WO2020146779A1 - Inhibiteurs de mtorc1 pour activer l'autophagie - Google Patents

Inhibiteurs de mtorc1 pour activer l'autophagie Download PDF

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WO2020146779A1
WO2020146779A1 PCT/US2020/013158 US2020013158W WO2020146779A1 WO 2020146779 A1 WO2020146779 A1 WO 2020146779A1 US 2020013158 W US2020013158 W US 2020013158W WO 2020146779 A1 WO2020146779 A1 WO 2020146779A1
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substituted
unsubstituted
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membered
independently
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Daniel K. Nomura
Roberto ZONCU
Yik Sham Clive CHUNG
Hijai SHIN
Stephen CANHAM
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Novartis AG
University of California Berkeley
University of California, San Diego
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Novartis AG
University of California Berkeley
University of California, San Diego
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals

Definitions

  • Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. It is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating aggregated proteins and damaged organelles. Accordingly, alterations in autophagy have been linked to a wide range of diseases and conditions, including aging, cancer, metabolic disorders, and
  • Ring A is a phenyl or 5 to 6 membered heteroaryl.
  • Ring B is a phenyl or 5 to 6 membered heteroaryl.
  • L 1 is independently a bond, -S(O) 2 -, -N(R 5 )-, -O-, -S-, -C(O)-, -C(O)N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 )C(O)NH-, -NHC(O)N(R 5 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent -L 1 -R 1 substituents may optionally be joined to form a substituted or
  • E is an electrophilic moiety.
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl,
  • R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl,
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3
  • R 4 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.
  • R 3 and R 4 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3
  • X 1 is independently–F, -Cl, -Br, or–I.
  • n1 is independently an integer from 0 to 4.
  • m1 and v1 are independently 1 or 2.
  • z1 is independently an integer from 0 to 5.
  • z3 is independently an integer from 0 to 2.
  • z4 is independently an integer from 0 to 5.
  • a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method for treating cancer in a subject in need thereof including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating a neurodegenerative disease the method including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating a metabolic disease the method including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating aging including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a subject in need thereof the method including administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell the method including contacting a Vacuolar H + -ATPase in the cell with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase including contacting the Vacuolar H + -ATPase with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase protein complex the method including contacting a ATP6V1A in the Vacuolar H + - ATPase protein complex with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell including contacting a ATP6V1A in the cell with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of an ATP6V1A the method including contacting the ATP6V1A with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for increasing autophagy in a subject in need thereof the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • Vacuolar H + -ATPase protein complex covalently bonded to a compound described herein, or a pharmaceutically acceptable salt thereof, which may be referred to herein as a Vacuolar H + -ATPase protein complex-compound complex.
  • a ATP6V1A protein covalently bonded to a compound described herein, or a pharmaceutically acceptable salt thereof, which may be referred to herein as a ATP6V1A protein-compound complex.
  • FIGS.1A-1F Covalent ligand screen for autophagy activators.
  • FIG.1A A covalent ligand screen in MEF cells. MEF cells expressing a fluorescent probe GFP-LC3- RFP-LC3DG to measure autophagic flux 32, were treated with vehicle DMSO or a covalent ligand (50 mM) for 24 h and GFP/RFP ratios were analyzed.
  • the covalent ligand or vehicle is: Torin 1, TRH 1-194, Rapamycin, EN6, KEA 1-37, DKM 3-16, DKM 2- 37, DKM 2-98, TRH 1-170, DKM 3-30, TRH 1-168, TRH 1-60, EN2, KEA 1-69, KEA 1- 100, TRH 1-57, DKM 3-3, KEA 1-46, TRH 1-179, TRH 1-58, TRH 1-140, TRH 1-152, EN59, EN53, KEA1-31, TRH 1-78, EN84, TRH 1-20, DKM 3-12, KEA 1-98, KEA 1-40, EN51, TRH 1-12, TRH 1-27, DKM 2-47, DKM 3-36, DKM 3-9, EN8, EN71, DKM 3-7, TRH 1-156, TRH 1-65, DKM 2-85, DKM 2-116, DKM 2-43, KEA 1-91, TRH 1-54, DKM 2- 71, EN62, TRH 1-59, EN54, KE
  • FIG.1B Compounds that showed significantly (p ⁇ 0.05 compared to vehicle-treated controls) lower GFP/RFP ratios in MEF cells were screened in HEK293A cells expressing the same fluorescent autophagic flux probe.
  • the covalent ligand or vehicle is: Torin1, EN6, DKM 3-16, Rapamycin, EN2, DKM 3-30, DKM 3-70, DKM 2-84, KEA 1-46, TRH 1-168, EN14, KEA 1-100, DKM 2-72, KEA 1-80, KEA 1-36, KEA 1-75, TRH 1-170, DKM 2-102, DKM 2-95, EN30, TRH 1-170, TRH 1-60, TRH 1-140, EN28, KEA 1-37, KEA 1-79, TRH 1-194, DMSO, DKM 3-3, DKM 2-89, KEA 1-69, DKM 2-37, TRH 1-50, DKM 2-98, and TRH 1- 155.
  • FIG.1C Structure of cysteine-reactive covalent ligand hit EN6 that shows autophagy activating in both MEF and HEK293A cells.
  • FIG.1D Dose-response of EN6 in HEK293A cells expressing the fluorescent autophagic flux probe.
  • FIG.1E LC3B levels in HEK293A cells treated with EN6 (50 mM).
  • FIG.1F LC3B puncta in HEK293 cells treated with vehicle DMSO, EN6 (50 mM), or Torin1 (0.25 mM).
  • FIGS.2A-2C Chemoproteomic profiling to identify targets of EN6.
  • FIG.2A Schematic of isoTOP-ABPP in which cells were pre-treated with DMSO or EN6 (50 mM, 4 h in situ) prior to labeling of proteomes in vitro with IA-alkyne (100 mM, 1 h), followed by appendage of isotopically light (for DMSO-treated) or heavy (for EN6-treated) TEV protease cleavable biotin-azide tags by copper-catalyzed azide-alkyne cycloaddition (CuAAC).
  • CuAAC copper-catalyzed azide-alkyne cycloaddition
  • FIG.2B isoTOP-ABPP analysis of EN6 (50 mM) in MEF cells in situ analyzed as described in FIG.2A.
  • FIG.2C Gel-based ABPP analysis of EN6 interactions with recombinant ATP6V1A.
  • FIGS.3A-3E EN6 inhibits mTORC1 signaling and lysosomal recruitment.
  • FIG. 3A mTORC1 signaling with EN6 treatment in HEK293A cells.
  • FIG.3B AKT signaling in HEK293 cells treated with vehicle DMSO, rapamycin (0.1 mM), Torin1 (0.25 mM), or EN6 (25 mM) for 4 h. AKT signaling was assessed by Western blotting.
  • FIG.3C ATP6V1A knockdown by short hairpin (shRNA) assessed by Western blotting.
  • FIG.3D LC3B levels and mTORC1 signaling in Hela cells treated with EN6.
  • FIG.4B Localization of TFEB- GFP in Hela cells treated with vehicle DMSO or EN6 (25 mM, 4 h). Cells were stained with Hoechst 33342 and GFP-TFEB were imaged by microscopy.
  • FIG. 4D Lysosomal acidification of HEK293A cells treated with vehicle DMSO, bafilomycin A1 (0.2 mM), EN6 (50 mM), or with co-treatment of EN6 and bafilomycin A1 for 4 h, readout by LysoSensor DND-160.
  • FIG.4E Quantification of lysosomal acidification from experiment described in FIG.4D. Statistical significance calculated with unpaired two- tailed Student’s t-tests. Significance in FIG.4B and FIG.4C expressed as *p ⁇ 0.05 compared to vehicle-treated controls or 0 h EN6-treated controls, respectively. Significance in FIG.4E is expressed as *p ⁇ 0.05 compared to the vehicle-treated group, #p ⁇ 0.05 compared to EN6- treated group. [0042] FIGS.5A-5B. EN6 improves clearance of TDP-43 aggregates in cells. Effect of EN6 and bafilomycin treatment on TDP-43 aggregate clearance.
  • U2OS cells expressing an IPTG-inducible GFP-TDP-43 were co-treated with vehicle DMSO, IPTG (50 mM), IPTG and EN6 (25 mM), or IPTG, EN6, and bafilomycin (0.2 mM) for 7 h.
  • Cells were stained with Hoechst 33342 and GFP-TDP-43 puncta were imaged by microscopy in FIG.5A.
  • FIGS.6A-6C EN6 inhibits mTORC1 signaling in mice.
  • C57BL/6 male mice were treated intraperitoneally with vehicle (18:1:1 saline:ethanol:PEG40), rapamycin (10 mg/kg) or EN6 (50 mg/kg) for 4 h.
  • mTORC1 signaling and LC3B levels were measured by Western blotting and quantified by densitometry.
  • FIG.7 Scheme of v-ATPase/mTORC1 regulation of autophagy and action of EN6.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C 1 -C 10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • 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, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • the term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • the term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 ,
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • the term“heteroalkynyl,” by itself or in combination with another term means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • a heteroalkyl (or heteroalkylene) group will have from 2 to 24 atoms including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), with those groups having 10 or fewer atoms being preferred herein.
  • 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 -NH-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(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • a cycloalkyl (or cycloalkylene) group will have from 3 to 8 carbon atoms.
  • a cycloalkyl (or cycloalkylene) group will have from 3 to 8 carbon atoms.
  • heterocycloalkyl (or heterocycloalkylene) group will have from 3 to 8 atoms including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S).
  • heteroatom e.g., O, N, P, Si, and S.
  • halo(C 1 -C 4 )alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • 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,
  • Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • An“arylene” and a“heteroarylene,” alone or as part of another substituent mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • an aryl (or arylene) group will have from 6 to 10 carbon atoms.
  • a heteroaryl (or heteroarylene) group will have from 5 to 10 atoms including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S).
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom.
  • the individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • the alkylarylene group has the formula: [0060]
  • 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 , -CCl 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 CH 3 , -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or
  • heterocycloalkyl “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
  • 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 for rings e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are
  • q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 )r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'- (C''R''R'') d -, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • the terms“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, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,
  • unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 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 C 5 -C 6 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 - C 10 aryl, C 10 aryl, or phenyl
  • heteroalkyl cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -
  • A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroary
  • 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 C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a group selected
  • 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 C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 - C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 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 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • each substituted or unsubstituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • each R substituent or L linker that is described as being“substituted” without reference as to the identity of any chemical moiety that composes the“substituted” group also referred to herein as an“open substitution” on an R substituent or L linker or an“openly substituted” R substituent or L linker
  • the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.
  • the first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R 1 may be substituted with one or more first substituent groups denoted by R 1.1 , R 2 may be substituted with one or more first substituent groups denoted by R 2.1 , R 3 may be substituted with one or more first substituent groups denoted by R 3.1 , R 4 may be substituted with one or more first substituent groups denoted by R 4.1 , R 5 may be substituted with one or more first substituent groups denoted by R 5.1 , and the like up to or exceeding an R 100 that may be substituted with one or more first substituent groups denoted by R 100.1 .
