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WO2018144869A1 - Compositions et procédés de modulation d'uba5 - Google Patents

Compositions et procédés de modulation d'uba5 Download PDF

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Publication number
WO2018144869A1
WO2018144869A1 PCT/US2018/016649 US2018016649W WO2018144869A1 WO 2018144869 A1 WO2018144869 A1 WO 2018144869A1 US 2018016649 W US2018016649 W US 2018016649W WO 2018144869 A1 WO2018144869 A1 WO 2018144869A1
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substituted
unsubstituted
membered
independently
heteroaryl
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Inventor
Daniel K. Nomura
Allison M. ROBERTS
Leslie A. BATEMAN
David K. MIYAMOTO
Tucker R. HUFFMAN
Carl C. WARD
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Definitions

  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • L 1 and an adjacent R 1 substituent may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the symbol zl is an integer from 0 to 5.
  • L 1 is a
  • R 4 is hydrogen, -CX 4 3 , -CHX 4 2 , - CH2X 4 , -OCX 4 3, -OCH2X 4 , -OCHX 4 2, -CN, -C(0)R 4A , -C(0)-OR 4A , -C(0)NR 4A R 4B , -OR 4A , 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.
  • L 2 is a
  • R 5 is hydrogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , -OCH2X 5 , -OCHX 5 2, -CN, -C(0)R 5A , -C(0)-OR 5A , -C(0)NR 5A R 5B , -OR 5A , 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.
  • the symbol E is an electrophilic moiety.
  • Each R 1A , R , R , R , R , R , R , and R 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • each X, X 1 , X 4 , and X 5 is independently - F, -CI, -Br, or -I.
  • the symbols nl, n4, and n5 are independently an integer from 0 to 4.
  • the symbols ml, m4, m5, vl, v4, and v5 are independently an integer from 1 to 2.
  • a pharmaceutical composition including a Ubiquitin-like modifier activating enzyme 5 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 Ubiquitin-like modifier activating enzyme 5 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 treating a disease associated with ubiquitin-like modifier activating enzyme 5 activity including administering to a subject in need thereof an effective amount of a Ubiquitin-like modifier activating enzyme 5 inhibitor.
  • a method of inhibiting ubiquitin-like modifier activating enzyme 5 activity including contacting the ubiquitin-like modifier activating enzyme 5 with a Ubiquitin-like modifier activating enzyme 5 inhibitor.
  • a method of inhibiting ubiquitin-like modifier activating enzyme 5 activity including contacting the Ubiquitin-like modifier activating enzyme 5 with a compound described herein.
  • a ubiquitin-like modifier activating enzyme 5 protein covalently bonded to a Ubiquitin-like modifier activating enzyme 5 inhibitor through the reacted residue of an electrophilic moiety.
  • a ubiquitin-like modifier activating enzyme 5 protein covalently bonded to a compound described herein.
  • FIGS. 1A-1D Coupling Reactive Fragment Screening with isoTOP-ABPP to Identify Covalent Ligands, Targets, and Druggable Hotspots for Pancreatic Cancer (FIG. 1 A), by coupling screening of cysteine-reactive fragment libraries with chemoproteomics. Shown schematically in FIGS. 1 A-1D is isoTOP-ABPP for target identification of lead cysteine-reactive fragments that impair triple-negative breast cancer cell viability. A library of cysteine-reactive fragments was screened in pancreatic cancer cells to identify leads that impair pancreatic cancer pathogenicity and used isoTOP-ABPP platforms to identify the targets and site of labeling of these leads (FIG. IB).
  • the compounds tested, from left to right in FIG. IB, are DKM 2-72, TRH 1-23, DKM 2-67, DKM 3-30, DKM 2-79, DKM 3-22, DKM 2-85, TRH 1-17, DKM 2-90, DKM 2-94, DKM 2-71, DKM 2-76, DKM 3-8, TRH, 1- 65, DKM 2-52, DKM 3-29, DKM 2-119, DKM 3-10, DKM 2-101, DKM 2-93, DKM 2-80, DKM 2-95, DKM 2-40, DKM 2-91, TRH 1-55, TRH 1-12, DKM 2-83, DKM 2-107, DKM
  • a library of cysteine-reactive acrylamides and chloroacetamides were screened in PaCa2 pancreatic cancer cells (50 ⁇ ) to identify any compounds that impaired PaCa2 48 h serum -free cell survival. Cell survival was assessed using Hoescht staining, (FIG. 1C). The compounds tested, from left to right in FIG.
  • 1C are TRH 1-12, DKM 2-76, DKM 2-101, DKM 2-72, DKM 3-30, DKM 2-40, DKM 2-71, DKM 2-85, TRH 1-65, DKM 2-91, DKM 2- 94, DKM 2-52, DKM 2-98, TRH 1-56, DKM 2-79, TRH 1-23, DKM 3-10, DKM 2-90, DKM 2-119, TRH 1-17, DKM 3-7, DKM 3-22, DKM 2-80, DKM 2-107, DKM 2-93, DKM 2-83, and DKM 2-67. Leads from this screen were counterscreened in HPDE cells to identify agents that did not significantly impair serum-free cell survival in these cells. (FIG.
  • FIGS. 2A-2F DKM 2-93 Targets the Catalytic Cysteine of UBA5, (FIG. 2A).
  • PaCa2 proteomes were pre-treated with DMSO or DKM 2-93 (50 ⁇ ) prior to labeling proteomes with IAyne and appending a biotin-azide handle bearing a TEV protease recognition site and an isotopically light (for DMSO-treated) and heavy (for DKM 2-93- treated) tag.
  • DMSO and DKM 2-93-treated proteomes were then mixed in a 1 : 1 ratio and subsequently avi din-enriched, tryptically digested, and then probe-modified tryptic peptides were released by TEV protease and analyzed using quantitative proteomic approaches.
  • Peptide ratios shown are average ratios for those probe-modified peptides that were identified in at least 2 out of 3 biological replicates. A light to heavy ratio of 1 indicates that the probe- labeled cysteine-bearing peptide was not bound by DKM 2-93, whereas a ratio >3 indicates bound sites, (FIG. 2D). Gel -based ABPP validation of UBA5 as a target of DKM 2-93.
  • DMSO or DKM 2-93 was preincubated with pure human UBA5 (30 min) prior to labeling with IAyne (10 ⁇ , 30 min), followed by rhodamine-azide conjugation by CuAAC,
  • FIG. 2F IsoTOP- ABPP analysis of cysteine-reactivity in pooled primary human pancreatic ductal
  • FIGS. 3 A-3C UBA5 Knockdown Impairs Pancreatic Cancer Pathogenicity.
  • FIG. 3 A UBA5 expression in Paca2 cells. UBA5 was transiently knocked down with siRNA and stably knocked down with shRNA and expression was determined by qPCR.
  • FIG. 3B Serum-free cell survival (48 h) from transient siRNA or stable shRNA knockdown of UBA5 in PaCa2 cells.
  • FIG. 4 Body weight of mice after tumor xenograft study. PaCa2 tumor xenograft growth in immune-deficient SCID mice. Mice were subcutaneously injected with PaCa2 cells to initiate the tumor xenograft study and treatments of mice were initiated with vehicle or
  • DKM 2-93 selectively alkylates C250 on protein UBA5.
  • C250 is the active site catalytic cysteine of UBA5, and projects outward toward into a small hole formed by the junctions of Ufml with UBA5.
  • Surrounding C250 are amino acids Asn-210, Glu-209, Leu- 254, Ser-253, and Ala-251.
  • DKM 2-93 may be participating in hydrogen bonding with the protein backbone or these amino acids. Along with hydrogen bonding, these amino acids may impart steric limits which DKM 2-93 is able to overcome, thus providing specificity of this compound.
  • DKM 2-93 blocks the active site cysteine thus preventing thioester bond formation between C250 on UBA5 and the adenylated C-terminal glycine of UFMl .
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(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-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - 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, 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, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • 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, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 - H-CH 2 -.
  • 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) 2 R'- represents both -C(0) 2 R'- 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 -S0 2 R.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like. [0027]
  • 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,
  • cycloalkyl en e 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.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula:
  • 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
  • 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.
  • 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.
  • each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.
  • substituents 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(0) -, -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), and silicon (Si).
  • a "substituent group,” as used herein, means a group selected from the following moieties: (A) oxo,
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S 0 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 , - HC(0) H 2 , - HS0 2 H,
  • -HC(0)H - HC(0)H, - HC(0)OH, - HOH, -OCCb, -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OC HI 2 , -OCHF 2 , unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl),
  • 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., C 3 -C 8 cycloalkyl, C 3 -C 6 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 -Cio aryl, C10 aryl, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S 0 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 ,- HC(0) H 2 , - HS0 2 H,
  • 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., 3 to 8 membered heterocycloalkyl, 3 to 6
  • - HSO2H 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocyclo
  • -HC(0)H - HC(0)H, - HC(0)OH, -NHOH, -OCCb, -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI2, -OCHF2, 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalky
  • 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 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 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 heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted moiety e.g., substituted alkyl, substituted
  • heteroalkyl substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group 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
  • each substituent group, size-limited substituent group, and/or lower substituent group is 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.
  • R Optically active
  • S S
  • D dibenzyl- and (L)-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.
  • 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.
  • 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.
  • 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. [0062] 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 distinguished as R 13 1 , R 13 2 , R 13 3 , R 13 4 , etc., wherein each of R 13 R 13 2 , R 13 3 , R 13 4 , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • a "covalent cysteine modifier moiety" as used herein refers to a substituent that is capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g.
  • cysteine corresponding to C250 of the human ubiquitin-like modifier activating enzyme 5 of SEQ ID NO:337) to form a covalent bond.
  • the covalent cysteine modifier moiety is typically electrophilic.
  • 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.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
  • 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.
  • 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 excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • a "Ubiquitin-like modifier activating enzyme 5 protein inhibitor” and "UBA5 inhibitor” is a substance (e.g., oligonucleotide, protein, composition, or compound) that negatively affects (e.g. decreases) the activity or function of ubiquitin-like modifier activating enzyme 5 relative to the activity or function of ubiquitin-like modifier activating enzyme 5 in the absence of the inhibitor (e.g., wherein the UBA5 inhibitor binds ubiquitin-like modifier activating enzyme 5).
  • a "ubiquitin-like modifier activating enzyme 5 inhibitor compound” or "UBA5 inhibitor compound” refers to a compound (e.g. a compound described herein, including embodiments) that reduces the activity of ubiquitin-like modifier activating enzyme 5 when compared to a control (e.g., the absence of the compound or a compound with known inactivity).
  • a control e.g., the absence of the compound or a compound with known inactivity.
  • 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 Cys250 when the selected residue occupies the same essential structural and/or spatial position as Cys250 in SEQ ID NO:337.
  • the position in the aligned selected protein aligning with Cys250 is said to correspond to Cys250.
  • 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 reticulon 4 protein (reference sequence) and the overall structures compared.
  • the amino acid that occupies the same essential structural position as Cys250 in the structural model relative to the reference sequence is said to correspond to the Cys250 residue.
  • 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.
  • 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.
  • activation activate
  • activating activator
  • 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.
  • 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).
  • UBE1DC1 refer to a protein (including homologs, isoforms, and functional fragments thereof) with ubiquitin-like modifier activating enzyme 5 activity.
  • the term includes any recombinant or naturally-occurring form of ubiquitin-like modifier activating enzyme 5 or variants thereof that maintain ubiquitin-like modifier activating enzyme 5 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype ubiquitin-like modifier activating enzyme 5).
  • the ubiquitin-like modifier activating enzyme 5 protein encoded by the UBA5 gene has the amino acid sequence set forth in or corresponding to Entrez 79876, UniProt Q9GZZ9, UniProt E7EQ61, UniProt E7EWE1, or RefSeq (protein) P 079094.
  • the ubiquitin-like modifier activating enzyme 5 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 P 079094.1. In embodiments, the sequence corresponds to
  • the ubiquitin-like modifier activating enzyme 5 is a human ubiquitin-like modifier activating enzyme 5, such as a human cancer causing ubiquitin-like modifier activating enzyme 5.
  • UBA5 has the following sequence:
  • 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 mye
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, 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.
  • 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, cerebnform 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, encepha
  • 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. In embodiments, the treating or treatment is no prophylactic treatment.
