound has a formula:
Figure imgf000210_0003
24. The compound of claim 20, wherein the compound has a formula:
Figure imgf000211_0001
25. The compound of any one of claims 21 to 24, wherein R2 is hydrogen.
26. The compound of any one of claims 21 to 25, wherein X3 and X4 are each independently -Br, -F, or -CI.
27. The compound of any one of claims 21 to 26, wherein z20 is 0, 1, or 2; and R20 is -Br, -F, -CI, -CN, -CF3, -CH3, -CH2CH3, -C6H5, -OH, -OCH3, or -OCH2CH3
28. The compound of claim 1, wherein the compound is:
Figure imgf000211_0002
29. A pharmaceutical composition comprising the compound of any claims 1 to 28 and a pharmaceutically acceptable excipient.
30. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a thioredoxin inhibitor.
31. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of one of claims 1 to 28.
32. The method of one of claims 30 to 31, wherein the cancer is breast cancer.
33. The method of one of claims 30 to 31, wherein the cancer is triple negative breast cancer.
34. The method of one of claims 30 to 31, wherein the effective amount of the thioredoxin inhibitor is administered by intraperitoneal injection.
35. A method of increasing Caspase 3 protein activity, said method comprising contacting a thioredoxin protein with a compound of one of claims 1 to 28.
36. The method of claim 35, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
37. The method of claim 35, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
38. A method of increasing apoptosis of a cell, said method comprising contacting a cell with a compound of one of claims 1 to 28.
39. The method of claim 38, wherein the compound contacts a thioredoxin in the cell.
40. The method of claim 39, wherein the compound contacts an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
41. The method of claim 39, wherein the compound covalently binds to an amino acid of the thioredoxin corresponding to lysine 72 of SEQ ID NO: 1.
42. The method of claim 38, comprising increasing Caspase 3 protein activity in the cell.
PCT/US2018/024134 2017-03-24 2018-03-23 Thioredoxin modulators and uses thereof Ceased WO2018175958A1 (en)

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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 *
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