  • R 1A may be substituted with one or more first substituent groups denoted by R 1A.1
  • R 2A may be substituted with one or more first substituent groups denoted by R 2A.1
  • R 3A may be substituted with one or more first substituent groups denoted by R 3A.1
  • R 4A may be substituted with one or more first substituent groups denoted by R 4A.1
  • R 5A may be substituted with one or more first substituent groups denoted by R 5A.1 and the like up to or exceeding an R 100A may be substituted with one or more first substituent groups denoted by R 100A.1 .
  • L 1 may be substituted with one or more first substituent groups denoted by R L1.1
  • L 2 may be substituted with one or more first substituent groups denoted by R L2.1
  • L 3 may be substituted with one or more first substituent groups denoted by R L3.1
  • L 4 may be substituted with one or more first substituent groups denoted by R L4.1
  • L 5 may be substituted with one or more first substituent groups denoted by R L5.1 and the like up to or exceeding an L 100 which may be substituted with one or more first substituent groups denoted by R L100.1 .
  • each numbered R group or L group may be substituted with one or more first substituent groups denoted by R L1.1
  • L 2 may be substituted with one or more first substituent groups denoted by R L2.1
  • L 3 may be substituted with one or more first substituent groups denoted by R L3.1
  • L 4 may be substituted with one or more first substituent groups denoted by R L4.1
  • L 5 may be substituted with one
  • R WW or L WW wherein“WW” represents the stated superscript number of the subject R group or L group may be substituted with one or more first substituent groups referred to herein generally as R WW.1 or R LWW.1 , respectively.
  • each first substituent group (e.g., R 1.1 , R 2.1 , R 3.1 , R 4.1 , R 5.1 ... R 100.1 ; R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ... R 100A.1 ; R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ... R L100.1 ) may be further substituted with one or more second substituent groups (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2 , respectively).
  • each first substituent group which may alternatively be represented herein as R WW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R WW.2 .
  • each second substituent group e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2
  • may be further substituted with one or more third substituent groups e.g., R 1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ... R 100.3 ; R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.
  • each second substituent group which may alternatively be represented herein as R WW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R WW.3 .
  • Each of the first substituent groups may be optionally different.
  • Each of the second substituent groups may be optionally different.
  • Each of the third substituent groups may be optionally different.
  • R WW represents a substituent recited in a claim or chemical formula description herein which is openly substituted.“WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • L WW is a linker recited in a claim or chemical formula description herein which is openly substituted.
  • “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • each R WW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R WW.3 .
  • each L WW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R LWW.1 ; each first substituent group, R LWW.1 , may be unsubstituted or
  • each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R LWW.3 .
  • Each first substituent group is optionally different.
  • Each second substituent group is optionally different.
  • Each third substituent group is optionally different.
  • R WW is phenyl
  • the said phenyl group is optionally substituted by one or more R WW.1 groups as defined herein below, e.g., when R WW.1 is R WW.2 -substituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R WW.2 , which R WW.2 is optionally substituted by one or more R WW.3 .
  • R WW.1 is alkyl
  • groups that could be formed include but are not limited to:
  • R WW.1 is independently oxo, halogen, -CX WW.1 3, -CHX WW.1 2, -CH 2 X WW.1 ,
  • R WW.2 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R WW.2 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R WW.2 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 - C 6
  • R WW.2 -substituted or unsubstituted heterocycloalkyl e.g., 3
  • R WW.2 is independently oxo, halogen, -CX WW.2 3, -CHX WW.2 2, -CH 2 X WW.2 ,
  • R WW.3 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R WW.3 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R WW.3 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 - C 6
  • R WW.3 -substituted or unsubstituted heterocycloalkyl e.g.,
  • R WW.3 is independently oxo, halogen, -CX WW.3 3 , -CHX WW.3 2 , -CH 2 X WW.3 ,
  • unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -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 , C3- C 6 , C 4 -C 6 , or C 5 -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 WW.3 is independently–F, -Cl, -Br, or–I.
  • the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group, R WW.2 , may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R WW.3 ; and each third substituent group, R WW.3 , is unsubstituted.
  • Each first substituent group is optionally different.
  • Each second substituent group is optionally different.
  • Each third substituent group is optionally different.
  • the“WW” symbol in the R WW.1 , R WW.2 and R WW.3 refers to the designated number of one of the two different R WW substituents.
  • R WW.1 is R 100A.1
  • R WW.2 is R 100A.2
  • R WW.3 is R 100A.3 .
  • R WW.1 is R 100B.1
  • R WW.2 is R 100B.2
  • R WW.3 is R 100B.3 .
  • R WW.1 , R WW.2 and R WW.3 in this paragraph are as defined in the preceding paragraphs.
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3 ,
  • X LWW.1 is independently–F, -Cl, -Br, or–I.
  • R LWW.3 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R LWW.3 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • R WW.3 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 - C 6
  • R LWW.3 -substituted or unsubstituted heterocycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 - C
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3,
  • X LWW.2 is independently–F, -Cl, -Br, or–I.
  • unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -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-C 6 , or C 5 -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 LWW.3 is independently–F, -Cl, -Br, or–I.
  • R WW substituent any R group recited in a claim or chemical formula description set forth herein (R WW substituent) is not specifically defined in this disclosure, then that R group (R WW group) is hereby defined as independently oxo, halogen, -CX WW 3, -CHX WW 2,
  • X WW is independently–F, -Cl, -Br, or–I.
  • “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • R WW.1 , R WW.2 , and R WW.3 are as defined above.
  • L group L WW group is herein defined as independently a bond,–O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -S-, -SO 2 NH-, R LWW.1 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2 to
  • R LWW.1 represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • R LWW.1 as well as R LWW.2 and R LWW.3 are as defined above.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • the term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • bioconjugate and“bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect.
  • a conjugate between a first bioconjugate reactive group (e.g.,–NH 2 ,–COOH,–N- hydroxysuccinimide, or–maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like).
  • a first bioconjugate reactive group e.g.,–NH 2 ,–COOH,–N- hydroxysuccinimi
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
  • bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group e.g.,–N- hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g.,–sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N- hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • Analog “Analog,”“analogue,” or“derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • 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, is“substituted with an unsubstituted C 1 -C 20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc.
  • 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 disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
  • the present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • a polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type).
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene is recombinant.
  • the term“about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • 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. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • the terms“treating” or“treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of
  • treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors.
  • the term“treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
  • treating is preventing.
  • treating does not include preventing.
  • the treating or treatment is no prophylactic treatment.
  • An“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition (e.g., reduce signaling pathway stimulated by an autophagy adapter protein, reduce the signaling pathway activity of an autophagy protein).
  • An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount” when referred to in this context.
  • A“reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An“activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. 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,
  • 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.
  • a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • the term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
  • the term“inhibition,”“inhibit,”“inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or
  • a cellular component e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or
  • inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component).
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular
  • a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular
  • “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.
  • “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.
  • Disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & 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 approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved.
  • B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma,
  • 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.
  • the term“sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma,
  • lymphosarcoma melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,
  • immunoblastic sarcoma of T-cells Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
  • the term“melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • the term“carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma
  • autoimmune disease refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject.
  • autoimmune diseases include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myo
  • Acute Disseminated Encephalomyelitis Acute necrotizing hemorrhagic le
  • cryoglobulinemia Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes
  • Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic’s), Neutropenia, Ocular cica
  • Polyarteritis nodosa Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial
  • Takayasu’s arteritis Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis,
  • UCTD Undifferentiated connective tissue disease
  • Uveitis a disease or condition in which the function of a subject’s nervous system becomes impaired.
  • Vasculitis a disease or condition in which the function of a subject’s nervous system becomes impaired.
  • GPA Polyangiitis
  • neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-St syndromesler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus- Merzbacher Disease, Pick’s disease,
  • metabolic disease refers to a disease or condition in which a subject’s metabolism or metabolic system (e.g., function of storing or utilizing energy) becomes impaired.
  • metabolic diseases include diabetes (e.g., type I or type II), obesity, metabolic syndrome, or a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function).
  • the term“cellular component associated disease” e.g., the cellular component may be a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, vesicle, small molecule, protein complex, protein aggregate, or macromolecule; the disease may be a neurodegenerative disease, cancer, a metabolic disease, authoimmune disease, inflammatory disease, or infectious disease) (also referred to herein as“cellular component related disease”) refers to a disease caused by the celllular component.
  • Other diseases that are associated with aberrant activity or level of the cellular component are well known in the art and determining such diseases are within the skill of a person of skill in the art.
  • “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • “pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • 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,
  • 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).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy.
  • the compounds of the invention can be administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
  • Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • the compounds described herein can be co-administered with conventional chemotherapeutic agents including alkylating agents (e.g.,
  • cyclophosphamide ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.
  • anti-metabolites e.g., 5-fluorouracil, azathioprine, methotrexate, leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.
  • plant alkaloids e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.
  • topoisomerase inhibitors e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.
  • the compounds described herein can also be co-administered with conventional hormonal therapeutic agents including, but not limited to, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, tamoxifen, and gonadotropin-releasing hormone agonists (GnRH) such as goserelin.
  • steroids e.g., dexamethasone
  • finasteride e.g., aromatase inhibitors
  • tamoxifen e.g., tamoxifen
  • GnRH gonadotropin-releasing hormone agonists
  • the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti- VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 111 In, 90 Y, or 131 I, etc.).
  • immunostimulants e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interfer
  • the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
  • radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
  • compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of
  • a daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of cancer diagnosed in a particular patient.
  • the dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a compound in a particular patient.
  • the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • the term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease means that the disease (e.g., neurodegenerative disease, cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component).
  • a neurodegenerative disease associated with a protein aggregate may be a neurodegenerative disease that results (entirely or partially) from aberrant protein aggregation or a neurodegenerative disease wherein a particular symptom of the disease is caused (entirely or partially) by aberrant protein aggregation.
  • a neurodegenerative disease associated with aberrant protein aggregation or a protein aggregate associated neurodegenerative disease may be treated with a protein aggregate modulator or protein aggregate targeted autophagy degrader, in the instance where increased protein aggregation causes the neurodegenerative disease.
  • aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • Anti-cancer agent is used in accordance with its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) having
  • 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.
  • an anti-cancer agent is an inhibitor of K-Ras, RAF, MEK, Erk, PI3K, Akt, RTK, or mTOR.
  • an anti-cancer agent is an MDM2 inhibitor or a genotoxic anti-cancer agent.
  • an anti-cancer agent is nutlin-1, nutlin-2, nutlin-3, nutlin-3a, nutlin-3b, YH239-EE, MI-219, MI-773, MI-77301, MI-888, MX69, RG7112, RG7388, RITA, idasanutlin, DS-3032b, or AMG232.
  • an anti-cancer agent is an alkylating agent, intercalating agent, or DNA replication inhibitor.
  • anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 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),
  • LY294002 Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor- related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25
  • ATRA trans-retinoic acid
  • TRAIL tumor necrosis factor-
  • amifostine aminolevulinic acid
  • amrubicin amsacrine
  • anagrelide anastrozole
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
  • benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
  • calcipotriol calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
  • carboxamide-amino-triazole carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
  • didemnin B didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; 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;
  • 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 benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral end
  • octreotide okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;
  • palmitoylrhizoxin pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
  • pegaspargase peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor;
  • protein kinase C inhibitors microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
  • oligonucleotides oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
  • spiromustine splenopentin
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stem-cell division inhibitors
  • stromelysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic glycosaminoglycans;
  • tallimustine tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
  • thrombopoietin mimetic thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;
  • triciribine trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
  • tyrphostins UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, 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;
  • melphalan menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;
  • Taxotere.TM compounds comprising the taxane skeleton, Erbulozole (i.e., R- 55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI- 980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,
  • Altorhyrtins e.g., Altorhyrtin A and Altorhyrtin C
  • Spongistatins e.g., Spongist
  • Epothilones e.g., Epothilone A, Epothilone B, Epothilone C (i.e., desoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N- oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21- hydroxyepothilone D (i.e., Desoxyepothilone F and dEpoF), 26-fluoroepothilones (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., desoxyepothilone A or dEpoA), Epothilone D
  • 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.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE- 8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin
  • steroids e.g., dexamethasone
  • finasteride aromatase inhibitors
  • GnRH gonadotropin-releasing hormone agonists
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • estrogens e.g., diethlystilbestrol, ethinyl estradiol
  • antiestrogen e.g., tamoxifen
  • androgens e.g., testosterone propionate, fluoxymesterone
  • antiandrogen e.g., flutamide
  • immunostimulants e.g., testosterone propionate, fluoxymesterone
  • antiandrogen e.g., flutamide
  • a moiety of an anti-cancer agent is a monovalent anti-cancer agent (e.g., a monovalent form of an agent listed above).
  • “Chemotherapeutic” or“chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
  • the term“electrophilic” as used herein refers to a chemical group that is capable of accepting electron density.
  • an“electrophilic substituent,”“electrophilic chemical moiety,” or“electrophic moiety” refers to an electron-poor chemical group, substitutent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.
  • the electrophilic substituent of the compound is capable of reacting with a cysteine residue.
  • the electrophilic substituent is capable of forming a covalent bond with a cysteine residue (e.g., ATP6V1A) and may be referred to as a“covalent cysteine modifier moiety” or“covalent cysteine modifier substituent.”
  • the covalent bond formed between the electrophilic substituent and the sulfhydryl group of the cysteine may be a reversible or irreversible bond.
  • the electrophilic substituent of the compound is capable of reacting with a lysine residue.
  • the electrophilic substituent of the compound is capable of reacting with a serine residue.
  • the electrophilic substituent of the compound is capable of reacting with a methionine residue.
  • “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.
  • An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue.
  • a selected residue in a selected protein corresponds to C277 of human Vacuolar H + - ATPase protein when the selected residue occupies the same essential spatial or other structural relationship as C277 in human Vacuolar H + -ATPase protein.
  • a selected protein is aligned for maximum homology with the human Vacuolar H + -ATPase protein
  • the position in the aligned selected protein aligning with C277 is said to correspond to C277.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human Vacuolar H + -ATPase protein and the overall structures compared.
  • an amino acid that occupies the same essential position as C277 in the structural model is said to correspond to the C277 residue.
  • An amino acid residue in a protein“corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue.
  • a selected residue in a selected protein corresponds to C277 of human ATP6V1A protein when the selected residue occupies the same essential spatial or other structural relationship as C277 in human ATP6V1A protein.
  • the position in the aligned selected protein aligning with C277 is said to correspond to C277.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human ATP6V1A protein and the overall structures compared.
  • nucleic acid or protein when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, g- carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • non-naturally occurring amino acid and“unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • polypeptide “peptide,” and“protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids.
  • 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.
  • 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.
  • amino acid or nucleotide base“position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion.
  • protein complex is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.
  • protein aggregate is used in accordance with its plain ordinary meaning and refers to an abberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protien misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes. In
  • the protein aggregate is TDP43, HTT, APP, SNCA, or MAPT.
  • the protein aggregate includes the protein Beta amyloid, Amyloid precursor protein, IAPP (Amylin), Alpha-synuclein, PrPSc, PrPSc, Huntingtin, Calcitonin, Atrial natriuretic factor, Apolipoprotein AI, Serum amyloid A, Medin, Prolactin, Transthyretin, Lysozyme, Beta-2 microglobulin, Gelsolin, Keratoepithelin, Beta amyloid, Cystatin, Immunoglobulin light chain AL, TDP43, or S-IBM.
  • the term“vesicle” is used in accordance with its plain ordinary meaning and refers to a small membrane enclosed compartment within a cell.
  • Vesicles are typically involved in transport, buoyancy control, or enzyme storage within a cell. Some vesicles, for example a lysosome, may include enzymes, proteins, polysaccharides, lipids, nucleic acids, or organelles within the compartment. Vesicles are typically formed within cells as a result of exocytosis or phagocytosis, however some vesicles are formed at the Golgi complex and transported to the cell membrane. Vesicles may be unilamellar or multilamellar.
  • V-ATPase refers to an enzyme that acidifies a wide array of intracellular organelles (e.g., lysosomes) and pump protons across the plasma membranes of cells.
  • V-ATPases including ATP6V1A as a component, couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells.
  • ATP6V1A refers to a gene that encodes a component of vacuolar ATPase (v-ATPase), which is an enzyme that mediates amino acid-dependent recruitment of mTORC1 to the lysosome.
  • ATP6V1A refers to UniProt P38606-1.
  • ATP6V1A refers to human ATP6V1A.
  • ATP6V1A refers to Entrez 523.
  • ATP6V1A refers to RefSeq NM_001690.3.
  • ATP6V1A refers to RefSeq NP_001681.2.
  • ATP6V1A has the sequence:
  • mTOR may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeq NP_004949).
  • the term“mTOR” includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof.
  • “mTOR” is wild-type mTOR.
  • “mTOR” is one or more mutant forms.
  • mTOR refers to a nucleotide sequence or protein of a mutant mTOR wherein the Y numbered amino acid of mTOR that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant.
  • an mTOR is the human mTOR.
  • the mTOR has the following amino acid sequence:
  • mTORC1 refers to the protein complex including mTOR and Raptor (regulatory-associated protein of mTOR). mTORC1 may also include MLST8 (mammalian lethal with SEC13 protein 8), PRAS40, and/or DEPTOR. mTORC1 may function as a nutrient/energy/redox sensor and regulator of protein synthesis.
  • the term“mTORC1 pathway” or“mTORC1 signal transduction pathway” refers to a cellular pathway including mTORC1. An mTORC1 pathway includes the pathway components upstream and downstream from mTORC1. An mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity.
  • an mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity but not by modulation of mTORC2 activity. In embodiments, an mTORC1 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC1 activity than by modulation of mTORC2 activity.
  • the term“mTORC2” refers to the protein complex including mTOR and RICTOR (rapamycin-insensitive companion of mTOR). mTORC2 may also include GbL, mSIN1 (mammalian stress-activated protein kinase interacting protein 1), Protor 1/2, DEPTOR, TTI1, and/or TEL2.
  • mTORC2 may regulate cellular metabolism and the cytoskeleton.
  • the term“mTORC2 pathway” or“mTORC2 signal transduction pathway” refers to a cellular pathway including mTORC2.
  • An mTORC2 pathway includes the pathway components upstream and downstream from mTORC2.
  • An mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity.
  • an mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity but not by modulation of mTORC1 activity.
  • an mTORC2 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC2 activity than by modulation of mTORC1 activity.
  • the term“Sequestosome-1” or“SQSTM1” or“p62/SQSTM1” or“ubiquitin- binding protein p62” or“p62” refers to an autophagosome cargo protein (including homologs, isoforms, and functional fragments thereof) that targets other proteins that bind to it for selective autophagy. p62 harbors active nuclear import and export signals and shuttles between the nucleus and cytoplasm.
  • the term“p62” refers to the nucleotide sequences or proteins of human p62.
  • the term“p62” includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments,“p62” is wild- type p62.
  • “p62” is one or more mutant forms.
  • the term“p62” XYZ refers to a nucleotide sequence or protein of a mutant p62 wherein the Y numbered amino acid of p62 that has an X amino acid in the wildtype instead has a Z amino acid in the mutant.
  • p62 is a functional fragment thereof.
  • p62 refers to UniProt C9J6J8, having the sequence: MASLTVKAYLLGKEDAAREIRRFSFCCSPEPEAEAEAAAGPGPCERLLSRVAALFPAL RPGGFQAHYRGGGFR (SEQ ID NO:3).
  • p62 refers to Entrez 8878.
  • p62 refers to RefSeq NM_001142298.1, RefSeq NM_001142299.1, RefSeq NM_003900.4, RefSeq
  • NP_001135770.1 RefSeq NP_001135771.1
  • RefSeq NP_003891.1 RefSeq NP_003891.1
  • p62 refers to UniProt Q13501, having the sequence:
  • LC3B refers to a central protein in the autophagy pathway, where it functions, for example, in autophagy substrate selection.
  • the term“LC3B” may refer to the nucleotide sequence or protein sequence of human LC3B.
  • LC3B is LC3BII.
  • LC3B is Entrez 81631, Uniprot Q9GZQ8, RefSeq NM_022818.4, or RefSeq NP_073729.1.
  • the LC3B has the following amino acid sequence:
  • the term“4EBP1” or“eukaryotic translation initiation factor 4E-binding protein 1” refers to a protein that interacts with eukaryotic translation initiation factor 4E, which is a component of the multisubunit complex that recruits 40S ribosomal subunits to the 5’ end of mRNAs.
  • the term“4EBP1” may refer to the nucleotide sequence or protein sequence of human 4EBP1. In embodiments, 4EBP1 is Entrez 1978, Uniprot Q13541, RefSeq
  • the 4EBP1 has the following amino acid sequence:
  • TFEB or“transcription factor EB” refers to a protein involved in lysosomal biogenesis.
  • the TFEB protein coordinates, for example, expression of lysosomal hydrolases, membrane proteins, and genes involved in autophagy.
  • the TFEB protein is encoded by the TFEB gene.
  • the term“TFEB” may refer to the nucleotide sequence or protein sequence of human TFEB.
  • TFEB is Entrez 7942, Uniprot P19484, RefSeq NM_001167827.2, RefSeq NM_001271943.1, RefSeq NM_001271944.1, RefSeq NM_001271945.1, RefSeq NM_007162.2, RefSeq NP_001161299.2, RefSeq
  • the TFEB has the following amino acid sequence:
  • TFE3 or“transcription factor E3” refers to a protein that activates expression of CD30L in T-cells.
  • the TFE3 protein is encoded by the TFE3 gene.
  • TFE3 may refer to the nucleotide sequence or protein sequence of human TFE3.
  • TFE3 is Entrez 7030, Uniprot P19532, RefSeq NM_001282142.1, RefSeq NM_006521.5, RefSeq NP_001269071.1, or RefSeq NP_006512.2.
  • the TFE3 has the following amino acid sequence:
  • autophagosome is used in accordance with its plain ordinary meaning and refers to a vesicle that contains a cellular component slated to be degraded by autophagy.
  • autophagosome formation is a multistep process that includes the biogenesis of the phagophore, followed by its elongation and closure.
  • more than 15 autophagy-related ATG proteins, as well as class III PI3 kinases, may be required to construct the autophagosome, including the transmembrane ATG protein ATG9, along with
  • Nucleic acid refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides.
  • the terms“polynucleotide,”“oligonucleotide,” “oligo,” or the like refer, in the usual and customary sense, to a linear sequence of
  • nucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length.
  • Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. In certain embodiments the nucleic acids herein contain phosphodiester bonds.