  • 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.
  • the administering does not include administration of any active agent other than the recited active agent.
  • 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.
  • 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 ubiquitin-like modifier activating enzyme 5 associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with ubiquitin-like modifier activating enzyme 5 (e.g. cancer).
  • a ubiquitin-like modifier activating enzyme 5 modulator is a compound that increases or decreases the activity or function or level of activity or level of function of ubiquitin-like modifier activating enzyme 5.
  • the modulator is an inhibitor of UBA5.
  • the modulator is an activator of UBA5.
  • 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.
  • a disease e.g. a protein associated disease, a cancer associated with ubiquitin-like modifier activating enzyme 5 activity, ubiquitin-like modifier activating enzyme 5 associated cancer, ubiquitin-like modifier activating enzyme 5 associated disease
  • the disease e.g. cancer
  • a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • a cancer associated with ubiquitin-like modifier activating enzyme 5 activity or function may be a cancer that results (entirely or partially) from aberrant ubiquitin-like modifier activating enzyme 5 function (e.g.
  • ubiquitin-like modifier activating enzyme 5 activity or function e.g. signaling pathway activity
  • a cancer associated with ubiquitin-like modifier activating enzyme 5 activity or function or a ubiquitin-like modifier activating enzyme 5 associated cancer may be treated with a ubiquitin-like modifier activating enzyme 5 modulator or ubiquitin-like modifier activating enzyme 5 inhibitor, in the instance where ubiquitin-like modifier activating enzyme 5 activity or function (e.g. signaling pathway activity) causes the cancer.
  • 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.
  • signalaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g.
  • binding of a ubiquitin-like modifier activating enzyme 5 protein with a compound as described herein may reduce the interactions between the ubiquitin-like modifier activating enzyme 5 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.
  • 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 N210, E209, L254, S253, and A251 of SEQ ID NO:337) 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.
  • 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 N210, E209, L254, S253, and A251 of SEQ ID NO:337).
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to N210, E209, L254, S253, and A251 of SEQ ID NO:337) 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 N210, E209, L254, S253, and A251 of SEQ ID NO:337) in a cell. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g.
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for a nucleic acid coding for one or more amino acids corresponding to N210, E209, L254, S253, and A251 of SEQ ID NO:337) 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 N210, E209, L254, S253, and A251 of SEQ ID NO:337) 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 N210, E209, L254, S253, and A251 of SEQ ID NO:337) and inhibit its function relative to the absence of the antisense nucleic
  • 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.
  • the nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence.
  • 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.
  • 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).
  • 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.
  • 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. 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., hex
  • 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;
  • 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 SA; ebselen; ecomustine; edelfosine; edrecolomab; efl ornithine; elemene; emitefur;
  • 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;
  • 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
  • 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
  • Strom elysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic glycosaminoglycans;
  • 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;
  • 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 beta- la
  • interferon gamma-lb 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; saf
  • Taxotere.TM compounds comprising the taxane skeleton, Erbulozole (i.e. R-
  • Dolastatin 10 i.e. DLS-10 and NSC-376128
  • Mivobulin isethionate i.e. as CI-980
  • Vincristine i.e. as 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.
  • Soblidotin i.e. TZT-1027
  • LS-4559-P Pulacia, i.e. LS-4577
  • LS-4578 Pulacia, i.e. LS-477-P
  • LS-4477 Pulacia
  • LS-4559 Pulsotin
  • 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.
  • NSCL-96F03-7 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.
  • Ubiquitin-like modifier activating enzyme 5 protein (UBA5) activity refers to the biological activity of the protein. Ubiquitin-like modifier activating enzyme 5 protein (UBA5) activity may be quantified by measuring the rate of cell division, cell survival, cell migration, liver toxicity, or cell death.
  • ubiquitin-like modifier activating enzyme 5 protein-ubiquitin-like modifier activating enzyme 5 inhibitor complex refers to a ubiquitin-like modifier activating enzyme 5 protein bonded (e.g., covalently bonded) to a Ubiquitin-like modifier activating enzyme 5 inhibitor (e.g., a compound described herein).
  • R 1 is independently halogen, -CXS, -CHX ⁇ , -CH2X 1 , -OCX ⁇ , -
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • L 1 and an adjacent R 1 substituent may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the symbol zl is an integer from 0 to 5.
  • L 1 is a
  • R 4 is hydrogen, -CX 4 3 , -CHX 4 2 , - CH2X 4 , -OCX 4 3 , -OCH2X 4 , -OCHX 4 2, -CN, -C(0)R 4A , -C(0)-OR 4A , -C(0) R 4A R 4B , -OR 4A , 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.
  • L 2 is a
  • R 5 is hydrogen, -CX 5 3 , -CHX 5 2, -CH2X 5 , -OCX 5 3 , - OCH2X 5 , -OCHX 5 2, -CN, -C(0)R 5A , -C(0)-OR 5A , -C(0)NR 5A R 5B , -OR 5A , 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.
  • the symbol E is an electrophilic moiety.
  • Each R 1A , R 1B , R 1C , R 1D , R 4A , R 4B , R 5A , and R 5B 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 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • each X, X 1 , X 4 , and X 5 is independently - F, -CI, -Br, or -I.
  • the symbols nl, n4, and n5 are independently an integer from 0 to 4.
  • the symbols ml, m4, m5, vl, v4, and v5 are independently an integer from 1 to 2. [0123]
  • the compound has the formula: (Ia), wherein R 1 , zl, L 2 , and E are as described herein including embodiments.
  • the compound has the formula: (lb), wherein R 1 , zl, L 2 , and E are as described herein including embodiments.
  • the compound has the formula: ( ⁇ ), wherein R 1 , L 1 , L 2 , and E are as described herein including embodiments.
  • the compound has the formula: (Ila), wherein R 1 , L 2 , and E are as described herein including embodiments
  • the compound has the formula: (lib), wherein R 1 , L 2 , and E are as described herein including embodiments
  • the compound has the formula: (He), wherein R 1 , L 2 , and E are as described herein including embodiments
  • the compound has the formula: (III), wherein L 1 , L 2 , and E are as described herein including embodiments.
  • R 1 1 and R 1 2 are independently hydrogen, halogen, -CX ⁇ , -CHX 1 !, -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX 1 !, -CN, -SOniR 1D ,
  • the compound has the formula:
  • R 1 J , R 1 2 , L 2 , and E are as described herein including embodiments.
  • the compound has the formula:
  • R 1 J , R 1 2 , L 2 , and E are as described herein including embodiments.
  • the compound has the formula: (Illb), wherein L 2 , and E are as described herein including embodiments.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX 1 !, -CN, -SR 1D , - R 1A R 1B , -C(0)R 1C , -C(0)OR lc , -C(0) R 1A R 1B , -OR 1D , 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.
  • the compound has the formula: (IV), wherein L 1 , L 2 , and E are as described herein including embodiments.
  • R , R 1 2 , R 1 ⁇ R 1 5 , and R 1 6 are independently hydrogen, halogen, -CX ⁇ , -CHX 1 !, -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D ,
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the compound has the formula: (IVa), wherein L 1 , L 2 , R 1 5 , and E are as described herein including embodiments.
  • the compound has the formula: (IVb), wherein
  • L 1 , L 2 , R 1 3 , and E are as described herein including embodiments.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH 2 X ⁇ -OCHX ⁇ , -CN, -SH, - H 2 , -C(0)OH, -C(0) H 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C3-C8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci 2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH 2 X ⁇ -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C3-C8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • two adjacent R 1 substituents are joined to form an unsubstituted cycloalkyl.
  • two adjacent R 1 substituents are joined to form an unsubstituted C3-C6 cycloalkyl.
  • R 1 is independently -CX X 3 . In embodiments, R 1 is independently - CHX In embodiments, R 1 is independently -CH2X 1 . In embodiments, R 1 is
  • R 1 independently -OCXS. In embodiments, R 1 is independently -OCH2X 1 . In embodiments, R 1 is independently -OCHX In embodiments, R 1 is independently -CN. In embodiments, R 1 is independently -SO n iR 1D . In embodiments, R 1 is independently -SO v i R 1A R 1B . In embodiments, R 1 is independently - HC(0) R 1A R 1B . In embodiments, R 1 is
  • R 1 is independently -N(0) m i.
  • R 1 is independently - R 1A R 1B .
  • R 1 is independently -C(0)R 1C .
  • R 1 is independently -C(0)-OR lc .
  • R 1 is independently -C(0) R 1A R 1B .
  • R 1 is
  • R 1 is independently -OR 1D .
  • R 1 is independently -NR 1A S0 2 R 1D .
  • R 1 is independently - R 1A C(0)R 1C .
  • R 1 is independently - R 1A C(0)OR lc .
  • R 1 is independently - R 1A OR lc .
  • R 1 is independently -OH.
  • R 1 is independently -OCH3,
  • R 1 is independently - H 2 .
  • R 1 is independently -COOH.
  • R 1 is independently -CO H2.
  • R 1 is independently -NO2.
  • R 1 is independently -SH.
  • R 1 is independently halogen.
  • R 1 is independently -F. In embodiments, R 1 is independently -CI. In embodiments, R 1 is independently -Br. In embodiments, R 1 is independently -I. In embodiments, R 1 is independently -CF3. In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CH 2 F. In embodiments, R 1 is independently -OCF3. In embodiments, R 1 is independently -OCH2F. In embodiments, R 1 is independently -OCHF2. In embodiments, R 1 is independently -OCH3. In embodiments, R 1 is independently -OCH2CH3. In embodiments, R 1 is independently - OCH2CH2CH3.
  • R 1 is independently -OCH(CH 3 ) 2 . In embodiments, R 1 is independently -OC(CH3)3. In embodiments, R 1 is independently -SCH3. In embodiments, R 1 is independently -SCH2CH3. In embodiments, R 1 is independently -SCH(CH3) 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 -CH2CH3. In embodiments, R 1 is independently -CH2CH2CH3. In embodiments, R 1 is independently -CH(CH 3 )2. In embodiments, R 1 is independently -C(CH 3 ) 3 . In
  • R 1 is independently -OCH2CH 3 . In embodiments, R 1 is independently -OCH3. In embodiments, R 1 is independently -N 3 . In embodiments, R 1 is independently -C(0)CH 3 . In embodiments, R 1 is independently -C(0)OCH 3 . In embodiments, R 1 is independently - C(0)OCH 2 CH 3 . In embodiments, R 1 is independently -C(0)OCH 2 CH 2 CH 3 . In
  • R 1 is independently -C(0)OCH(CH 3 )2. In embodiments, R 1 is independently -C(0)OC(CH 3 ) 3 . ** [0141] In embodiments, R 1 is independently hydrogen, halogen, -CX X 3 , -CHX X 2 , -
  • R 1 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl.
  • R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 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 1 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 1 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 1 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 1 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • 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). In embodiments, R 1 is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, R 1 is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 is independently unsubstituted aryl (e.g., C 6 -C 12 , 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). In embodiments, 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).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • a substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6.
  • two adjacent R 1 substituents may optionally be joined to form a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally 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).
  • two adjacent R 1 substituents 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).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 1 substituents may optionally be joined to form a substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally 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).
  • two adjacent R 1 substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally 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 1A is independently hydrogen. In embodiments, R 1A is independently -CX 1A 3 . In embodiments, R 1A is independently -CHX 1A 2 . In embodiments, R 1A is independently -CH 2 X 1A . In embodiments, R 1A is independently -CN. In
  • R 1A is independently -COOH. In embodiments, R 1A is
  • R 1A is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1A is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ).
  • R 1A is independently unsubstituted methyl. In embodiments, R 1A is independently unsubstituted ethyl. In embodiments, R 1A is independently unsubstituted propyl. In embodiments, R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted tert-butyl. In embodiments, R 1A 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 1A 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, R 1A 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, R 1A is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, 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 ). In embodiments, R 1A is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ). In embodiments, 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). In embodiments, R 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 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 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 heterocycloalkyl (e.
  • R 1A independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1A is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1A is independently unsubstituted aryl (e.g., C 6 -C 12 , 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). In embodiments, R 1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1B is independently hydrogen. In embodiments, R 1B is independently -CX 1B 3 . In embodiments, R 1B is independently -CHX 1B 2. In embodiments, R 1B is independently -03 ⁇ 4 ⁇ 1 ⁇ . In embodiments, R 1B is independently -CN. In embodiments, R 1B is independently -COOH. In embodiments, R 1B is independently -CO H2. In
  • X 1B is independently -F, -CI, -Br, or -I.