  • nucleic acid analogs are included that may have alternate backbones, comprising, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphosphoroamidite linkages (see, Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press); and peptide nucleic acid backbones and linkages.
  • Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Patent Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580,
  • nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • nucleic acid is a monomer of the nucleic acid (e.g., a nucleotide).
  • nucleoside refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose).
  • nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. Nucleosides may be modified at the base and/or and the sugar.
  • 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.
  • nucleic acid examples include any types of RNA, e.g., mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof.
  • the term“duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness.
  • Nucleic acids can be linear or branched.
  • 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.
  • nucleotide refers to a nucleoside-5’-polyphosphate compound, or a structural analog thereof, which can be incorporated (e.g., partially incorporated as a nucleoside-5’-monophosphate or derivative thereof) by a nucleic acid polymerase to extend a growing nucleic acid chain (such as a primer).
  • Nucleotides may comprise bases such as A, C, G, T, U, or analogues thereof, and may comprise 2, 3, 4, 5, 6, 7, 8, or more phosphates in the phosphate group.
  • Nucleotides may be modified at one or more of the base, sugar, or phosphate group.
  • a nucleotide may have a label or tag attached (a“labeled nucleotide” or “tagged nucleotide”).
  • the terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g.,
  • phosphoramidate, phosphorodiamidate, phosphorothioate also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate
  • phosphorodithioate also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate
  • phosphonocarboxylic acids also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate
  • phosphonocarboxylic acids also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate
  • phosphonocarboxylates also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate
  • phosphonoacetic acid also known as phosphonoformic acid
  • phosphonoformic acid methyl phosphonate
  • boron phosphonate or O-methylphosphoroamidite linkages
  • nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.
  • Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip.
  • Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.
  • Nucleic acids can include nonspecific sequences.
  • 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 C277 of human ATP6V1A protein) and is capable of reducing transcription of the target nucleic acid (e.g., mRNA from DNA), reducing the translation of the target nucleic acid (e.g., mRNA), altering transcript splicing (e.g., single stranded morpholino oligo), or interfering with the target nucleic acid (e.g., mRNA from DNA), reducing the translation of the target nucleic acid (e.g., mRNA), altering transcript splicing (e.g., single stranded morpholino oligo), or interfering with the target nucleic acid (e.g., mRNA from
  • 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 C277 of human ATP6V1A protein).
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to C277 of human ATP6V1A protein) 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 C277 of human ATP6V1A protein) in a cell. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to C277 of human ATP6V1A protein) in an organism.
  • the target nucleic acid e.g., a nucleic acid coding for one or more amino acids corresponding to C277 of human ATP6V1A protein
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to C277 of human ATP6V1A protein) 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 C277 of human ATP6V1A protein) 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 C277 of human ATP6V1A protein) and inhibit its function relative to the absence of the antisense nucleic acid.
  • the double-stranded molecule may be degraded via the RNAi pathway.
  • antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)). Further, antisense molecules which bind directly to the DNA may be used.
  • Antisense nucleic acids may be single or double stranded nucleic acids.
  • Non-limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre- cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors.
  • siRNAs including their derivatives or pre- cursors, such as nucleotide analogs
  • shRNA short hairpin RNAs
  • miRNA micro RNAs
  • saRNAs small activating RNAs
  • small nucleolar RNAs small nucleolar RNAs
  • a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence.
  • the nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence.
  • 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).
  • the term“antibody” refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one“heavy” chain (about 50-70 kDa).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms“variable heavy chain,”“VH,” or“VH” refer to the variable region of an immunoglobulin heavy chain, including an Fv, scFv, dsFv, or Fab; while the terms“variable light chain,”“VL,” or“VL” refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv, dsFv, or Fab.
  • 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., F UNDAMENTAL 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.
  • the term“irreversible covalent bond” is used in accordance with its plain ordinary meaning in the art and refers to the resulting association between atoms or molecules of (e.g., electrophilic chemical moiety and nucleophilic moiety) wherein the probability of dissociation is low.
  • 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 cysteine).
  • Ring A is a phenyl or 5 to 6 membered heteroaryl.
  • Ring B is a phenyl or 5 to 6 membered heteroaryl.
  • L 1 is independently a bond, -S(O) 2 -, -N(R 5 )-, -O-, -S-, -C(O)-, -C(O)N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 )C(O)NH-, -NHC(O)N(R 5 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent -L 1 -R 1 substituents may optionally be joined to form a substituted or
  • E is an electrophilic moiety.
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl,
  • R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl,
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3
  • R 4 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.
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • X 1 is independently–F, -Cl, -Br, or–I.
  • n1 is independently an integer from 0 to 4.
  • m1 and v1 are independently 1 or 2.
  • z1 is independently an integer from 0 to 5.
  • z3 is independently an integer from 0 to 2.
  • z4 is independently an integer from 0 to 5.
  • the compound has the formula:
  • L 1 , E, R 1 , z1, R 4 , and z4 are as described herein, including in embodiments.
  • the compound has the formula: L 1 , E, R 1 , and R 4 are as described herein, including in embodiments.
  • the compound has the formula:
  • L 1 , E, R 1 , and R 4 are as described herein, including in
  • the compound has the formula:
  • L 1 , E, R 1 , z1, R 3 , R 4 , and z4 are as described herein,
  • the compound has the formula:
  • L 1 , E, R 1 , z1, R 3 , R 4 , and z4 are as described
  • the compound has the formula:
  • L 1 , E, R 1 , R 3 , and R 4 are as described herein, including in embodiments.
  • the compound has the formula:
  • L 1 , E, R 1 , R 3 , and R 4 are as described herein,
  • the compound has the formula:
  • L 1 , E, R 1 , R 3 , and R 4 are as described herein, including in embodiments.
  • the compound has the formula: L 1 , E, R 1 , R 3 , and R 4 are as described herein, including in embodiments. [0219] In embodiments, the compound has the formula:
  • L 1 , E, R 1 , z1, R 2 , R 4 , and z4 are as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl. [0220] In embodiments, the compound has the formula:
  • L 1 , E, R 1 , R 2 , and R 4 are as described herein, including in
  • R 2 is independently C 1 -C 6 alkyl. In embodiments, R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl. [0221] In embodiments, the compound has the formula: L 1 , E, R 1 , R 2 , and R 4 are as described herein, including in embodiments. In embodiments, R 2 is independently C 1 -C 6 alkyl. In embodiments, R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl. [0222] In embodiments, the compound has the formula:
  • L 1 , E, R 1 , z1, R 2 , R 3 , R 4 , and z4 are as described herein,
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl. [0223] In embodiments, the compound has the formula:
  • L 1 , E, R 1 , z1, R 2 , R 3 , R 4 , and z4 are as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • L 1 , E, R 1 , R 2 , R 3 , and R 4 are as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • L 1 , E, R 1 , R 2 , R 3 , and R 4 are as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • L 1 , E, R 1 , R 2 , R 3 , and R 4 are as described
  • R 2 is independently C 1 -C 6 alkyl. In embodiments, R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl. [0227] In embodiments, the compound has the formula:
  • L 1 , E, R 1 , R 2 , R 3 , and R 4 are as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • L 1 is independently a bond, -S(O) 2 -, -N(R 5 )-, -O-, -S-, -C(O)-, -C(O)N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 )C(O)NH-, -NHC(O)N(R 5 )-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g.,
  • heteroalkylene substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • the substituted L 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • L 1 when L 1 is substituted, it is substituted with at least one substituent group. In embodiments, when L 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 1 is substituted, it is substituted with at least one lower substituent group. [0230] In embodiments, L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene.
  • L 1 is independently -S(O) 2 -, -NH-, or substituted or unsubstituted 5 to 6 membered heterocycloalkylene.
  • L 1 is independently -S(O) 2 -, -NH-, unsubstituted pyrrolidinylene, unsubstituted piperidinylene, or unsubstituted piperazinylene.
  • L 1 is independently -NH-.
  • L 1 is independently -N(R 5 )-, and R 5 is as described herein, including in embodiments.
  • L 1 is independently -N(R 5 )-, and R 5 is independently hydrogen or unsubstituted alkyl. In embodiments, L 1 is independently -N(R 5 )-, and R 5 is independently hydrogen or substituted or unsubstituted alkyl. In embodiments, L 1 is independently -N(R 5 )-, and R 5 is independently hydrogen or
  • L 1 is independently -N(R 5 )-, and R 5 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, L 1 is independently -N(R 5 )-, and R 5 is independently hydrogen or unsubstituted methyl.
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • a substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1 is substituted, it is substituted with at least one substituent group.
  • R 1 when R 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent group.
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O
  • 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 a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or substituted (e.
  • substituted e.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by joining two adjacent R 1 substituents is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 1 substituents when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 1 substituents is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 1 substituents is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted cycloalkyl, substituted
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC
  • R 1 is independently halogen. In embodiments, R 1 is independently –F. In embodiments, R 1 is independently–Cl. In embodiments, R 1 is independently–Br. In embodiments, R 1 is independently–I. [0243] In embodiments, R 1 is independently halogen. [0244] In embodiments, R 1 is -F.
  • R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted
  • R 1 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OH, -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -SCH 3 , or -SCH 2 CH 3 .
  • R 1 is substituted or unsubstituted C 1 -C 6 alkyl.
  • R 1 is substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 1 is substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • R 1 is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 1 is substituted or unsubstituted phenyl. In embodiments, R 1 is substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 1 is independently halogen. In embodiments, R 1 is independently -CX 1 3 . In embodiments, R 1 is independently -CHX 1 2 . In embodiments, R 1 is independently -CH 2 X 1 . In embodiments, R 1 is independently -OCX 1 3. In embodiments, R 1 is independently -OCH 2 X 1 . In embodiments, R 1 is independently
  • R 1 is independently -OCHX 1 2 .
  • R 1 is independently -OCH 2 X 1 .
  • R 1 is independently -CN.
  • R 1 is independently -SOn1R 1D .
  • R 1 is independently -SOv1NR 1A R 1B .
  • R 1 is independently -NHC(O)NR 1A R 1B .
  • R 1 is independently -N(O) m1 .
  • R 1 is independently -NR 1A R 1B .
  • R 1 is independently -C(O)R 1C .
  • R 1 is independently -C(O)OR 1C .
  • R 1 is independently -C(O)NR 1A R 1B . In embodiments, R 1 is independently -OR 1D . In embodiments, R 1 is independently -NR 1A SO 2 R 1D . In embodiments, R 1 is independently -NR 1A C(O)R 1C . In embodiments, R 1 is independently -NR 1A C(O)OR 1C . In embodiments, R 1 is independently -NR 1A OR 1C . In embodiments, R 1 is independently -OH. In embodiments, R 1 is independently -NH 2 . In embodiments, R 1 is independently -COOH. In embodiments, R 1 is independently -CONH 2 . In embodiments, R 1 is independently -NO 2 .
  • R 1 is independently -SH. In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CH 2 F. In embodiments, R 1 is independently -OCF 3 . In embodiments, R 1 is independently -OCH 2 F. In embodiments, R 1 is independently -OCHF 2 . In embodiments, R 1 is independently–OCH 3 . In embodiments, R 1 is independently–OCH 2 CH 3 . In embodiments, R 1 is independently –OCH 2 CH 2 CH 3 . In embodiments, R 1 is independently–OCH(CH 3 ) 2 . In embodiments, R 1 is independently–OC(CH 3 ) 3 .