  • R 1B is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1B is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1B is independently unsubstituted methyl. In embodiments, R 1B is independently unsubstituted ethyl. In embodiments, R 1B is
  • R 1B 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 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 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 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 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 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B 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 1B is
  • R 1B is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • 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). In embodiments, R 1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • 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).
  • R is independently hydrogen.
  • R is independently -CX 1C 3 .
  • R 1C is independently -CHX 1C 2.
  • R 1C is independently -01 ⁇ 4 ⁇ 1 ⁇ : .
  • R 1C is independently -CN.
  • R 1C is independently -COOH.
  • R 1C is independently -CO H2.
  • X 1C is independently -F, -CI, -Br, or -I.
  • R 1C is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1C is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1C is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1C is independently unsubstituted methyl. In embodiments, R 1C is independently unsubstituted ethyl. In embodiments, R 1C is
  • R 1C independently unsubstituted propyl.
  • R 1C is independently unsubstituted isopropyl.
  • R 1C is independently unsubstituted tert-butyl.
  • R 1C 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 1C 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 1C 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 1C is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, 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-G5).
  • 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
  • R 1C independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • 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).
  • 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).
  • 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).
  • R is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1D is independently hydrogen. In embodiments, R 1D is independently -CX 1D 3. In embodiments, R 1D is independently -CHX 1D 2. In embodiments, R 1D is independently -CIHhX 10 . In embodiments, R 1D is independently -CN. In
  • R 1D is independently -COOH. In embodiments, R 1D is
  • X 1D is independently -F, -CI, -Br, or -I.
  • R 1D is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl.
  • R 1D is independently unsubstituted propyl. In embodiments, 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 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 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 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-G5, 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-C6, or C5-C 6 ).
  • 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). In embodiments, R 1D is
  • R 1D is independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • R 1D is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1D is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 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 membered). In embodiments, R 1D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 is independently hydrogen
  • R 1 is independently hydrogen
  • 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 1 is independently -OCH3.
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -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).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -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).
  • two adjacent R 1 substituents 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).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally 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 20 is independently oxo
  • R 20 is independently oxo
  • R 20 is independently unsubstituted ethyl. In embodiments, R 20 is
  • R 20 is independently substituted phenyl.
  • R 20 is independently unsubstituted phenyl.
  • R 20 is independently -CH 3 .
  • R 20 is independently - OCH 3 .
  • R 20 is independently -SCH 3 .
  • R 20 is independently - CN.
  • R 20 is independently R 21 -substituted phenyl.
  • R 20 is independently -CN.
  • R 20 is independently halogen.
  • R 20 is independently -CI.
  • R 20 is independently -F.
  • R 21 is independently oxo
  • R 21 is independently oxo
  • R 21 is independently unsubstituted ethyl. In embodiments, R 21 is -CN.
  • R 22 is independently oxo
  • R 22 is independently unsubstituted ethyl.
  • R 1A is independently
  • R 20A - substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 20A - 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 20A - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 20A -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered
  • R 1A is independently hydrogen, -CX 1A 3 , -CHX 1A 2 , -CH 2 X 1A , -CN, -COOH, -CO H 2 , 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 alkyl (e
  • 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 -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 20A - 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 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 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 j oined 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 , -CN, -OH, -NH 2, -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • halogen -CX 20A 3 , -CHX 20A 2 , -CH 2 X 20A , -OCX 20A 3 , -OCH 2 X 20A , -OCHX 20A 2 , -CN, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 ,
  • R 21A is independently oxo
  • halogen -CX 21A 3 , -CHX 21A 2 , -CH 2 X 21A , -OCX 21A 3 , -OCH 2 X 21A , -OCHX 21A 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • halogen -CX 21A 3 , -CHX 21A 2 , -CH 2 X 21A , -OCX 21A 3 , -OCH 2 X 21A , -OCHX 21A 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 22A is independently oxo
  • R 1B is independently
  • R 20B - substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2
  • 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 , C 4 -C 6 , or C5-C 6
  • R 20B - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 1B is independently
  • unsubstituted alkyl e.g., Ci- C 8 , Ci-C 6 , Ci-C 4 , 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 , C 4 -C 6 , 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.,
  • 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 j oined 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 , -CN, -OH, -NH 2 , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2 H2, - HNH2, -O H2,
  • R 21B is independently oxo
  • halogen -CX 21B 3 , -CHX 21B 2 , -CH 2 X 21B , -OCX 21B 3 , -OCH 2 X 21B , -OCHX 21B 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • 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. [0169] R is independently oxo,
  • 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., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 20C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 1C 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 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 c is independently oxo,
  • halogen -CX 20C 3 , -CHX 20C 2 , -CH 2 X 20C , -OCX 20C 3 , -OCH 2 X 20C , -OCHX 20C 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • R 21C is independently oxo
  • R 22C is independently oxo
  • halogen -CX 22C 3 , -CHX 22C 2 , -CH 2 X 22C , -OCX 22C 3 , -OCH 2 X 22C , -OCHX 22C 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 1D is independently
  • R 20D -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2
  • 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 , C 4 -C 6 , or C5-C 6
  • R 20D -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membere
  • 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 , -CN, -OH, -NH 2, -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • halogen -CX 20D 3 , -CHX 20D 2 , -CH 2 X 20D , -OCX 20D 3 , -OCH 2 X 20D , -OCHX 20D 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • R 21D is independently oxo
  • R 22D is independently oxo
  • zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In embodiments, zl is 4. In embodiments, zl is 5. In embodiments, zl is 0, 1, or 2.
  • L 1 is a bond, substituted or unsubstituted Ci-C 8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 - C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene.
  • L 1 is a bond.
  • L 1 is a bond.
  • L 1 is -S(0) 2 -.
  • L 1 is - R 4 -.
  • L 1 is -0-. In embodiments, L 1 is -S-. In embodiments, L 1 is -C(O)- . In embodiments, L 1 is -C(0) R 4 -. In embodiments, L 1 is - R 4 C(0)- . In embodiments, L 1 is - R 4 C(0) H-. In embodiments, L 1 is - HC(0)NR 4 -. In embodiments, L 1 is -C(0)0-. In embodiments, L 1 is -OC(O)-. In embodiments, L 1 is -NH-. In
  • L 1 is -C(0) H-. In embodiments, L 1 is - HC(O)- . In embodiments, L 1 is - HC(0) H-. In embodiments, L 1 is -CH 2 -. In embodiments, L 1 is -OCH 2 -. In embodiments, L 1 is -CH 2 0-. In embodiments, L 1 is -CH 2 CH 2 -. In embodiments, L 1 is - HCH 2 -. In embodiments, L 1 is -CH 2 H-. In embodiments, L 1 is a bond. In embodiments, L 1 is -CH 2 R 4 -. [0181] In embodiments, L 1 is a
  • 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 unsubstituted arylene e.g., C 6 -Cio or phenyl
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • 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 independently unsubstituted methylene. In embodiments, L 1 is independently unsubstituted ethylene.
  • 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). In embodiments, 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).
  • 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 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).
  • L 1 is independently substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6).
  • L 1 is independently substituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5- C 6 ).
  • L 1 is independently unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • 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). In embodiments, 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).
  • 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). [0183] In embodiments, 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 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 or unsubstituted heteroarylene (e.g
  • R 35 -substituted or unsubstituted alkylene e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 35 -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 35 -substituted or unsubstituted cycloalkylene e.g., C 3 -C 8 , C 3 -
  • L 1 is independently bond, -S(0) 2 -, -N(R 4 )-, -0-, -S-, -C(O)-, -C(0)N(R 4 )-, -N(R 4 )C(0)-, -N(R 4 )C(0) H-, - HC( 0)N(R 4 )-, -C(0)0-, -OC(O)-, unsubstituted alkylene (e.g., Ci-C 8 , Ci-Ce, 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
  • L 1 is independently unsubstituted ethylene. In embodiments, L 1 is
  • L 1 is independently - H-. In embodiments, L 1 is independently - CH2- H-. In embodiments, L 1 is independently -OCH2CH2 H-. In embodiments, L 1 is independently -CH2CH2CH2 H-. In embodiments, L is independently embodiments, L 1 is independently In embodiments, L 1 is independently
  • L 1 is independently .
  • L 1 i is
  • R is independently oxo
  • X 35 is independently -F, -CI, -Br, or -I. In embodiments, R 35 is independently unsubstituted methyl. In embodiments, R 35 is independently unsubstituted ethyl. In embodiments, R 35 is independently unsubstituted phenyl. [0186] R 36 is independently oxo,
  • X 36 is independently -F, -CI, -Br, or -I.
  • R 36 is independently unsubstituted methyl.
  • R 36 is independently unsubstituted ethyl.
  • R 37 is independently oxo,
  • R 4 is independently hydrogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCX 4 3 , - OCH 2 X 4 , -OCHX 4 2 , -CN, -C(0)R 4A , -C(0)OR 4A , -C(0)NR 4A R 4B , -OR 4A , substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C
  • R 4 is independently hydrogen. In embodiments, R 4 is
  • R 4 independently -CX 4 3 .
  • R 4 is independently -CHX 4 2 .
  • R 4 is independently -CH 2 X 4 .
  • R 4 is independently -CN.
  • R 4 is independently -C(0)R 4A .
  • R 4 is independently -C(0)-OR 4A .
  • R 4 is independently -C(0) R 4A R 4B . In embodiments, R 4 is
  • R 4 independently -COOH. In embodiments, R 4 is independently -CO H 2 . In embodiments, R 4 is independently -CF 3 . In embodiments, R 4 is independently -CHF 2 . In embodiments, R 4 is independently -CH 2 F. In embodiments, R 4 is independently -CH 3 . In embodiments, R 4 is independently -CH 2 CH 3 . In embodiments, R 4 is independently -CH 2 CH 2 CH 3 . In embodiments, R 4 is independently -CH(CH 3 ) 2 . In embodiments, R 4 is independently - C(CH 3 ) 3 .
  • R 4 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4 is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl.
  • R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted tert-butyl. In embodiments, R 4 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 4 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 4 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 4 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 4 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4 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 4 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 4 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 4 is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 4 is
  • R 4 independently substituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 4 is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 4 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 4 is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 4 is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A is independently hydrogen. In embodiments, R 4A is independently -CX 4A 3 . In embodiments, R 4A is independently -CHX 4A 2 . In embodiments, R 4A is independently -CH 2 X 4A . In embodiments, R 4A is independently -CN. In
  • R 4A is independently -COOH. In embodiments, R 4A is
  • X 4A is independently -F, -CI, -Br, or -I.
  • R 4A is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4A is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 4A is independently unsubstituted methyl. In embodiments, R 4A is independently unsubstituted ethyl.
  • R 4A is independently unsubstituted propyl. In embodiments, R 4A is independently unsubstituted isopropyl. In embodiments, R 4A is independently unsubstituted tert-butyl. In embodiments, R 4A 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 4A 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 4A 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 4A 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 4A is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 4A is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4A is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4A 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 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 4A 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 4A is
  • R 4A is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 4A is independently substituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 4A is
  • R 4A is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 4A is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 4A independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4B is independently hydrogen. In embodiments, R 4B is independently -CX 4B 3 . In embodiments, R 4B is independently -CHX 4B 2. In embodiments, R 4B is independently -03 ⁇ 4 ⁇ 4 ⁇ . In embodiments, R 4B is independently -CN. In embodiments, R 4B is independently -COOH. In embodiments, R 4B is independently -CO H2. In
  • X 4B is independently -F, -CI, -Br, or -I.
  • R 4B is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 4B is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 4B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 4B is independently unsubstituted methyl. In embodiments, R 4B is independently unsubstituted ethyl. In embodiments, R 4B is
  • R 4B is independently unsubstituted propyl.
  • R 4B is independently unsubstituted isopropyl.
  • R 4B is independently unsubstituted tert-butyl.
  • R 4B 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 4B 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 4B 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 4B is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 4B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 4B 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 4B 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 4B 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 4B is
  • R 4B is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 4B is independently substituted aryl (e.g., C 6 -Cio or phenyl).
  • R 4B is
  • R 4B is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 4B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A and R 4B 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 4A and R 4B 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 4A and R 4B 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 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4A and R 4B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 4 is independently
  • R 29 -substituted or unsubstituted alkyl e.g., Ci-Cs, Ci-C 6 , C1-C4, or Ci-C 2
  • R 29 -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 29 -substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C 6
  • R 29 - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membere
  • 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 -C
  • R 4 independently hydrogen. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl.
  • R 29 is independently oxo
  • R 30 is independently oxo
  • R 31 is independently oxo
  • R 4A is independently
  • R 29A -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2
  • R 29A -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 29A -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 29A -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 member
  • R 4A is independently hydrogen, -CX 4A 3 , -CHX 4A 2 , -CH 2 X 4A , -CN, -COOH, -CONH2, 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 (
  • X 4A is independently -F, -CI, -Br, or -I.
  • R 4A is independently hydrogen.
  • R 4A is independently unsubstituted methyl.
  • R 4A is independently unsubstituted ethyl.
  • R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29A -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 29A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 29A -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 29A -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to
  • R 4A and R 4B 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 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 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29A -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 4A and R 4B 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 29A is independently oxo
  • R 30A is independently oxo
  • R 31A is independently oxo
  • X 31A is independently -F, -CI, -Br, or -I.
  • R 31A is independently unsubstituted methyl.
  • R 31A is independently unsubstituted ethyl. [0206] In embodiments, R is independently
  • R 29B -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2
  • R 29B -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 29B -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 29B - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membere
  • R 4B is independently hydrogen, -CX 4B 3 , -CHX 4B 2 , -CH 2 X 4B , -CN, -COOH, -CONH 2 , 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 ary
  • X 4B is independently -F, -CI, -Br, or -I.
  • R 4B is independently hydrogen.
  • R 4B is independently unsubstituted methyl.
  • R 4B is independently unsubstituted ethyl.
  • R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29B -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 29B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 29B -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 29B -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to
  • R 4A and R 4B 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 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 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a R 29B -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 4A and R 4B 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 29B is independently oxo
  • R 30B is independently oxo
  • halogen -CX 30B 3 , -CHX 30B 2 , -CH 2 X 30B , -OCX 30B 3 , -OCH 2 X 30B , -OCHX 30B 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • R 31B is independently oxo
  • halogen -CX 31B 3 , -CHX 31B 2 , -CH 2 X 31B , -OCX 31B 3 , -OCH 2 X 31B , -OCHX 31B 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • L 2 is -NR 5 - or substituted or unsubstituted heterocycloalkyl ene including a ring nitrogen bonded directly to E. In embodiments, L 2 is -NR 5 -.
  • L 2 is a bond. In embodiments, L 2 is -S(0) 2 -. In embodiments, L 2 is -NR 5 -. In embodiments, L 2 is -0-. In embodiments, L 2 is -S-. In embodiments, L 2 is -C(O)- . In embodiments, L 2 is -C(0)NR 5 -. In embodiments, L 2 is -NR 5 C(0)- . In embodiments, L 2 is -NR 5 C(0)NH-. In embodiments, L 2 is -NHC(0)NR 5 -. In embodiments, L 2 is -C(0)0-. In embodiments, L 2 is -OC(O)-. In embodiments, L 2 is -NH-.
  • L 2 is -C(0) H-. In embodiments, L 2 is - HC(O)- . In embodiments, L 2 is - HC(0) H-. In embodiments, L 2 is -CH 2 -. In embodiments, L 2 is -OCH 2 -. In embodiments, L 2 is -CH 2 0-. In embodiments, L 2 is - HCH 2 -. In embodiments, L 2 is - CH 2 H-. [0213] In embodiments, L 2 is a
  • cycloalkylene e.g., C3-C8, C3-C6, C 4 -C 6 , 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 unsubstituted arylene e.g., C 6 -Cio or phenyl
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • L 2 is independently substituted or unsubstituted alkylene (e.g., Ci- C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2 ).
  • L 2 is independently substituted alkylene (e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2 ). In embodiments, L 2 is independently unsubstituted alkylene (e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2 ). In embodiments, L 2 is independently unsubstituted methylene. In embodiments, L 2 is independently unsubstituted ethylene. In embodiments, L 2 is independently unsubstituted propylene. In embodiments, L 2 is independently unsubstituted isopropylene. In embodiments, L 2 is independently unsubstituted tert-butylene.
  • L 2 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).
  • L 2 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).
  • L 2 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).
  • L 2 is independently substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C 6 ). In embodiments, L 2 is independently substituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5- C 6 ). In embodiments, L 2 is independently unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C 6 ).
  • L 2 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 2 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 2 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 2 is independently substituted or unsubstituted arylene (e.g., C 6 -Cio or phenylene). In embodiments, L 2 is independently substituted arylene (e.g., C 6 -Cio or phenylene). In embodiments, L 2 is independently unsubstituted arylene (e.g., C 6 -Cio or phenylene). In embodiments, L 2 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • L 2 is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L 2 is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • L 2 is independently
  • R 38 -substituted or unsubstituted alkylene e.g., Ci-C 8 , Ci-Ce, C1-C4, or Ci-C 2
  • R 38 -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 38 -substituted or unsubstituted cycloalkylene e.g., C 3 -C 8 , C 3 -C
  • L 2 is independently bond, -S(0) 2 -, -N(R 5 )-, -0-, -S-, -C(O)-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -N(R 5 )C(0) H-, - HC( 0)N(R 5 )-, -C(0)0-, -OC(O)-, unsubstituted alkylene (e.g., Ci-C 8 , Ci-Ce, 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
  • L 2 is independently unsubstituted ethylene. In embodiments, L 2 is
  • R 38 is independently oxo
  • R 39 is independently oxo
  • R 40 is independently oxo
  • R 5 is hydrogen, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is hydrogen or unsubstituted Ci-C 3 alkyl. In embodiments, R 5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. In embodiments, R 5 is hydrogen.
  • R 5 is independently hydrogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , - OCH 2 X 5 , -OCHX 5 2 , -CN, -C(0)R 5A , -C(0)OR 5A , -C(0)NR 5A R 5B , -OR 5A , substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , or Ci-C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ), substituted or unsubstituted alkyl (
  • R 5 is independently hydrogen. In embodiments, R 5 is
  • R 5 is independently -CX 5 3 .
  • R 5 is independently -CHX 5 2.
  • R 5 is independently -CH2X 5 .
  • R 5 is independently -CN.
  • R 5 is independently -C(0)R 5A .
  • R 5 is independently -C(0)-OR 5A .
  • R 5 is independently -C(0) R 5A R 5B . In embodiments, R 5 is
  • R 5 is independently -COOH. In embodiments, R 5 is independently -CO H2. In embodiments, R 5 is independently -CF 3 . In embodiments, R 5 is independently -CHF2. In embodiments, R 5 is independently -CH2F. In embodiments, R 5 is independently -CH 3 . In embodiments, R 5 is independently -CH2CH3. In embodiments, R 5 is independently -CH2CH2CH3. In embodiments, R 5 is independently -CH(CH 3 )2. In embodiments, R 5 is independently - C(CH 3 ) 3 . In embodiments, R 5 is hydrogen, substituted or unsubstituted Ci-C 6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 5 is hydrogen or unsubstituted Ci-C 3 alkyl. In embodiments, R 5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. [0222] In embodiments, R 5 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 5 is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl. In embodiments, R 5 is independently unsubstituted propyl. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted tert-butyl.
  • R 5 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 5 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 5 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 5 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ). In embodiments, R 5 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 5 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 5 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 5 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 5 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 5 is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5 is
  • R 5 independently substituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5 is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5 is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5 is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A is independently hydrogen. In embodiments, R 5A is independently -CX 5A 3. In embodiments, R 5A is independently -CHX 5A 2. In embodiments, R 5A is independently -03 ⁇ 4 ⁇ 5 ⁇ . In embodiments, R 5A is independently -CN. In embodiments, R 5A is independently hydrogen. In embodiments, R 5A is independently -CX 5A 3. In embodiments, R 5A is independently -CHX 5A 2. In embodiments, R 5A is independently -03 ⁇ 4 ⁇ 5 ⁇ . In embodiments, R 5A is independently -CN. In
  • R 5A is independently -COOH. In embodiments, R 5A is
  • X 5A is independently -F, -CI, -Br, or -I.
  • R 5A is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5A is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5A is independently unsubstituted methyl. In embodiments, R 5A is independently unsubstituted ethyl.
  • R 5A is independently unsubstituted propyl. In embodiments, R 5A is independently unsubstituted isopropyl. In embodiments, R 5A is independently unsubstituted tert-butyl. In embodiments, R 5A 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 5A 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 5A 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 5A 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 5A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 5A 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 5A 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 5A 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 5A is
  • R 5A is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 5A is independently substituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 5A is
  • R 5A is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5A is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5A independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5B is independently hydrogen. In embodiments, R 5B is independently -CX 5B 3. In embodiments, R 5B is independently -CHX 5B 2. In embodiments, R 5B is independently -CH2X 5B . In embodiments, R 5B is independently -CN. In embodiments, R 5B is independently -COOH. In embodiments, R 5B is independently -CO H2. In embodiments, R 5B is independently hydrogen. In embodiments, R 5B is independently -CX 5B 3. In embodiments, R 5B is independently -CHX 5B 2. In embodiments, R 5B is independently -CH2X 5B . In embodiments, R 5B is independently -CN. In embodiments, R 5B is independently -COOH. In embodiments, R 5B is independently -CO H2. In
  • X 5B is independently -F, -CI, -Br, or -I.
  • R 5B is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5B is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 5B is independently unsubstituted methyl. In embodiments, R 5B is independently unsubstituted ethyl. In embodiments, R 5B is
  • R 5B is independently unsubstituted propyl.
  • R 5B is independently unsubstituted isopropyl.
  • R 5B is independently unsubstituted tert-butyl.
  • R 5B 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 5B 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 5B 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 5B is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 5B is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 5B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 5B 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 5B 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 5B 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 5B is
  • R 5B is independently substituted or unsubstituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 5B is independently substituted aryl (e.g., C 6 -Cio or phenyl). In embodiments, R 5B is
  • R 5B is independently unsubstituted aryl (e.g., C 6 -Cio or phenyl).
  • R 5B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A and R 5B substituents bonded to the same nitrogen atom may 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 5A and R 5B 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 5A and R 5B 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 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 5A and R 5B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • an unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 5 is independently
  • R 32 -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2
  • R 32 -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 32 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 32 - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membere
  • 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 -C
  • R 5 is independently hydrogen. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl.
  • R 32 is independently oxo
  • R 33 is independently oxo
  • R 34 is independently oxo
  • X 34 is independently -F, -CI, -Br, or -I.
  • R 34 is independently unsubstituted methyl.
  • R 34 is independently unsubstituted ethyl.
  • R 5A is independently
  • R 32A -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2
  • R 32A -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 32A -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C 6
  • R 32A -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered
  • R 5A is independently hydrogen, -CX 5A 3 , -CHX 5A 2 , -CH 2 X 5A , -CN, -COOH, -CONH 2 , unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , Ci-C 4 , 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 , C 4 -C 6 , 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 al
  • X 5A is independently -F, -CI, -Br, or -I.
  • R 5A is independently hydrogen.
  • R 5A is independently unsubstituted methyl.
  • R 5A is independently unsubstituted ethyl.
  • R and R substituents bonded to the same nitrogen atom may optionally be joined to form a R 32A -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 32A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 32A -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 32A -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered
  • R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • 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 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32A -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 5A and R 5B 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 32A is independently oxo
  • halogen -CX 32A 3 , -CHX 32A 2 , -CH 2 X 32A , -OCX 32A 3 , -OCH 2 X 32A , -OCHX 32A 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • X 32A is independently -F, -CI, -Br, or -I. In embodiments, R 32A is independently unsubstituted methyl. In embodiments, R 32A is independently unsubstituted ethyl. [0236] R 33A is independently oxo,
  • halogen -CX 33A 3 , -CHX 33A 2 , -CH 2 X 33A , -OCX 33A 3 , -OCH 2 X 33A , -OCHX 33A 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 34A is independently oxo
  • halogen -CX 34A 3 , -CHX 34A 2 , -CH 2 X 34A , -OCX 34A 3 , -OCH 2 X 34A , -OCHX 34A 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 5B is independently
  • R 32B -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2
  • R 32B -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 32B -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6
  • R 32B - substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membere
  • R 5B is independently hydrogen, -CX 5B 3 , -CHX 5B 2 , -CH 2 X 5B , -CN, -COOH, -CONH 2 , 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 ary
  • X 5B is independently -F, -CI, -Br, or -I.