  • R 1 is independently–SCH 3 . In embodiments, R 1 is independently–SCH 2 CH 3 . In embodiments, R 1 is independently–SCH 2 CH 2 CH 3 . In embodiments, R 1 is independently–SCH(CH 3 ) 2 . In embodiments, R 1 is independently –SC(CH 3 ) 3 . In embodiments, R 1 is independently–CH 3 . In embodiments, R 1 is
  • R 1 is independently–CH 2 CH 2 CH 3 .
  • R 1 is independently–CH 2 CH 2 CH 3 .
  • R 1 is independently–CH(CH 3 ) 2 . In embodiments, R 1 is independently –C(CH 3 )3. In embodiments, R 1 is independently–F. In embodiments, R 1 is independently –Cl. In embodiments, R 1 is independently–Br. In embodiments, R 1 is independently–I. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is
  • R 1 independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted isobutyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted pentyl.
  • two adjacent -L 1 -R 1 substituents are joined to form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl),
  • substituted e.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by joining two adjacent -L 1 -R 1 substituents is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent -L 1 -R 1 substituents is substituted, it is substituted with at least one substituent group.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent -L 1 -R 1 substituents when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent -L 1 -R 1 substituents is substituted, it is substituted with at least one size-limited substituent group.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent -L 1 -R 1 substituents when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent -L 1 -R 1 substituents is substituted, it is substituted with at least one lower substituent group.
  • two adjacent -L 1 -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 -L 1 -R 1 substituents are joined to form a substituted or unsubstituted cycloalkyl.
  • two adjacent -L 1 -R 1 substituents are joined to form a substituted or
  • two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted aryl.
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted heteroaryl.
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted heteroaryl.
  • adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted C 6 -C 10 aryl. In embodiments, two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted C 3 -C 6 cycloalkyl.
  • two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted 3 to 6 membered
  • heterocycloalkyl In embodiments, two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two adjacent -L 1 -R 1 substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. It will be understood that when two adjacent L 1 substituents are a bond, two adjacent -L 1 -R 1 substituents that are joined are equivalent to two adjacent -R 1 substituents being joined and may be depicted as such in a formula.
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3
  • R 1A is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • a substituted R 1A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1A is substituted, it is substituted with at least one substituent group.
  • R 1A when R 1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1A is substituted, it is substituted with at least one lower substituent group.
  • 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 independently
  • X 1A is independently–F, -Cl, -Br, or -I.
  • R 1A is independently substituted or unsubstituted alkyl (e.g., C1- C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1A is independently substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1A is independently unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1A is independently unsubstituted methyl. In embodiments, R 1A is independently unsubstituted ethyl. In embodiments, R 1A is independently unsubstituted propyl. In embodiments, R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted tert-butyl.
  • 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).
  • 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).
  • 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).
  • R 1A is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ). In embodiments, R 1A is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ). In embodiments, R 1A is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ).
  • R 1A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • 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 or
  • R 1A is independently substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1A is independently substituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1A is
  • R 1A is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1A is
  • R 1A independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • a substituted R 1B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1B is substituted, it is substituted with at least one substituent group.
  • R 1B when R 1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1B is substituted, it is substituted with at least one lower substituent group.
  • 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 -CH 2 X 1B . In embodiments, R 1B is independently -CN. In embodiments, R 1B is independently -COOH. In embodiments, R 1B is independently -CONH 2 .
  • X 1B is independently–F, -Cl, -Br, or -I.
  • R 1B is independently substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1B is independently substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1B is independently unsubstituted alkyl (e.g., C 1 - C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). 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-C 6 , or C 5 -C 6 ).
  • R 1B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 1B is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ).
  • R 1B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 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 aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1B is
  • R 1B is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) 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).
  • a substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted 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).
  • 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.
  • 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.
  • a substituted heterocycloalkyl formed by joining R 1A and R 1B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a substituted heterocycloalkyl formed by joining R 1A and R 1B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group.
  • 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).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 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 (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 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 (e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membere
  • 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 1A and R 1B 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).
  • a substituted heteroaryl formed by joining R 1A and R 1B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when a substituted heteroaryl formed by joining R 1A and R 1B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group.
  • 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 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1A and R 1B 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 1C is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • a substituted R 1C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1C is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1C is substituted, it is substituted with at least one substituent group.
  • R 1C when R 1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1C is substituted, it is substituted with at least one lower substituent group.
  • R 1C is independently hydrogen. In embodiments, R 1C is independently -CX 1C 3 . In embodiments, R 1C is independently -CHX 1C 2 . In embodiments, R 1C is independently -CH 2 X 1C . In embodiments, R 1C is independently -CN. In embodiments, R 1C is independently -COOH. In embodiments, R 1C is independently -CONH 2 .
  • X 1C is independently–F, -Cl, -Br, or -I.
  • R 1C is independently substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1C is independently substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1C is independently unsubstituted alkyl (e.g., C1- C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). 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 , C 4 -C 6 , or C 5 -C 6 ).
  • R 1C is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ).
  • R 1C is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ).
  • 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 is independently substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1C is independently substituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1C is
  • R 1C is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1C is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1C independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1C is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1C is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • a substituted R 1D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1D is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1D is substituted, it is substituted with at least one substituent group.
  • R 1D when R 1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one lower substituent group.
  • R 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 -CH 2 X 1D . In embodiments, R 1D is independently -CN. In
  • R 1D is independently -COOH. In embodiments, R 1D is independently
  • X 1D is independently–F, -Cl, -Br, or -I.
  • R 1D is independently substituted or unsubstituted alkyl (e.g., C 1 - C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1D is independently substituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1D is independently unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl. In embodiments, R 1D is independently unsubstituted propyl. In embodiments, R 1D is independently unsubstituted isopropyl. In embodiments, R 1D is independently unsubstituted tert-butyl.
  • 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).
  • 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 , C 4 -C 6 , or C 5 -C 6 ). In embodiments, R 1D is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ). In embodiments, R 1D is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -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).
  • 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 or
  • R 1D is independently substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1D is independently substituted aryl (e.g., C 6 -C 10 or phenyl). In embodiments, R 1D is
  • R 1D is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1D is independently unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 1D independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • 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 10 -substituted or unsubstituted aryl e.g., C 6 -C 10 or phenyl
  • R 10 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • X 1 is independently–F, -Cl, -Br, or–I.
  • R 1 is independently unsubstituted methyl.
  • R 1 is independently unsubstituted ethyl.
  • R 1 is independently R 10 -substituted 2 membered heteroalkyl.
  • R 1 is independently R 10 -substituted methoxy.
  • R 10 - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6
  • R 10 -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 10 -substituted or unsubstituted aryl e.g., C 6 -C 10 or phenyl
  • R 10 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • two adjacent–L 1 -R 1 substituents are joined to form an unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -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 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6
  • unsubstituted heterocycloalkyl e.g
  • two adjacent–L 1 -R 1 substituents are joined to form a R 10 -substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ).
  • two adjacent–L 1 -R 1 substituents are joined to form a R 10 -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–L 1 -R 1 substituents are joined to form a R 10 -substituted aryl (e.g., C 6 -C 10 or phenyl).
  • two adjacent–L 1 -R 1 substituents are joined to form a R 10 -substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent–L 1 -R 1 substituents are joined to form an unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6 ).
  • two adjacent–L 1 -R 1 substituents are 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–L 1 -R 1 substituents are joined to form an unsubstituted aryl (e.g., C 6 -C 10 or phenyl).
  • R 11 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R 11 -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 11 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6
  • R 11 -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered
  • R 12 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R 12 -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 12 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C 6 , or C 5 -C 6
  • R 12 -substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • R 12 unsubstituted 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 12 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or R 12 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • X 11 is independently–F, -Cl, -Br, or–I.
  • R 11 is independently unsubstituted methyl.
  • R 11 is independently
  • unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -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 C 5 - 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 10 or phenyl
  • X 12 is independently–F, -Cl, -Br, or–I. In embodiments, R 12 is independently unsubstituted methyl. In embodiments, R 12 is independently unsubstituted ethyl.
  • n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, v1 is 1. In embodiments, v1 is 2. [0278] In embodiments, z1 is independently an integer from 0 to 4. In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2.
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3
  • a substituted R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 2 is substituted, it is substituted with at least one substituent group.
  • R 2 when R 2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2 is substituted, it is substituted with at least one lower substituent group.
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)
  • R 2 is independently hydrogen. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted n-propyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted butyl. In embodiments, R 2 is independently unsubstituted n- butyl. In embodiments, R 2 is independently unsubstituted isobutyl. In embodiments, R 2 is independently unsubstituted tert-butyl.
  • R 2 is independently unsubstituted pentyl.
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OC
  • R 2 is independently -CCl 3 .
  • R 2 is independently -CBr 3 .
  • R 2 is independently -CF 3 .
  • R 2 is independently -CI 3 .
  • R 2 is independently -CH 2 Cl.
  • R 2 is independently -CH 2 Br.
  • R 2 is independently -CH 2 F.
  • R 2 is independently -CH 2 I.
  • R 2 is independently -CHCl 2 .
  • R 2 is independently -CHBr 2 .
  • R 2 is independently -CHF 2 .
  • R 2 is independently -CHI 2 .
  • R 2 is independently unsubstituted C 1 -C 6 alkyl. In embodiments, R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted n-propyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted butyl. In embodiments, R 2 is independently unsubstituted n-butyl.
  • R 2 is independently unsubstituted isobutyl. In embodiments, R 2 is independently unsubstituted tert-butyl. In embodiments, R 2 is independently unsubstituted pentyl. In embodiments, R 2 is independently unsubstituted hexyl. In embodiments, R 2 is independently unsubstituted C 3 -C 6 cycloalkyl.
  • R 3 and R 4 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -
  • R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • a substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 3 is substituted, it is substituted with at least one substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O
  • R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • R 3 is independently halogen. In embodiments, R 3 is independently –F. In embodiments, R 3 is independently–Cl. In embodiments, R 3 is independently–Br. In embodiments, R 3 is independently–I. In embodiments, R 3 is independently -CCl 3 . In embodiments, R 3 is independently -CBr 3 . In embodiments, R 3 is independently -CF 3 . In embodiments, R 3 is independently -CI 3 . In embodiments, R 3 is independently -CH 2 Cl. In embodiments, R 3 is independently -CH 2 Br. In embodiments, R 3 is independently -CH 2 F. In embodiments, R 3 is independently -CH 2 I.
  • R 3 is independently -CHCl 2 . In embodiments, R 3 is independently -CHBr 2 . In embodiments, R 3 is independently -CHF 2 . In embodiments, R 3 is independently -CHI 2 . In embodiments, R 3 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independently unsubstituted propyl. In embodiments, R 3 is independently unsubstituted n-propyl.
  • R 3 is independently unsubstituted isopropyl. In embodiments, R 3 is independently unsubstituted butyl. In embodiments, R 3 is independently unsubstituted n-butyl. In embodiments, R 3 is independently unsubstituted isobutyl. In embodiments, R 3 is independently unsubstituted tert-butyl. [0291] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2.
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted aryl e.g., C 6 -C 10 or phenyl
  • substituted e.g., substituted with at least one substituent group, size- limited substituent group, or lower substituent group
  • unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • a substituted R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 4 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 4 is substituted, it is substituted with at least one substituent group.