  • R 5B is independently hydrogen.
  • R 5B is independently unsubstituted methyl.
  • R 5B is independently unsubstituted ethyl.
  • R 5A and R 5B substituents bonded to the same nitrogen atom may optionally be joined to form a R 32B -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 32B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • a R 32B -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 32B -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to
  • R 5A and R 5B 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 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 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R and R substituents bonded to the same nitrogen atom may optionally be joined to form a R 32B -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 5A and R 5B 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 32B is independently oxo
  • R 33B -substituted or unsubstituted alkyl e.g., Ci-C 8 , Ci-Ce, C1-C4, or Ci-C 2
  • R 33B -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 33B - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C 6
  • R 33B -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 33B - substituted or unsubstituted aryl
  • halogen -CX 32B 3 , -CHX 32B 2 , -CH 2 X 32B , -OCX 32B 3 , -OCH 2 X 32B , -OCHX 32B 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • X 32B is independently -F, -CI, -Br, or -I. In embodiments, R 32B is independently unsubstituted methyl. In embodiments, R 32B is independently unsubstituted ethyl. [0241] R 33B is independently oxo,
  • R 34B is independently oxo
  • X 34B is independently -F, -CI, -Br, or -I. In embodiments, R 34B is independently unsubstituted methyl. In embodiments, R 34B is independently unsubstituted ethyl. [0243] In embodiments, 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
  • X 1 is -Br. In embodiments, X 1 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 5 is -F. In embodiments, X 5 is -CI. In embodiments, X 5 is -Br. In embodiments, X 5 is -I.
  • 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, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4.
  • ml is 1. In embodiments, ml is 2. In embodiments, m4 is 1. In embodiments, m4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2.
  • vl is 1. In embodiments, vl is 2. In embodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments, v5 is 2.
  • R 1 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX 1 !, -CN, -SH, - H2, -C(0)OH, -C(0) H 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci 2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 1 is independently -CXV In embodiments, R 1 1 is
  • R 1 1 independently -CHX ⁇ . In embodiments, R 1 1 is independently -CH2X 1 . In embodiments, R 1 1 is independently -OCXS. In embodiments, R 1 1 is independently -OCH2X 1 . In embodiments, R 1 1 is independently -OCHX In embodiments, R 1 1 is independently -CN. In embodiments, R 1 1 is independently -SO n iR 1D . In embodiments, R 1 1 is
  • R 1 1 is independently -SO v i R 1A R 1B . In embodiments, R 1 1 is independently -NHC(0) R 1A R 1B . In embodiments, R 1 1 is independently -N(0) m i. In embodiments, R 1 1 is
  • R 1 1 is independently - R 1A R 1B . In embodiments, R 1 1 is independently -C(0)R 1C . In embodiments, R 1 1 is independently -C(0)-0R 1C . In embodiments, R 1 1 is independently -C(0) R 1A R 1B . In embodiments, R 1 1 is independently -OR 1D . In embodiments, R 1 1 is
  • R 1 1 is independently - R 1A S0 2 R 1D .
  • R 1 1 is independently - R 1A C(0)R 1C .
  • R 1 1 is independently - R 1A C(0)0R 1C .
  • R 1 1 is
  • R 1 1 is independently - R 1A 0R 1C .
  • R 1 1 is independently -OH.
  • R 1 1 is independently -OCH3,
  • R 1 1 is independently - H 2 .
  • R 1 1 is independently -COOH.
  • R 1 1 is independently -CO H 2 .
  • R 1 1 is independently -N0 2 .
  • R 1 1 is independently -SH.
  • R 1 1 is independently halogen.
  • R 1 1 is independently -F.
  • R 1 1 1 is independently -CI.
  • R 1 1 1 is independently -Br.
  • R 1 1 is independently -I.
  • R 1 1 is independently -CF3. In embodiments, R 1 1 is independently -CHF 2 . In embodiments, R 1 1 is independently -CH 2 F. In embodiments, R 1 1 is independently -OCF3. In embodiments, R 1 1 is independently -OCH 2 F. In embodiments, R 1 1 is independently -OCHF 2 . In embodiments, R 1 1 is independently - OCH3. In embodiments, R 1 1 is independently -OCH 2 CH3. In embodiments, R 1 1 is independently -OCH 2 CH 2 CH 3 . In embodiments, R 1 1 is independently -OCH(CH 3 ) 2 . In embodiments, R 1 1 is independently -00( ⁇ 3 ⁇ 4)3.
  • R 1 1 is independently - SCH3. In embodiments, R 1 1 is independently -SCH 2 CH3. In embodiments, R 1 1 is independently -SCH 2 CH 2 CH3. In embodiments, R 1 1 is independently -SCH(CH3) 2 . In embodiments, R 1 1 is independently -SC(CH3)3. In embodiments, R 1 1 is independently - CH3. In embodiments, R 1 1 is independently -CH 2 CH3. In embodiments, R 1 1 is
  • R 1 1 is independently -CH 2 CH 2 CH3. In embodiments, R 1 1 is independently -CH(CH3) 2 . In embodiments, R 1 1 is independently -0( ⁇ 3 ⁇ 4)3.
  • R 1 1 is independently hydrogen, halogen, -CX ⁇ , -CHX ⁇ , - CH 2 X ⁇ -OCX , - OCH 2 X ⁇ -OCHX ⁇ , -CN, -SO n iR 1D , -SO v i R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i,
  • R 1 1 is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 1 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 1 is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 1 is independently unsubstituted methyl. In embodiments, R 1 1 is independently unsubstituted ethyl.
  • R 1 1 is independently unsubstituted propyl. In embodiments, R 1 1 is independently unsubstituted isopropyl. In embodiments, R 1 1 is independently unsubstituted tert-butyl. In embodiments, R 1 1 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 1 1 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 1 1 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 1 1 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, R 1 1 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ). In embodiments, R 1 1 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 1 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 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 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 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). In embodiments, R 1 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). In embodiments, R 1 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). In embodiments, R 1 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). In embodiments, R 1
  • R 1 1 independently substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1 1 is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1 1 is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1 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 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 1 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 1 is independently hydrogen
  • R 1 1 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 1 is independently hydrogen.
  • R 1 1 is independently unsubstituted methyl.
  • R 1 1 is independently unsubstituted ethyl.
  • R 1 1 is independently -OCH3.
  • R 1 1 is independently -
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C 8 , C3-C5, C4-C5, or C5-C5).
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclobutyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclopentyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclohexyl.
  • R 1 1 and R 1 2 are joined to form a substituted cyclobutyl.
  • R 1 1 and R 1 2 are joined to form a substituted cyclopentyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted cyclohexyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted cyclobutyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted cyclopentyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted cyclohexyl.
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkenyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ).
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclobutenyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclopentenyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted cyclohexenyl.
  • R 1 1 and R 1 2 are joined to form a substituted cyclobutenyl.
  • R 1 1 and R 1 2 are joined to form a substituted cyclopentenyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted cyclohexenyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted cyclobutenyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted cyclopentenyl. In embodiments, R 1 1 and R 1 2 are joined to form an
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heterocycloalkyl. In
  • R 1 1 and R 1 2 are joined to form a substituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 5 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 5 membered
  • R 1 1 and R 1 2 are joined to form an unsubstituted 6 membered heterocycloalkyl.
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkenyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 4 membered heterocycloalkenyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heterocycloalkenyl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 4 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 5 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 6 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 4 membered heterocycloalkenyl.
  • R 1 1 and R 1 2 are joined to form an unsubstituted 5 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 6 membered heterocycloalkenyl.
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted C 6 -Ci2 aryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted C 6 aryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted Co aryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted C 6 aryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted C12 aryl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted C 6 aryl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted C 12 aryl.
  • R 1 1 and R 1 2 may optionally be joined to form a substituted or unsubstituted 5 to 12 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 7 membered heteroaryl.
  • R 1 1 and R 1 2 are joined to form a substituted or unsubstituted 8 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 5 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 6 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 7 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form a substituted 8 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 5 membered heteroaryl.
  • R 1 1 and R 1 2 are joined to form an unsubstituted 6 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 7 membered heteroaryl. In embodiments, R 1 1 and R 1 2 are joined to form an unsubstituted 8 membered heteroaryl.
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-G5, C4-G5, or C5-G5). In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclobutyl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclopentyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclohexyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclobutyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclopentyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclohexyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted cyclobutyl.
  • R 1 1 and R 1 6 are joined to form an unsubstituted cyclopentyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted cyclohexyl. R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkenyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ). In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclobutenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclopentenyl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted cyclohexenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclobutenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclopentenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted cyclohexenyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted cyclobutenyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted cyclopentenyl. In embodiments, R 1 1 and R 1 6 are joined to form an
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heterocycloalkyl. In
  • R 1 1 and R 1 6 are joined to form a substituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 5 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 5 membered
  • R 1 1 and R 1 6 are joined to form an unsubstituted 6 membered heterocycloalkyl.
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkenyl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 4 membered heterocycloalkenyl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heterocycloalkenyl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 4 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 5 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 6 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 4 membered heterocycloalkenyl.
  • R 1 1 and R 1 6 are joined to form an unsubstituted 5 membered heterocycloalkenyl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 6 membered heterocycloalkenyl.
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted C 6 -Ci2 aryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted C 6 aryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted or unsubstituted Co aryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted C 6 aryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted C12 aryl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted C 6 aryl.
  • R 1 1 and R 1 6 are joined to form an unsubstituted C12 aryl.
  • R 1 1 and R 1 6 may optionally be joined to form a substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heteroaryl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heteroaryl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 7 membered heteroaryl.
  • R 1 1 and R 1 6 are joined to form a substituted or unsubstituted 8 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 5 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 6 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 7 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form a substituted 8 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 5 membered heteroaryl.
  • R 1 1 and R 1 6 are joined to form an unsubstituted 6 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 7 membered heteroaryl. In embodiments, R 1 1 and R 1 6 are joined to form an unsubstituted 8 membered heteroaryl.
  • R 1 2 is independently halogen, -CX ⁇ , -CHX 1 !, -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, - H 2 , -C(0)OH, -C(0) H 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C3-C8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 2 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX 1 !, -CN, -SH, - H 2 , -C(0)OH, -C(0) H 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C3-C8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 2 is independently -CXV In embodiments, R 1 2 is
  • R 1 2 independently -CHX ⁇ . In embodiments, R 1 2 is independently -CH2X 1 . In embodiments, R 1 2 is independently -OCXS. In embodiments, R 1 2 is independently -OCH2X 1 . In embodiments, R 1 2 is independently -OCHX In embodiments, R 1 2 is independently -CN. In embodiments, R 1 2 is independently -SO n iR 1D . In embodiments, R 1 2 is
  • R 1 2 is independently -SO v iNR 1A R 1B .
  • R 1 2 is independently -NHC(0)NR 1A R 1B .
  • R 1 2 is independently -N(0)mi.
  • R 1 2 is
  • R 1 2 is independently -NR 1A R 1B .
  • R 1 2 is independently -C(0)R 1C .
  • R 1 2 is independently -C(0)-0R 1C .
  • R 1 2 is independently -C(0)NR 1A R 1B .
  • R 1 2 is independently -OR 1D .
  • R 1 2 is
  • R 1 2 is independently -NR 1A S0 2 R 1D .
  • R 1 2 is independently -NR 1A C(0)R 1C .
  • R 1 2 is independently -NR 1A C(0)OR lc .
  • R 1 2 is
  • R 1 2 is independently -OH. In embodiments, R 1 2 is independently -OCH3, In embodiments, R 1 2 is independently -NH 2 . In embodiments, R 1 2 is independently -COOH. In embodiments, R 1 2 is independently -CONH2. In embodiments, R 1 2 is independently -NO2. In embodiments, R 1 2 is independently -SH. In embodiments, R 1 2 is independently halogen. In embodiments, R 1 2 is independently -F. In embodiments, R 1 2 is independently -CI. In embodiments, R 1 2 is independently -Br. In embodiments, R 1 2 is independently -I. In embodiments, R 1 2 is independently -CF3.