  • R 4 when R 4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4 is substituted, it is substituted with at least one lower substituent group.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by joining two adjacent R 4 substituents is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 4 substituents when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 4 substituents is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl formed by two adjacent R 4 substituents is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted cycloalkyl, substituted
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • R 4 is independently halogen. In embodiments, R 4 is independently –F. In embodiments, R 4 is independently–Cl. In embodiments, R 4 is independently–Br. In embodiments, R 4 is independently–I. In embodiments, R 4 is independently–OH. In embodiments, R 4 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted n-propyl.
  • R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted butyl. In embodiments, R 4 is independently unsubstituted n-butyl. In embodiments, R 4 is independently unsubstituted isobutyl. In embodiments, R 4 is independently unsubstituted tert-butyl. [0298] In embodiments, R 4 is independently halogen. [0299] In embodiments, R 4 is independently -F.
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2
  • z4 is independently an integer from 0 to 5. [0303] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5.
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OC
  • a substituted R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 5 is substituted, it is substituted with at least one substituent group.
  • R 5 when R 5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one lower substituent group.
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)
  • R 5 is independently hydrogen. 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 n-propyl. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted butyl. In embodiments, R 5 is independently unsubstituted n- butyl. In embodiments, R 5 is independently unsubstituted isobutyl. In embodiments, R 5 is independently unsubstituted tert-butyl.
  • R 5 is independently unsubstituted pentyl.
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OC
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 16 is independently hydrogen, halogen, -CX 16 3, -CHX 16 2, -CH 2 X 16 , -CN,
  • R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted or unsubstituted al
  • X, X 16 , X 17 , X 18 and X 19 are independently–F, -Cl, -Br, or–I.
  • n16, n17, n18, and n19 are independently an integer from 0 to 4.
  • m16, m17, m18, m19, v16, v17, v18, and v19 are independently 1 or 2.
  • E is
  • E is a covalent cysteine modifier moiety.
  • E is In embodiments, E is . In
  • E is . In embodiments, E is . In embodiments, E is . In
  • E is . In embodiments, E is In
  • E is . In embodiments, E is In
  • E is . In embodiments, E is In embodiments, E is . In embodiments, E is In embodiments, E is . In embodiments, E is . In embodiments, E is . In embodiments, E is . In embodiments, E is R 16 ,
  • R 17 , R 18 , R 19 , and X 17 are as described herein. [0321] In embodiments, R 1 is independently
  • R 1 is independently .
  • R 16 , R 17 , R 18 , R 19 , and X 17 are as described herein. [0322] In embodiments, R 1 is independently
  • R 1 is independently a covalent cysteine modifier moiety.
  • R 1 is independently . In embodiments, R 1 is
  • R 1 is independently In
  • R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In
  • R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In
  • R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is independently . In embodiments, R 1 is
  • R 1 is independently .
  • R 1 is independently .
  • R 16 , R 17 , R 18 , R 19 , and X 17 are as described herein.
  • X may independently be–F.
  • X may independently be–Cl.
  • X may independently be–Br.
  • X may independently be–I.
  • X 16 may independently be–F.
  • X 16 may independently be–Cl.
  • X 16 may independently be–Br.
  • X 16 may independently be–I.
  • X 17 may
  • n16 may independently be 0. n16 may independently be 1. n16 may independently be 2. n16 may independently be 3. n16 may independently be 4. n17 may independently be 0. n17 may independently be 0. n17 may independently be 1. n17 may independently be 2. n17 may independently be 3. n17 may independently be 4. n18 may independently be 0.
  • n18 may independently be 1. n18 may independently be 2. n18 may independently be 3. n18 may independently be 4. n19 may independently be 0. n19 may independently be 1. n19 may independently be 2. n19 may independently be 3. n19 may independently be 4. [0327] v16 may independently be 1. v16 may independently be 2. v17 may independently be 1. v17 may independently be 2. v18 may independently be 1. v18 may independently be 2. v19 may independently be 1. v19 may independently be 2. [0328] m16 may independently be 1. m16 may independently be 2. m17 may each
  • R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are examples of substituents.
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted alkyl e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2
  • substituted e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • 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 e.g., substituted with at least one substituent group, size-limited substituent group, or lower substituent group
  • unsubstituted cycloalkyl e.
  • a substituted R 16A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 16A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 16A is substituted, it is substituted with at least one substituent group.
  • R 16A when R 16A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 16A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 16B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 16B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 16B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 16B when R 16B is substituted, it is substituted with at least one substituent group. In embodiments, when R 16B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 16B is substituted, it is substituted with at least one lower substituent group.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 16A and R 16B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or the substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 16A and R 16B bonded to the same nitrogen when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 16A and R 16B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 16A and R 16B bonded to the same nitrogen is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 16A and R 16B bonded to the same nitrogen is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 17A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 17A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 17A is substituted, it is substituted with at least one substituent group.
  • R 17A when R 17A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 17A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 17B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 17B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 17B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 17B when R 17B is substituted, it is substituted with at least one substituent group. In embodiments, when R 17B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 17B is substituted, it is substituted with at least one lower substituent group.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 17A and R 17B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or the substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 17A and R 17B bonded to the same nitrogen when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 17A and R 17B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 17A and R 17B bonded to the same nitrogen is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 17A and R 17B bonded to the same nitrogen is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 18A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 18A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 18A is substituted, it is substituted with at least one substituent group.
  • R 18A when R 18A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 18A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 18B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 18B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 18B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 18B when R 18B is substituted, it is substituted with at least one substituent group. In embodiments, when R 18B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 18B is substituted, it is substituted with at least one lower substituent group.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 18A and R 18B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or the substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 18A and R 18B bonded to the same nitrogen when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 18A and R 18B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 18A and R 18B bonded to the same nitrogen is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 18A and R 18B bonded to the same nitrogen is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 19A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 19A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 19A is substituted, it is substituted with at least one substituent group.
  • R 19A when R 19A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 19A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 19B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 19B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 19B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 19B when R 19B is substituted, it is substituted with at least one substituent group. In embodiments, when R 19B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 19B is substituted, it is substituted with at least one lower substituent group.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 19A and R 19B bonded to the same nitrogen is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted heterocycloalkyl or the substituted heteroaryl is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 19A and R 19B bonded to the same nitrogen when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 19A and R 19B bonded to the same nitrogen is substituted, it is substituted with at least one substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 19A and R 19B bonded to the same nitrogen is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when a substituted heterocycloalkyl or a substituted heteroaryl formed by joining R 19A and R 19B bonded to the same nitrogen is substituted, it is substituted with at least one lower substituent group.
  • R 16 is independently hydrogen, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -CN, -SO n16 R 16A , -SO v16 NR 16A R 16B , -NH NR 16A R 16B , -ONR 16A R 16B ,
  • a substituted R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 16 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 16 is substituted, it is substituted with at least one substituent group.
  • R 16 when R 16 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 16 is substituted, it is substituted with at least one lower substituent group.
  • R 16 is independently hydrogen. In embodiments, R 16 is independently halogen. In embodiments, R 16 is independently–CN. In embodiments, R 16 is independently unsubstituted methyl. In embodiments, R 16 is independently unsubstituted ethyl. In embodiments, R 16 is independently unsubstituted propyl. In embodiments, R 16 is independently unsubstituted isopropyl. In embodiments, R 16 is independently unsubstituted butyl.
  • R 16 is independently unsubstituted tert-butyl. In embodiments, R 16 is independently–CH 2 Ph. In embodiments, R 16 is independently -F. In embodiments, R 16 is independently -Cl. In embodiments, R 16 is independently -Br. In embodiments, R 16 is independently -I. In embodiments, R 16 is independently unsubstituted methoxy. In embodiments, R 16 is independently unsubstituted ethoxy. In embodiments, R 16 is
  • R 16 is independently -CF 3 . In embodiments, R 16 is independently -CCl 3 . In embodiments, R 16 is independently -CX 16 3 . In embodiments, R 16 is independently -OH. In embodiments, R 16 is independently -NH 2 . In embodiments, R 16 is independently -COOH. In embodiments, R 16 is independently -CONH 2 . In embodiments, R 16 is independently -NO 2 . In embodiments, R 16 is independently -SH. In embodiments, R 16 is independently -SO 3 H. In embodiments, R 16 is independently -SO 4 H. In embodiments, R 16 is independently -SO 2 NH 2 . In embodiments, R 16 is independently -NH NH 2 . In embodiments, R 16 is independently -ONH 2 . In embodiments, R 16 is independently -NH C(O)NHNH 2 . In embodiments, R 16 is independently
  • R 16 is independently -NHSO 2 H. In embodiments, R 16 is independently -NHC(O)H. In embodiments, R 16 is independently -NHC(O)OH. In embodiments, R 16 is independently -NHOH. [0345] In embodiments, R 16A is independently hydrogen. In embodiments, R 16A is independently -CX3. In embodiments, R 16A is independently -CN. In embodiments, R 16A is independently -COOH. In embodiments, R 16A is independently -CONH 2 . In embodiments, R 16A is independently -CHX 2 . In embodiments, R 16A is independently -CH 2 X. In
  • R 16A is independently unsubstituted methyl. In embodiments, R 16A is independently unsubstituted ethyl. In embodiments, R 16A is independently unsubstituted propyl. In embodiments, R 16A is independently unsubstituted isopropyl. In embodiments, R 16A is independently unsubstituted butyl. In embodiments, R 16A is independently unsubstituted tert-butyl. [0346] In embodiments, R 16B is independently hydrogen. In embodiments, R 16B is independently -CX 3 . In embodiments, R 16B is independently -CN. In embodiments, R 16B is independently -COOH. In embodiments, R 16B is independently -CONH 2 . In embodiments, R 16B is independently -CHX2. In embodiments, R 16B is independently -CH 2 X. In
  • R 16B is independently unsubstituted methyl. In embodiments, R 16B is independently unsubstituted ethyl. In embodiments, R 16B is independently unsubstituted propyl. In embodiments, R 16B is independently unsubstituted isopropyl. In embodiments, R 16B is independently unsubstituted butyl. In embodiments, R 16B is independently unsubstituted tert-butyl.
  • R 17 is independently hydrogen, halogen, -CX 17 3, -CHX 17 2, -CH 2 X 17 , -CN, -SO n17 R 17A , -SO v17 NR 17A R 17B , -NH NR 17A R 17B , -ONR 17A R 17B ,
  • a substituted R 17 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 17 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 17 is substituted, it is substituted with at least one substituent group.
  • R 17 when R 17 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 17 is substituted, it is substituted with at least one lower substituent group.
  • R 17 is independently hydrogen. In embodiments, R 17 is independently halogen. In embodiments, R 17 is independently–CN. In embodiments, R 17 is independently unsubstituted methyl. In embodiments, R 17 is independently unsubstituted ethyl. In embodiments, R 17 is independently unsubstituted propyl. In embodiments, R 17 is independently unsubstituted isopropyl. In embodiments, R 17 is independently unsubstituted butyl.
  • R 17 is independently unsubstituted tert-butyl. In embodiments, R 17 is independently–CH 2 Ph. In embodiments, R 17 is independently -F. In embodiments, R 17 is independently -Cl. In embodiments, R 17 is independently -Br. In embodiments, R 17 is independently -I. In embodiments, R 17 is independently unsubstituted methoxy. In embodiments, R 17 is independently unsubstituted ethoxy. In embodiments, R 17 is
  • R 17 is independently -CF 3 . In embodiments, R 17 is independently -CCl 3 . In embodiments, R 17 is independently -CX 17 3 . In embodiments, R 17 is independently -OH. In embodiments, R 17 is independently -NH 2 . In embodiments, R 17 is independently -COOH. In embodiments, R 17 is independently -CONH 2 . In embodiments, R 17 is independently -NO 2 . In embodiments, R 17 is independently -SH. In embodiments, R 17 is independently -SO 3 H. In embodiments, R 17 is independently -SO 4 H. In embodiments, R 17 is independently -SO 2 NH 2 . In embodiments, R 17 is independently -NH NH 2 . In embodiments, R 17 is independently -ONH 2 . In embodiments, R 17 is independently -NH C(O)NHNH 2 . In embodiments, R 17 is independently
  • R 17 is independently -NHSO 2 H. In embodiments, R 17 is independently -NHC(O)H. In embodiments, R 17 is independently -NHC(O)OH. In embodiments, R 17 is independently -NHOH. [0350] In embodiments, R 17A is independently hydrogen. In embodiments, R 17A is independently -CX3. In embodiments, R 17A is independently -CN. In embodiments, R 17A is independently -COOH. In embodiments, R 17A is independently -CONH 2 . In embodiments, R 17A is independently -CHX 2 . In embodiments, R 17A is independently -CH 2 X. In
  • R 17A is independently unsubstituted methyl. In embodiments, R 17A is independently unsubstituted ethyl. In embodiments, R 17A is independently unsubstituted propyl. In embodiments, R 17A is independently unsubstituted isopropyl. In embodiments, R 17A is independently unsubstituted butyl. In embodiments, R 17A is independently unsubstituted tert-butyl. [0351] In embodiments, R 17B is independently hydrogen. In embodiments, R 17B is independently -CX 3 . In embodiments, R 17B is independently -CN. In embodiments, R 17B is independently -COOH. In embodiments, R 17B is independently -CONH 2 . In embodiments, R 17B is independently -CHX2. In embodiments, R 17B is independently -CH 2 X. In
  • R 17B is independently unsubstituted methyl. In embodiments, R 17B is independently unsubstituted ethyl. In embodiments, R 17B is independently unsubstituted propyl. In embodiments, R 17B is independently unsubstituted isopropyl. In embodiments, R 17B is independently unsubstituted butyl. In embodiments, R 17B is independently unsubstituted tert-butyl.
  • R 18 is independently hydrogen, halogen, -CX 18 3, -CHX 18 2, -CH 2 X 18 , -CN, -SO n18 R 18A , -SO v18 NR 18A R 18B , -NH NR 18A R 18B , -ONR 18A R 18B ,
  • a substituted R 18 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 18 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 18 is substituted, it is substituted with at least one substituent group.
  • R 18 when R 18 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 18 is substituted, it is substituted with at least one lower substituent group.
  • R 18 is independently hydrogen. In embodiments, R 18 is independently halogen. In embodiments, R 18 is independently–CN. In embodiments, R 18 is independently unsubstituted methyl. In embodiments, R 18 is independently unsubstituted ethyl. In embodiments, R 18 is independently unsubstituted propyl. In embodiments, R 18 is independently unsubstituted isopropyl. In embodiments, R 18 is independently unsubstituted butyl.
  • R 18 is independently unsubstituted tert-butyl. In embodiments, R 18 is independently–CH 2 Ph. In embodiments, R 18 is independently -F. In embodiments, R 18 is independently -Cl. In embodiments, R 18 is independently -Br. In embodiments, R 18 is independently -I. In embodiments, R 18 is independently unsubstituted methoxy. In embodiments, R 18 is independently unsubstituted ethoxy. In embodiments, R 18 is independently -CF 3 . In embodiments, R 18 is independently -CCl 3 . In embodiments, R 18 is independently -CX 18 3 . In embodiments, R 18 is independently -OH.
  • R 18 is independently -NH 2 . In embodiments, R 18 is independently -COOH. In embodiments, R 18 is independently -CONH 2 . In embodiments, R 18 is independently -NO 2 . In embodiments, R 18 is independently -SH. In embodiments, R 18 is independently -SO 3 H. In embodiments, R 18 is independently -SO 4 H. In embodiments, R 18 is independently -SO 2 NH 2 . In embodiments, R 18 is independently -NH NH 2 . In embodiments, R 18 is independently -ONH 2 . In embodiments, R 18 is independently -NH C(O)NHNH 2 . In embodiments, R 18 is independently
  • R 18 is independently -NHSO 2 H. In embodiments, R 18 is independently -NHC(O)H. In embodiments, R 18 is independently -NHC(O)OH. In embodiments, R 18 is independently -NHOH. [0355] In embodiments, R 18A is independently hydrogen. In embodiments, R 18A is independently -CX 3 . In embodiments, R 18A is independently -CN. In embodiments, R 18A is independently -COOH. In embodiments, R 18A is independently -CONH 2 . In embodiments, R 18A is independently -CHX 2 . In embodiments, R 18A is independently -CH 2 X. In
  • R 18A is independently unsubstituted methyl. In embodiments, R 18A is independently unsubstituted ethyl. In embodiments, R 18A is independently unsubstituted propyl. In embodiments, R 18A is independently unsubstituted isopropyl. In embodiments, R 18A is independently unsubstituted butyl. In embodiments, R 18A is independently unsubstituted tert-butyl. [0356] In embodiments, R 18B is independently hydrogen. In embodiments, R 18B is independently -CX 3 . In embodiments, R 18B is independently -CN. In embodiments, R 18B is independently -COOH. In embodiments, R 18B is independently -CONH 2 . In embodiments, R 18B is independently -CHX2. In embodiments, R 18B is independently -CH 2 X. In
  • R 18B is independently unsubstituted methyl. In embodiments, R 18B is independently unsubstituted ethyl. In embodiments, R 18B is independently unsubstituted propyl. In embodiments, R 18B is independently unsubstituted isopropyl. In embodiments, R 18B is independently unsubstituted butyl. In embodiments, R 18B is independently unsubstituted tert-butyl.
  • R 19 is independently hydrogen, halogen, -CX 19 3, -CHX 19 2, -CH 2 X 19 , -CN, -SOn19R 19A , -SOv19NR 19A R 19B , -NH NR 19A R 19B , -ONR 19A R 19B , -NHC(O)NHNR 19A R 19B , -NH C(O)NR 19A R 19B , -N(O)m19, -NR 19A R 19B , -C(O)R 19A ,
  • a substituted R 19 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 19 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 19 is substituted, it is substituted with at least one substituent group.
  • R 19 when R 19 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 19 is substituted, it is substituted with at least one lower substituent group.
  • R 19 is independently hydrogen. In embodiments, R 19 is independently halogen. In embodiments, R 19 is independently–CN. In embodiments, R 19 is independently unsubstituted methyl. In embodiments, R 19 is independently unsubstituted ethyl. In embodiments, R 19 is independently unsubstituted propyl. In embodiments, R 19 is independently unsubstituted isopropyl. In embodiments, R 19 is independently unsubstituted butyl.
  • R 19 is independently unsubstituted tert-butyl. In embodiments, R 19 is independently–CH 2 Ph. In embodiments, R 19 is independently -F. In embodiments, R 19 is independently -Cl. In embodiments, R 19 is independently -Br. In embodiments, R 19 is independently -I. In embodiments, R 19 is independently unsubstituted methoxy. In embodiments, R 19 is independently unsubstituted ethoxy. In embodiments, R 19 is
  • R 19 is independently -CF 3 . In embodiments, R 19 is independently -CCl 3 . In embodiments, R 19 is independently -CX 19 3 . In embodiments, R 19 is independently -OH. In embodiments, R 19 is independently -NH 2 . In embodiments, R 19 is independently -COOH. In embodiments, R 19 is independently -CONH 2 . In embodiments, R 19 is independently -NO 2 . In embodiments, R 19 is independently -SH. In embodiments, R 19 is independently -SO 3 H. In embodiments, R 19 is independently -SO 4 H. In embodiments, R 19 is independently -SO 2 NH 2 . In embodiments, R 19 is independently -NH NH 2 . In embodiments, R 19 is independently -ONH 2 . In embodiments, R 19 is independently -NH C(O)NHNH 2 . In embodiments, R 19 is independently
  • R 19 is independently -NHSO 2 H. In embodiments, R 19 is independently -NHC(O)H. In embodiments, R 19 is independently -NHC(O)OH. In embodiments, R 19 is independently -NHOH. [0360] In embodiments, R 19A is independently hydrogen. In embodiments, R 19A is independently -CX 3 . In embodiments, R 19A is independently -CN. In embodiments, R 19A is independently -COOH. In embodiments, R 19A is independently -CONH 2 . In embodiments, R 19A is independently -CHX 2 . In embodiments, R 19A is independently -CH 2 X. In
  • R 19A is independently unsubstituted methyl. In embodiments, R 19A is independently unsubstituted ethyl. In embodiments, R 19A is independently unsubstituted propyl. In embodiments, R 19A is independently unsubstituted isopropyl. In embodiments, R 19A is independently unsubstituted butyl. In embodiments, R 19A is independently unsubstituted tert-butyl. [0361] In embodiments, R 19B is independently hydrogen. In embodiments, R 19B is independently -CX 3 . In embodiments, R 19B is independently -CN. In embodiments, R 19B is independently -COOH. In embodiments, R 19B is independently -CONH 2 . In embodiments, R 19B is independently -CHX 2 . In embodiments, R 19B is independently -CH 2 X. In
  • R 1.1 substituent group when an R 1.1 substituent group is substituted, the R 1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1 , R 1.1 , R 1.2 , and R 1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 1 substituents when two adjacent R 1 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 1.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1.1 when an R 1.1 substituent group is substituted, the R 1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1 , R 1.1 , R 1.2 , and R 1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1.3 has values corresponding to the values of L WW , R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein L WW , R WW , R WW.1 , R WW.2 , and R WW.3 correspond to L 1 , R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 1A when R 1A is substituted, R 1A is substituted with one or more first substituent groups denoted by R 1A.1 as explained in the definitions section above in the description of“first substituent group(s)”. In embodiments, when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1A , R 1A.1 , R 1A.2 , and R 1A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1A , R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
  • R 1B when R 1B is substituted, R 1B is substituted with one or more first substituent groups denoted by R 1B.1 as explained in the definitions section above in the description of“first substituent group(s)”. In embodiments, when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1B , R 1B.1 , R 1B.2 , and R 1B.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1B , R 1B.1 , R 1B.2 , and R 1B.3 , respectively.
  • R 1A and R 1B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 1A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1A.1 when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1A , R 1A.1 , R 1A.2 , and R 1A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1A , R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
  • R 1A and R 1B when R 1A and R 1B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 1B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1B.1 when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1B , R 1B.1 , R 1B.2 , and R 1B.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1B , R 1B.1 , R 1B.2 , and R 1B.3 , respectively.
  • R 1C when R 1C is substituted, R 1C is substituted with one or more first substituent groups denoted by R 1C.1 as explained in the definitions section above in the description of“first substituent group(s)”. In embodiments, when an R 1C.1 substituent group is substituted, the R 1C.1 substituent group is substituted with one or more second substituent groups denoted by R 1C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1C.2 substituent group when an R 1C.2 substituent group is substituted, the R 1C.2 substituent group is substituted with one or more third substituent groups denoted by R 1C.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1C , R 1C.1 , R 1C.2 , and R 1C.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1C , R 1C.1 , R 1C.2 , and R 1C.3 , respectively.