  • R 1 2 is independently -CHF 2 . In embodiments, R 1 2 is independently -CH 2 F. In embodiments, R 1 2 is independently -OCF3. In embodiments, R 1 2 is independently -OCH2F. In embodiments, R 1 2 is independently -OCHF2. In embodiments, R 1 2 is independently - OCH3. In embodiments, R 1 2 is independently -OCH2CH3. In embodiments, R 1 2 is independently -OCH2CH2CH3. In embodiments, R 1 2 is independently -OCH(CH3) 2 . In embodiments, R 1 2 is independently -00( ⁇ 3 ⁇ 4)3. In embodiments, R 1 2 is independently - SCH3. In embodiments, R 1 2 is independently -SCH2CH3.
  • R 1 2 is independently -SCH2CH2CH3. In embodiments, R 1 2 is independently -SCH(CH3)2. In embodiments, R 1 2 is independently -SC(CH3)3. In embodiments, R 1 2 is independently - CH3. In embodiments, R 1 2 is independently -CH2CH3. In embodiments, R 1 2 is
  • R 1 2 is independently -CH2CH2CH3. In embodiments, R 1 2 is independently -CH(CI3 ⁇ 4)2. In embodiments, R 1 2 is independently -C(CH3)3.
  • R 1 2 is independently hydrogen, halogen, -CX X 3 , -CHX X 2 , -
  • R 1 2 is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 2 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 2 is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 2 is independently unsubstituted methyl. In embodiments, R 1 2 is independently unsubstituted ethyl.
  • R 1 2 is independently unsubstituted propyl. In embodiments, R 1 2 is independently unsubstituted isopropyl. In embodiments, R 1 2 is independently unsubstituted tert-butyl. In embodiments, R 1 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). In embodiments, R 1 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 1 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).
  • R 1 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 1 2 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C 8 , C3-C6, C4-G5, or C5-C 6 ).
  • R 1 2 is independently substituted cycloalkyl (e.g., C3-C 8 , C3-G5, C4-C6, or C5-C 6 ).
  • R 1 2 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 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 1 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).
  • R 1 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 1 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 1 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 1 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 1
  • R 1 2 is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 2 is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 2 is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 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).
  • R 1 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 1 2 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 2 is independently hydrogen
  • R 1 2 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 2 is independently hydrogen.
  • R 1 2 is independently unsubstituted methyl.
  • R 1 2 is independently unsubstituted ethyl.
  • R 1 2 is independently -OCH3.
  • R 1 2 is independently - OCH 2 CH 3 .
  • R 1 3 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, - H2, -C(0)OH, -C(0) H 2 , -OH, -OCH 3 , substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C 3 -C 8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci 2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 3 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH 3 , substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C 3 -C 8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 3 is independently -CXV In embodiments, R 1 3 is
  • R 1 3 independently -CHX ⁇ . In embodiments, R 1 3 is independently -CH2X 1 . In embodiments, R 1 3 is independently -OCXS. In embodiments, R 1 3 is independently -OCH2X 1 . In embodiments, R 1 3 is independently -OCHX In embodiments, R 1 3 is independently -CN. In embodiments, R 1 3 is independently -SO n iR 1D . In embodiments, R 1 3 is
  • R 1 3 is independently -SO v iNR 1A R 1B .
  • R 1 3 is independently -NHC(0)NR 1A R 1B .
  • R 1 3 is independently -N(0) m i.
  • R 1 3 is
  • R 1 3 is independently -NR 1A R 1B .
  • R 1 3 is independently -C(0)R 1C .
  • R 1 3 is independently -C(0)-OR lc .
  • R 1 3 is independently -C(0)NR 1A R 1B .
  • R 1 3 is independently -OR 1D .
  • R 1 3 is independently - R 1A S0 2 R 1D .
  • R 1 3 is independently - R 1A C(0)R 1C .
  • R 1 3 is independently - R 1A C(0)0R 1C .
  • R 1 3 is
  • R 1A 0R 1C independently - R 1A 0R 1C .
  • R 1 3 is independently -OH.
  • R 1 3 is independently -OCH3, In embodiments, R 1 3 is independently - H 2 .
  • R 1 3 is independently -COOH.
  • R 1 3 is independently -CO H 2 .
  • R 1 3 is independently -N0 2 .
  • R 1 3 is independently -SH.
  • R 1 3 is independently halogen.
  • R 1 3 is independently -F.
  • R 1 3 is independently -CI.
  • R 1 3 is independently -Br.
  • R 1 3 is independently -I.
  • R 1 3 is independently -CF3. In embodiments, R 1 3 is independently -CHF 2 . In embodiments, R 1 3 is independently -CH 2 F. In embodiments, R 1 3 is independently -OCF3. In embodiments, R 1 3 is independently -OCH 2 F. In embodiments, R 1 3 is independently -OCHF 2 . In embodiments, R 1 3 is independently - OCH3. In embodiments, R 1 3 is independently -OCH 2 CH 3 . In embodiments, R 1 3 is independently -OCH 2 CH 2 CH 3 . In embodiments, R 1 3 is independently -OCH(CH3) 2 . In embodiments, R 1 3 is independently -OC(CH3)3. In embodiments, R 1 3 is independently - SCH3.
  • R 1 3 is independently -SCH 2 CH3. In embodiments, R 1 3 is independently -SCH 2 CH 2 CH3. In embodiments, R 1 3 is independently -SCH(CH3) 2 . In embodiments, R 1 3 is independently -SC(CH3)3. In embodiments, R 1 3 is independently - CH3. In embodiments, R 1 3 is independently -CH 2 CH3. In embodiments, R 1 3 is
  • R 1 3 is independently -CH 2 CH 2 CH3. In embodiments, R 1 3 is independently -CH(CH3) 2 . In embodiments, R 1 3 is independently -C(CH3)3.
  • R 1 3 is independently hydrogen, halogen, -CX X 3 , -CHX X 2 , - cn 2 x -ocx , -
  • R 1A R 1B substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-Ce, C1-C4, or Ci-C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C 8 , C3-C6, C4-G5, or C5-C6), substituted or unsubstituted heterocycloalkyl
  • R 1 3 is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 3 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 3 is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 3 is independently unsubstituted methyl. In embodiments, R 1 3 is independently unsubstituted ethyl.
  • R 1 3 is independently unsubstituted propyl. In embodiments, R 1 3 is independently unsubstituted isopropyl. In embodiments, R 1 3 is independently unsubstituted tert-butyl. In embodiments, R 1 3 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 1 3 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 1 3 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 1 3 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, R 1 3 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ). In embodiments, R 1 3 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 3 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 3 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 3 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 3 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 1 3 is
  • R 1 3 independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • R 1 3 is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1 3 is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1 3 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 3 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 3 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 3 is independently hydrogen
  • R 1 3 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 3 is independently hydrogen.
  • R 1 3 is independently unsubstituted methyl.
  • R 1 3 is independently unsubstituted ethyl.
  • R 1 3 is independently -OCH3.
  • R 1 3 is independently -
  • R 1 5 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH3, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C3-C 8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 5 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH3, substituted or unsubstituted Ci-Cs alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • R 1 5 is independently -CXV In embodiments, R 1 5 is
  • R 1 5 independently -CHX ⁇ . In embodiments, R 1 5 is independently -CH2X 1 . In embodiments, R 1 5 is independently -OCXS. In embodiments, R 1 5 is independently -OCH2X 1 . In embodiments, R 1 5 is independently -OCHX In embodiments, R 1 5 is independently -CN. In embodiments, R 1 5 is independently -SO n iR 1D . In embodiments, R 1 5 is
  • R 1 5 is independently -SO v i R 1A R 1B .
  • R 1 5 is independently -NHC(0) R 1A R 1B .
  • R 1 5 is independently -N(0) m i.
  • R 1 5 is
  • R 1 5 is independently -C(0)R 1C . In embodiments, R 1 5 is independently -C(0)-0R 1C . In embodiments, R 1 5 is independently -C(0) R 1A R 1B . In embodiments, R 1 5 is independently -OR 1D . In embodiments, R 1 5 is
  • R 1A S0 2 R 1D independently - R 1A S0 2 R 1D .
  • R 1 5 is independently - R 1A C(0)R 1C .
  • R 1 5 is independently - R 1A C(0)0R 1C .
  • R 1 5 is
  • R 1 5 is independently - R 1A 0R 1C .
  • R 1 5 is independently -OH.
  • R 1 5 is independently -OCH3,
  • R 1 5 is independently - H 2 .
  • R 1 5 is independently -COOH.
  • R 1 5 is independently -CO H2.
  • R 1 5 is independently -NO2.
  • R 1 5 is independently -SH.
  • R 1 5 is independently halogen.
  • R 1 5 is independently -F.
  • R 1 5 is independently -CI.
  • R 1 5 is independently -Br.
  • R 1 5 is independently -I.
  • R 1 5 is independently -CF3.
  • R 1 5 is independently -CHF 2 . In embodiments, R 1 5 is independently -CH 2 F. In embodiments, R 1 5 is independently -OCF3. In embodiments, R 1 5 is independently -OCH2F. In embodiments, R 1 5 is independently -OCHF2. In embodiments, R 1 5 is independently - OCH3. In embodiments, R 1 5 is independently -OCH2CH3. In embodiments, R 1 5 is independently -OCH2CH2CH3. In embodiments, R 1 5 is independently -OCH(CH3) 2 . In embodiments, R 1 5 is independently -00( ⁇ 3 ⁇ 4)3. In embodiments, R 1 5 is independently - SCH3. In embodiments, R 1 5 is independently -SCH2CH3.
  • R 1 5 is independently -SCH2CH2CH3. In embodiments, R 1 5 is independently -SCH(CH3) 2 . In embodiments, R 1 5 is independently -SC(CH3)3. In embodiments, R 1 5 is independently - CH3. In embodiments, R 1 5 is independently -CH2CH3. In embodiments, R 1 5 is independently -CH2CH2CH3. In embodiments, R 1 5 is independently -CH(CH3)2. In embodiments, R 1 5 is independently -C(CH 3 ) 3 .
  • R 1 5 is independently hydrogen, halogen, -CX X 3 , -CHX ⁇ , -
  • R 1 5 is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 5 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 5 is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 5 is independently unsubstituted methyl. In embodiments, R 1 5 is independently unsubstituted ethyl.
  • R 1 5 is independently unsubstituted propyl. In embodiments, R 1 5 is independently unsubstituted isopropyl. In embodiments, R 1 5 is independently unsubstituted tert-butyl. In embodiments, R 1 5 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 1 5 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 1 5 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 1 5 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 1 5 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 5 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 1 5 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 5 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 5 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 1 5 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 1 5 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 1 5 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 1
  • R 1 5 is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 5 is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 5 is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 5 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 5 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 5 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 5 is independently hydrogen
  • R 1 5 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 5 is independently hydrogen.
  • R 1 5 is independently unsubstituted methyl.
  • R 1 5 is independently unsubstituted ethyl.
  • R 1 5 is independently -OCH3.
  • R 1 5 is independently -
  • R 1 6 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX 1 !, -CN, -SH, - H2, -C(0)OH, -C(0) H 2 , -OH, -OCH3, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C 3 -C 8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 6 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, -OCH 3 , substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl;
  • substituted or unsubstituted C 3 -C 8 cycloalkyl substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 6 is independently -CXV In embodiments, R 1 6 is
  • R 1 6 independently -CHX ⁇ . In embodiments, R 1 6 is independently -CH2X 1 . In embodiments, R 1 6 is independently -OCXS. In embodiments, R 1 6 is independently -OCH2X 1 . In embodiments, R 1 6 is independently -OCHX In embodiments, R 1 6 is independently -CN. In embodiments, R 1 6 is independently -SO n iR 1D . In embodiments, R 1 6 is
  • R 1 6 is independently -SO v iNR 1A R 1B .
  • R 1 6 is independently -NHC(0)NR 1A R 1B .
  • R 1 6 is independently -N(0) m i.
  • R 1 6 is
  • R 1 6 is independently -NR 1A R 1B . In embodiments, R 1 6 is independently -C(0)R 1C . In embodiments, R 1 6 is independently -C(0)-OR lc . In embodiments, R 1 6 is independently -C(0)NR 1A R 1B . In embodiments, R 1 6 is independently -OR 1D . In embodiments, R 1 6 is
  • R 1 6 is independently -NR 1A S0 2 R 1D .
  • R 1 6 is independently -NR 1A C(0)R 1C .
  • R 1 6 is independently -NR 1A C(0)OR lc .
  • R 1 6 is
  • R 1 6 is independently -OH. In embodiments, R 1 6 is independently -OCH 3 , In embodiments, R 1 6 is independently -NH2. In embodiments, R 1 6 is independently -COOH. In embodiments, R 1 6 is independently -CO H2. In embodiments, R 1 6 is independently -NO2. In embodiments, R 1 6 is independently -SH. In embodiments, R 1 6 is independently halogen. In embodiments, R 1 6 is independently -F. In embodiments, R 1 6 is independently -CI. In embodiments, R 1 6 is independently -Br. In embodiments, R 1 6 is independently -I. In embodiments, R 1 6 is independently -CF3.
  • R 1 6 is independently -CHF2. In embodiments, R 1 6 is independently -CH2F. In embodiments, R 1 6 is independently -OCF3. In embodiments, R 1 6 is independently -OCH2F. In embodiments, R 1 6 is independently -OCHF2. In embodiments, R 1 6 is independently - OCH3. In embodiments, R 1 6 is independently -OCH2CH3. In embodiments, R 1 6 is independently -OCH2CH2CH3. In embodiments, R 1 6 is independently -OCH(CH 3 ) 2 . In embodiments, R 1 6 is independently -OC(CH3)3. In embodiments, R 1 6 is independently - SCH3. In embodiments, R 1 6 is independently -SCH2CH3.
  • R 1 6 is independently -SCH2CH2CH3. In embodiments, R 1 6 is independently -SCH(CH 3 )2. In embodiments, R 1 6 is independently -SC(CH3)3. In embodiments, R 1 6 is independently - CH3. In embodiments, R 1 6 is independently -CH2CH3. In embodiments, R 1 6 is
  • R 1 6 is independently -CH2CH2CH3. In embodiments, R 1 6 is independently -CH(CH3)2. In embodiments, R 1 6 is independently -C(CH3)3.
  • R 1 6 is independently hydrogen, halogen, -CX ⁇ , -CHX ⁇ , -
  • R 1 6 is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 6 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 6 is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 6 is independently unsubstituted methyl. In embodiments, R 1 6 is independently unsubstituted ethyl.
  • R 1 6 is independently unsubstituted propyl. In embodiments, R 1 6 is independently unsubstituted isopropyl. In embodiments, R 1 6 is independently unsubstituted tert-butyl. In embodiments, R 1 6 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 1 6 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 1 6 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 1 6 is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 6 is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 6 is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1 6 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 6 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 6 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 1 6 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 1 6 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 1 6 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 1
  • R 1 6 independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 6 is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 6 is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1 6 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 6 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 6 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 6 is independently hydrogen
  • R 1 6 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 6 is independently hydrogen.
  • R 1 6 is independently unsubstituted methyl.
  • R 1 6 is independently unsubstituted ethyl.
  • R 1 6 is independently -OCH 3 .
  • R 1 6 is independently - OCH 2 CH 3 .
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents are joined to form an unsubstituted cycloalkyl.
  • two adjacent R 1 substituents are joined to form an unsubstituted C 3 -C 6 cycloalkyl.
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • may optionally be joined to form a substituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents may optionally 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).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • unsubstituted aryl e.g., C 6 -Ci2, C 6 -Cio, or phenyl
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • may optionally be joined to form a substituted aryl e.g., C 6 - Ci2, C 6 -Cio, or phenyl
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • may optionally be joined to form an unsubstituted aryl e.g., C 6 -Ci2, C 6 -Cio, or phenyl.
  • two adjacent R 1 substituents may optionally 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).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- C 6 ).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • may optionally be joined to form a R 20 -substituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • may optionally e.g., R 1 1 and R 1 2
  • be joined to form a R 20 -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.
  • two adjacent R 1 substituents may optionally be joined to form a R 20 - 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).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • 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 1 substituents e.g., R 1 1 and R 1 2
  • R 1 1 and R 1 2 may optionally be joined to form a R 20 -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
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents e.g., R 1 1 and R 1 2
  • two adjacent R 1 substituents may optionally 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).
  • an unsubstituted heteroaryl e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ).
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclobutyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclopentyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclohexyl.
  • R 1 3 and R 1 2 are joined to form a substituted cyclobutyl.
  • R 1 3 and R 1 2 are joined to form a substituted cyclopentyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted cyclohexyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclobutyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclopentyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclohexyl.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted cycloalkenyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C 6 ).
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclobutenyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclopentenyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted cyclohexenyl.
  • R 1 3 and R 1 2 are joined to form a substituted cyclobutenyl.
  • R 1 3 and R 1 2 are joined to form a substituted cyclopentenyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted cyclohexenyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclobutenyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclopentenyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted cyclohexenyl.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heterocycloalkyl. In
  • R 1 3 and R 1 2 are joined to form a substituted 4 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 5 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 5 membered
  • R 1 3 and R 1 2 are joined to form an unsubstituted 6 membered heterocycloalkyl.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkenyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 4 membered heterocycloalkenyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heterocycloalkenyl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heterocycloalkenyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 4 membered heterocycloalkenyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 5 membered heterocycloalkenyl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 6 membered heterocycloalkenyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 4 membered heterocycloalkenyl.
  • R 1 3 and R 1 2 are joined to form an unsubstituted 5 membered heterocycloalkenyl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 6 membered heterocycloalkenyl.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted C 6 -Ci2 aryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted or unsubstituted C 6 aryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted or unsubstituted Co aryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted C 6 aryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted C 12 aryl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted C 6 aryl.
  • R 1 3 and R 1 2 are joined to form an unsubstituted Co aryl.
  • R 1 3 and R 1 2 may optionally be joined to form a substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 5 membered heteroaryl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 6 membered heteroaryl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 7 membered heteroaryl.
  • R 1 3 and R 1 2 are joined to form a substituted or unsubstituted 8 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 5 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 6 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 7 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form a substituted 8 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 5 membered heteroaryl.
  • R 1 3 and R 1 2 are joined to form an unsubstituted 6 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 7 membered heteroaryl. In embodiments, R 1 3 and R 1 2 are joined to form an unsubstituted 8 membered heteroaryl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclobutyl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclopentyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclohexyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclobutyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclopentyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclohexyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted cyclobutyl.
  • R 1 5 and R 1 6 are joined to form an unsubstituted cyclopentyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted cyclohexyl. R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted cycloalkenyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclobutenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclopentenyl.
  • a substituted or unsubstituted cyclopentenyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted cyclohexenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclobutenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclopentenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted cyclohexenyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted cyclobutenyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted cyclopentenyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted cyclohexenyl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 3 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 5 membered hetero
  • R 1 5 and R 1 6 are joined to form a substituted 4 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 5 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 4 membered heterocycloalkyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 5 membered
  • R 1 5 and R 1 6 are joined to form an unsubstituted 6 membered heterocycloalkyl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkenyl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 4 membered heterocycloalkenyl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heterocycloalkenyl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heterocycloalkenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 4 membered heterocycloalkenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 5 membered heterocycloalkenyl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 6 membered heterocycloalkenyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 4 membered heterocycloalkenyl.
  • R 1 5 and R 1 6 are joined to form an unsubstituted 5 membered heterocycloalkenyl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 6 membered heterocycloalkenyl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted C 6 -Ci2 aryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted C 6 aryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted or unsubstituted Co aryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted C 6 aryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted C 12 aryl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted C 6 aryl.
  • R 1 5 and R 1 6 are joined to form an unsubstituted Co aryl.
  • R 1 5 and R 1 6 may optionally be joined to form a substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 5 membered heteroaryl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 6 membered heteroaryl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 7 membered heteroaryl.
  • R 1 5 and R 1 6 are joined to form a substituted or unsubstituted 8 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 5 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 6 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 7 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form a substituted 8 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 5 membered heteroaryl.
  • R 1 5 and R 1 6 are joined to form an unsubstituted 6 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 7 membered heteroaryl. In embodiments, R 1 5 and R 1 6 are joined to form an unsubstituted 8 membered heteroaryl. [0301] In embodiments, E is a covalent cysteine modifier moiety.
  • R is independently hydrogen, halogen, CX 15 3 , -CHX 15 2 , - CH 2 X 15 , -CN, -SOnisR 150 , -SOvi 5 R 15A R 15B , - HNR 15A R 15B , -O R 15A R 15B ,
  • -C(0)-OR 15C -C(0) R 15A R 15B , -OR 15D , - R 15A S0 2 R 15D , - R 15A C(0)R 15C , - R 15A C(0)OR 15C , - R 15A OR 15C , -OCX 15 3 , -OCHX 15 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 16 is independently hydrogen, halogen, CX 16 3 , -CHX 16 2 , - CH 2 X 16 , -CN, -SOnieR 160 , -SOvi 6 R 16A R 16B , - HNR 16A R 16B , -O R 16A R 16B ,
  • - HC (0) HNR 16A R 16B , - HC(0) R 16A R 16B , -N(0) m i6, - R 16A R 16B , -C(0)R 16C ,
  • R 17 is independently hydrogen, halogen, CX 17 3 , -CHX 17 2 , - CH 2 X 17 , -CN, -SOnivR 17D , -SOvivNR 17A R 17B , -NHNR 17A R 17B , -ONR 17A R 17B ,
  • -NHC (0)NHNR 17A R 17B , -NHC(0)NR 17A R 17B , -N(0) m iv, -NR 17A R 17B , -C(0)R 17C ,
  • R 18 is independently hydrogen, -CX 18 3 , -CHX 18 2 , -CH 2 X 18 ,
  • Each R 15A , R 15B , R 15C , R 15D , R 16A , R 16B , R 16C , R 16D , R 17A , R 17B , R 17C , R 17D , R 18A , R 18B , R 18C , R 18D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, 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 15A and R 15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or
  • Each X, X , X 16 , X 17 and X 18 is independently -F, -CI, -Br, or -I.
  • the symbols nl5, nl6, nl7, vl5, vl6, and vl7, are independently and integer from 0 to 4.
  • the symbols ml5, ml6, and ml7 are independently and integer between 1 and 2.
  • E is: and X is -CI. In embodiments, E is: . In embodiments, X is -CI.
  • E is: d R 15 , R 16 , and R 17 are independently
  • E is : .
  • R 15 , R 16 , and R 17 are independently hydrogen.
  • E is: R 17 ; R 15 is independently hydrogen; R 16 is independently hydrogen or -CH2 R 16A R 16B ; R 17 is independently hydrogen; and R 16A and R 16B are independently hydrogen or unsubstituted alkyl.
  • E is: .
  • R 15 is independently hydrogen.
  • R 16 is independently hydrogen or -CH2 R 16A R 16B .
  • R 17 is independently hydrogen.
  • R 16A and R 16B are independently hydrogen or unsubstituted alkyl.
  • R 16A and R 16B are independently unsubstituted methyl.
  • E is: .
  • E is: .
  • E is: .
  • In embodiments E is: . In
  • E is:
  • E is:
  • X may independently be -F.
  • X may independently be -CI.
  • X may independently be -Br.
  • X may independently be -I.
  • X 15 may independently be -F.
  • X 15 may independently be -CI.
  • X 15 may independently be -Br.
  • X 15 may independently be -I.
  • X 16 may
  • X 16 may independently be -CI.
  • X 16 may independently be -Br.
  • X 16 may independently be -I.
  • X 17 may independently be -F.
  • X 17 may independently be -CI.
  • X 1 may independently be -Br.
  • X 17 may independently be -I.
  • X 18 may independently be -F.
  • X may independently be -CI.
  • X 18 may independently be -Br.
  • X 18 may independently be -I.
  • nl5 may independently be 2.
  • nl5 may independently be 3.
  • nl5 may independently be 4.
  • nl6 may independently be 0.
  • nl6 may independently be 1.
  • nl6 may independently be 2.
  • nl6 may independently be 3.
  • nl6 may independently be 4. nl7 may independently be 0. nl7 may independently be 1. nl7 may independently be 2. nl7 may independently be 3. nl7 may independently be 4. vl5 may independently be 0. vl5 may independently be 1. vl5 may independently be 2. vl5 may independently be 3. vl5 may independently be 4. vl6 may independently be 0. vl6 may independently be 1. vl6 may independently be 2. vl6 may independently be 3. vl6 may independently be 4. vl7 may independently be 0. vl7 may independently be 1. vl7 may independently be 2. vl7 may independently be 3. vl7 may independently be 4. ml 5 may independently be 1. ml 5 may independently be 2. ml6 may independently be 1.
  • R 15 is hydrogen. In embodiments, R 15 is halogen. In embodiments, R 15 is CX 15 3 . In embodiments, R 15 is -CHX 15 2. In embodiments, R 15 is - CH 2 X 15 . In embodiments, R 15 is -CN. In embodiments, R 15 is -SOnisR 150 . In embodiments, R 15 is -SOvi 5 R 15A R 15B . In embodiments, R 15 is - HNR 15A R 15B . In embodiments, R 15 is -O R 15A R 15B .
  • R 15 is - R 15A C(0)OR 15C . In embodiments, R 15 is - R 15A OR 15C . In embodiments, R 15 is -OCX 15 3 . In embodiments, R 15 is -OCHX 15 2 . In embodiments, R 15 is substituted or unsubstituted alkyl. In embodiments, R 15 is substituted or unsubstituted heteroalkyl. In embodiments, R 15 is substituted or unsubstituted cycloalkyl. In embodiments, R 15 is substituted or unsubstituted heterocycloalkyl. In embodiments, R 15 is substituted or unsubstituted aryl.
  • R 15 is substituted or unsubstituted heteroaryl. In embodiments, R 15 is substituted alkyl. In embodiments, R 15 is substituted heteroalkyl. In embodiments, R 15 is substituted cycloalkyl. In embodiments, R 15 is substituted heterocycloalkyl. In embodiments, R 15 is substituted aryl. In embodiments, R 15 is substituted heteroaryl. In embodiments, R 15 is unsubstituted alkyl. In embodiments, R 15 is unsubstituted heteroalkyl. In embodiments, R 15 is unsubstituted cycloalkyl. In embodiments, R 15 is unsubstituted heterocycloalkyl.
  • R 15 is unsubstituted aryl. In embodiments, R 15 is unsubstituted heteroaryl. In embodiments, R 15 is unsubstituted methyl. In embodiments, R 15 is unsubstituted ethyl. In embodiments, R 15 is unsubstituted propyl. In embodiments, R 15 is unsubstituted isopropyl. In embodiments, R 15 is unsubstituted butyl. In embodiments, R 15 is unsubstituted tert-butyl. [0311] In embodiments, R 15A is hydrogen. In embodiments, R 15A is -CX 3 . In
  • R 15A is -CN. In embodiments, R 15A is -COOH. In embodiments, R 15A
  • R 15A is -CHX 2 . In embodiments, R 15A is -CH 2 X. In embodiments, R 15A is unsubstituted methyl. In embodiments, R 15A is unsubstituted ethyl. In embodiments, R 15A is unsubstituted propyl. In embodiments, R 15A is unsubstituted isopropyl. In embodiments, R 15A is unsubstituted butyl. In embodiments, R 15A is unsubstituted tert- butyl. [0312] In embodiments, R is hydrogen. In embodiments, R is -CX3. In embodiments, R 15B is -CN. In embodiments, R 15B is -COOH. In embodiments, R 15B is -CONHi. In embodiments, R 15B is -CHX 2 . In embodiments, R 15B is -CH 2 X. In
  • R 15B is unsubstituted methyl. In embodiments, R 15B is unsubstituted ethyl. In embodiments, R 15B is unsubstituted propyl. In embodiments, R 15B is unsubstituted isopropyl. In embodiments, R 15B is unsubstituted butyl. In embodiments, R 15B is unsubstituted tert- butyl.
  • R 15C is hydrogen. In embodiments, R 15C is -CX3. In
  • R 15C is -CN. In embodiments, R 15C is -COOH. In embodiments, R 15C
  • R 15C is -CHX 2 . In embodiments, R 15C is -CH 2 X. In embodiments, R 15C is -CH 2 X. In
  • R 15C is unsubstituted methyl. In embodiments, R 15C is unsubstituted ethyl. In embodiments, R 15C is unsubstituted propyl. In embodiments, R 15C is unsubstituted isopropyl. In embodiments, R 15C is unsubstituted butyl. In embodiments, R 15C is unsubstituted tert- butyl. [0314] In embodiments, R 15D is hydrogen. In embodiments, R 15D is -CX3. In
  • R 15D is -CN. In embodiments, R 15D is -COOH. In embodiments, R 15D
  • R 15D is -CHX 2 . In embodiments, R 15D is -CH 2 X. In embodiments, R 15D is unsubstituted methyl. In embodiments, R 15D is unsubstituted ethyl. In embodiments, R 15D is unsubstituted propyl. In embodiments, R 15D is unsubstituted isopropyl. In embodiments, R 15D is unsubstituted butyl. In embodiments, R 15D is unsubstituted tert- butyl.
  • R 15 is independently hydrogen, oxo,
  • R 73 is independently oxo
  • R 15A is independently hydrogen, oxo,
  • R 72A is independently oxo
  • X 72A is halogen. In embodiments, X 72A is F. [0320] R 73A is independently oxo,
  • R 15B is independently hydrogen, oxo,
  • R 72B is independently oxo
  • X 72B is halogen. In embodiments, X 72B is F.
  • R 73B is independently oxo
  • R 72C is independently oxo
  • X 72C is halogen. In embodiments, X 72C is F.
  • R 73C is independently oxo
  • R 15D is independently hydrogen, oxo,
  • R 73D is independently oxo
  • R 16 is hydrogen. In embodiments, R 16 is halogen. In
  • R 16 is CX 16 3 . In embodiments, R 16 is -CHX 16 2 . In embodiments, R 16 is -
  • R 16 is CH 2 X 16 .
  • R 16 is -CN.
  • R 16 is -SOnieR 160
  • R 16 is -SOvi 6 NR 16A R 16B .
  • R 16 is -NHNR 16A R 16B .
  • R 16 is -ONR 16A R 16B .
  • R 16 is -NHC(0)NR 16A R 16B .
  • R 16 is -N(0) m i6.
  • R 16 is -NR 16A R 16B .
  • R 16 is -C(0)R 16C .
  • R 16 is -C(0)-OR 16C . In embodiments, R 16 is -C(0)NR 16A R 16B . In embodiments, R 16 is -OR 16D . In embodiments, R 16 is - NR 16A S0 2 R 16D . In embodiments, R 16 is -NR 16A C(0)R 16C . In embodiments, R 16 is - NR 16A C(0)OR 16C . In embodiments, R 16 is -NR 16A OR 16C . In embodiments, R 16 is -OCX 16 3 . In embodiments, R 16 is -OCHX 16 2 . In embodiments, R 16 is substituted or unsubstituted alkyl.
  • R 16 is substituted or unsubstituted heteroalkyl. In embodiments, R 16 is substituted or unsubstituted cycloalkyl. In embodiments, R 16 is substituted or unsubstituted heterocycloalkyl. In embodiments, R 16 is substituted or unsubstituted aryl. In embodiments, R 16 is substituted or unsubstituted heteroaryl. In embodiments, R 16 is substituted alkyl. In embodiments, R 16 is substituted heteroalkyl. In embodiments, R 16 is substituted cycloalkyl. In embodiments, R 16 is substituted heterocycloalkyl. In embodiments, R 16 is substituted aryl. In embodiments, R 16 is substituted heteroaryl.
  • R 16 is unsubstituted alkyl. In embodiments, R 16 is unsubstituted heteroalkyl. In embodiments, R 16 is unsubstituted cycloalkyl. In embodiments, R 16 is unsubstituted heterocycloalkyl. In embodiments, R 16 is unsubstituted aryl. In embodiments, R 16 is unsubstituted heteroaryl. In embodiments, R 16 is unsubstituted methyl. In embodiments, R 16 is unsubstituted ethyl. In embodiments, R 16 is unsubstituted propyl. In embodiments, R 16 is unsubstituted isopropyl. In embodiments, R 16 is unsubstituted butyl. In embodiments, R 16 is unsubstituted tert-butyl.
  • R 16A is hydrogen. In embodiments, R 16A is -CX 3 . In
  • R 16A is -CN. In embodiments, R 16A is -COOH. In embodiments, R 16A is -CO Hi. In embodiments, R 16A is -CHX 2 . In embodiments, R 16A is -CH 2 X. In embodiments, R 16A is unsubstituted methyl. In embodiments, R 16A is unsubstituted ethyl. In embodiments, R 16A is unsubstituted propyl. In embodiments, R 16A is unsubstituted isopropyl. In embodiments, R 16A is unsubstituted butyl. In embodiments, R 16A is unsubstituted tert- butyl.
  • R 16B is hydrogen. In embodiments, R 16B is -CX 3 . In
  • R 16B is -CN. In embodiments, R 16B is -COOH. In embodiments, R 16B is -CONH 2 . In embodiments, R 16B is -CHX 2 . In embodiments, R 16B is -CH 2 X. In
  • R 16B is unsubstituted methyl. In embodiments, R 16B is unsubstituted ethyl. In embodiments, R 16B is unsubstituted propyl. In embodiments, R 16B is unsubstituted isopropyl. In embodiments, R 16B is unsubstituted butyl. In embodiments, R 16B is unsubstituted tert- butyl. [0333] In embodiments, R 16C is hydrogen. In embodiments, R 16C is -CX 3 . In
  • R 16C is -CN. In embodiments, R 16C is -COOH. In embodiments, R 16C is -CONH 2 . In embodiments, R 16C is -CHX 2 . In embodiments, R 16C is -CH 2 X. In
  • R 16C is unsubstituted methyl. In embodiments, R 16C is unsubstituted ethyl. In embodiments, R 16C is unsubstituted propyl. In embodiments, R 16C is unsubstituted isopropyl. In embodiments, R 16C is unsubstituted butyl. In embodiments, R 16C is unsubstituted tert- butyl.
  • R 16D is hydrogen. In embodiments, R 16D is -CX 3 . In
  • R 16D is -CN. In embodiments, R 16D is -COOH. In embodiments, R 16D is -CONH 2 . In embodiments, R 16D is -CHX 2 . In embodiments, R 16D is -CH 2 X. In embodiments, R 16D is unsubstituted methyl. In embodiments, R 16D is unsubstituted ethyl. In embodiments, R 16D is unsubstituted propyl. In embodiments, R 16D is unsubstituted isopropyl. In embodiments, R is unsubstituted butyl. In embodiments, R is unsubstituted tert- butyl.
  • R 16 is independently hydrogen, oxo,
  • X 16 is halogen. In embodiments, X 16 is F.
  • R 75 is independently oxo
  • R 76 is independently oxo

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Abstract

La présente invention concerne, entre autres choses, des compositions et des procédés utiles pour inhiber l'enzyme 5 d'activation de modificateur de type ubiquitine.<i />
PCT/US2018/016649 2017-02-03 2018-02-02 Compositions et procédés de modulation d'uba5 Ceased WO2018144869A1 (fr)

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WO2024031970A1 (fr) * 2022-08-09 2024-02-15 中国海洋大学 Composé à activité antitumorale, son procédé de préparation et son utilisation
EP4081202A4 (fr) * 2019-12-24 2024-02-21 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
CN119285579A (zh) * 2024-11-07 2025-01-10 浙江工业大学 一种可聚合的二苯甲酮光引发剂及其合成方法和应用

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
US20210093597A1 (en) * 2019-09-27 2021-04-01 Emory University KRAS Agonists, Pharmaceutical Compositions, and Uses in Managing Cancer
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WO2024031970A1 (fr) * 2022-08-09 2024-02-15 中国海洋大学 Composé à activité antitumorale, son procédé de préparation et son utilisation
CN119285579A (zh) * 2024-11-07 2025-01-10 浙江工业大学 一种可聚合的二苯甲酮光引发剂及其合成方法和应用

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