  • R 1D when R 1D is substituted, R 1D is substituted with one or more first substituent groups denoted by R 1D.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1D.1 when an R 1D.1 substituent group is substituted, the R 1D.1 substituent group is substituted with one or more second substituent groups denoted by R 1D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1D.2 substituent group when an R 1D.2 substituent group is substituted, the R 1D.2 substituent group is substituted with one or more third substituent groups denoted by R 1D.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 1D , R 1D.1 , R 1D.2 , and R 1D.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1D , R 1D.1 , R 1D.2 , and R 1D.3 , respectively.
  • R 2 when R 2 is substituted, R 2 is substituted with one or more first substituent groups denoted by R 2.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 2.1 substituent group when an R 2.1 substituent group is substituted, the R 2.1 substituent group is substituted with one or more second substituent groups denoted by R 2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2.2 substituent group when an R 2.2 substituent group is substituted, the R 2.2 substituent group is substituted with one or more third substituent groups denoted by R 2.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 2 , R 2.1 , R 2.2 , and R 2.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 2 , R 2.1 , R 2.2 , and R 2.3 , respectively.
  • R 3 when R 3 is substituted, R 3 is substituted with one or more first substituent groups denoted by R 3.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 3.1 substituent group when an R 3.1 substituent group is substituted, the R 3.1 substituent group is substituted with one or more second substituent groups denoted by R 3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 3.2 substituent group is substituted, the R 3.2 substituent group is substituted with one or more third substituent groups denoted by R 3.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 3 , R 3.1 , R 3.2 , and R 3.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 3 , R 3.1 , R 3.2 , and R 3.3 , respectively.
  • R 4 when R 4 is substituted, R 4 is substituted with one or more first substituent groups denoted by R 4.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 4.1 substituent group when an R 4.1 substituent group is substituted, the R 4.1 substituent group is substituted with one or more second substituent groups denoted by R 4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2 substituent group when an R 4.2 substituent group is substituted, the R 4.2 substituent group is substituted with one or more third substituent groups denoted by R 4.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 4 , R 4.1 , R 4.2 , and R 4.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
  • R 4 substituents when two adjacent R 4 substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 4.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 4.1 when an R 4.1 substituent group is substituted, the R 4.1 substituent group is substituted with one or more second substituent groups denoted by R 4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2 substituent group when an R 4.2 substituent group is substituted, the R 4.2 substituent group is substituted with one or more third substituent groups denoted by R 4.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 4 , R 4.1 , R 4.2 , and R 4.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
  • R 5 when R 5 is substituted, R 5 is substituted with one or more first substituent groups denoted by R 5.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 5.1 substituent group when an R 5.1 substituent group is substituted, the R 5.1 substituent group is substituted with one or more second substituent groups denoted by R 5.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5.2 substituent group when an R 5.2 substituent group is substituted, the R 5.2 substituent group is substituted with one or more third substituent groups denoted by R 5.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 5 , R 5.1 , R 5.2 , and R 5.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5 , R 5.1 , R 5.2 , and R 5.3 , respectively.
  • R 10 when R 10 is substituted, R 10 is substituted with one or more first substituent groups denoted by R 10.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 10.1 substituent group when an R 10.1 substituent group is substituted, the R 10.1 substituent group is substituted with one or more second substituent groups denoted by R 10.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 10.2 substituent group when an R 10.2 substituent group is substituted, the R 10.2 substituent group is substituted with one or more third substituent groups denoted by R 10.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 10 , R 10.1 , R 10.2 , and R 10.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 10 , R 10.1 , R 10.2 , and R 10.3 , respectively.
  • R 11 when R 11 is substituted, R 11 is substituted with one or more first substituent groups denoted by R 11.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 11.1 substituent group when an R 11.1 substituent group is substituted, the R 11.1 substituent group is substituted with one or more second substituent groups denoted by R 11.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 11.2 substituent group when an R 11.2 substituent group is substituted, the R 11.2 substituent group is substituted with one or more third substituent groups denoted by R 11.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 11 , R 11.1 , R 11.2 , and R 11.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 11 , R 11.1 , R 11.2 , and R 11.3 , respectively.
  • R 12 when R 12 is substituted, R 12 is substituted with one or more first substituent groups denoted by R 12.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 12.1 substituent group when an R 12.1 substituent group is substituted, the R 12.1 substituent group is substituted with one or more second substituent groups denoted by R 12.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 12.2 substituent group is substituted, the R 12.2 substituent group is substituted with one or more third substituent groups denoted by R 12.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 12 , R 12.1 , R 12.2 , and R 12.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 12 , R 12.1 , R 12.2 , and R 12.3 , respectively.
  • R 16 when R 16 is substituted, R 16 is substituted with one or more first substituent groups denoted by R 16.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16.1 substituent group when an R 16.1 substituent group is substituted, the R 16.1 substituent group is substituted with one or more second substituent groups denoted by R 16.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 16.2 substituent group is substituted, the R 16.2 substituent group is substituted with one or more third substituent groups denoted by R 16.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16 , R 16.1 , R 16.2 , and R 16.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 16 , R 16.1 , R 16.2 , and R 16.3 , respectively.
  • R 16A when R 16A is substituted, R 16A is substituted with one or more first substituent groups denoted by R 16A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16A.1 substituent group when an R 16A.1 substituent group is substituted, the R 16A.1 substituent group is substituted with one or more second substituent groups denoted by R 16A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 16A.2 substituent group when an R 16A.2 substituent group is substituted, the R 16A.2 substituent group is substituted with one or more third substituent groups denoted by R 16A.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16A , R 16A.1 , R 16A.2 , and R 16A.3 have values
  • R 16B when R 16B is substituted, R 16B is substituted with one or more first substituent groups denoted by R 16B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16B.1 substituent group when an R 16B.1 substituent group is substituted, the R 16B.1 substituent group is substituted with one or more second substituent groups denoted by R 16B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 16B.2 substituent group when an R 16B.2 substituent group is substituted, the R 16B.2 substituent group is substituted with one or more third substituent groups denoted by R 16B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16B , R 16B.1 , R 16B.2 , and R 16B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 16B , R 16B.1 , R 16B.2 , and R 16B.3 , respectively.
  • R 16A and R 16B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 16A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16A.1 when an R 16A.1 substituent group is substituted, the R 16A.1 substituent group is substituted with one or more second substituent groups denoted by R 16A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 16A , R 16A.1 , R 16A.2 , and R 16A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 16A , R 16A.1 , R 16A.2 , and R 16A.3 , respectively.
  • R 16A and R 16B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 16B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16B.1 when an R 16B.1 substituent group is substituted, the R 16B.1 substituent group is substituted with one or more second substituent groups denoted by R 16B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 16B.2 substituent group when an R 16B.2 substituent group is substituted, the R 16B.2 substituent group is substituted with one or more third substituent groups denoted by R 16B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 16B , R 16B.1 , R 16B.2 , and R 16B.3 have values
  • R 17 when R 17 is substituted, R 17 is substituted with one or more first substituent groups denoted by R 17.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • the R 17.1 substituent group when an R 17.1 substituent group is substituted, the R 17.1 substituent group is substituted with one or more second substituent groups denoted by R 17.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 17.2 substituent group is substituted, the R 17.2 substituent group is substituted with one or more third substituent groups denoted by R 17.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17 , R 17.1 , R 17.2 , and R 17.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 17 , R 17.1 , R 17.2 , and R 17.3 , respectively.
  • R 17A when R 17A is substituted, R 17A is substituted with one or more first substituent groups denoted by R 17A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17A , R 17A.1 , R 17A.2 , and R 17A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 17A , R 17A.1 , R 17A.2 , and R 17A.3 , respectively.
  • R 17B when R 17B is substituted, R 17B is substituted with one or more first substituent groups denoted by R 17B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17B.1 substituent group when an R 17B.1 substituent group is substituted, the R 17B.1 substituent group is substituted with one or more second substituent groups denoted by R 17B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 17B.2 substituent group when an R 17B.2 substituent group is substituted, the R 17B.2 substituent group is substituted with one or more third substituent groups denoted by R 17B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17B , R 17B.1 , R 17B.2 , and R 17B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 17B , R 17B.1 , R 17B.2 , and R 17B.3 , respectively.
  • R 17A and R 17B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 17A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17A.1 when an R 17A.1 substituent group is substituted, the R 17A.1 substituent group is substituted with one or more second substituent groups denoted by R 17A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 17A , R 17A.1 , R 17A.2 , and R 17A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 17A , R 17A.1 , R 17A.2 , and R 17A.3 , respectively.
  • R 17A and R 17B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 17B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17B.1 when an R 17B.1 substituent group is substituted, the R 17B.1 substituent group is substituted with one or more second substituent groups denoted by R 17B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 17B.2 substituent group when an R 17B.2 substituent group is substituted, the R 17B.2 substituent group is substituted with one or more third substituent groups denoted by R 17B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 17B , R 17B.1 , R 17B.2 , and R 17B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 17B , R 17B.1 , R 17B.2 , and R 17B.3 , respectively.
  • R 18 when R 18 is substituted, R 18 is substituted with one or more first substituent groups denoted by R 18.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18.1 substituent group when an R 18.1 substituent group is substituted, the R 18.1 substituent group is substituted with one or more second substituent groups denoted by R 18.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 18.2 substituent group is substituted, the R 18.2 substituent group is substituted with one or more third substituent groups denoted by R 18.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18 , R 18.1 , R 18.2 , and R 18.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 18 , R 18.1 , R 18.2 , and R 18.3 , respectively.
  • R 18A when R 18A is substituted, R 18A is substituted with one or more first substituent groups denoted by R 18A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18A.1 substituent group when an R 18A.1 substituent group is substituted, the R 18A.1 substituent group is substituted with one or more second substituent groups denoted by R 18A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 18A.2 substituent group when an R 18A.2 substituent group is substituted, the R 18A.2 substituent group is substituted with one or more third substituent groups denoted by R 18A.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18A , R 18A.1 , R 18A.2 , and R 18A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 18A , R 18A.1 , R 18A.2 , and R 18A.3 , respectively.
  • R 18B when R 18B is substituted, R 18B is substituted with one or more first substituent groups denoted by R 18B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18B.1 substituent group when an R 18B.1 substituent group is substituted, the R 18B.1 substituent group is substituted with one or more second substituent groups denoted by R 18B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 18B.2 substituent group when an R 18B.2 substituent group is substituted, the R 18B.2 substituent group is substituted with one or more third substituent groups denoted by R 18B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18B , R 18B.1 , R 18B.2 , and R 18B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 18B , R 18B.1 , R 18B.2 , and R 18B.3 , respectively.
  • R 18A and R 18B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 18A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18A.1 when an R 18A.1 substituent group is substituted, the R 18A.1 substituent group is substituted with one or more second substituent groups denoted by R 18A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 18A , R 18A.1 , R 18A.2 , and R 18A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 18A , R 18A.1 , R 18A.2 , and R 18A.3 , respectively.
  • R 18A and R 18B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 18B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18B.1 when an R 18B.1 substituent group is substituted, the R 18B.1 substituent group is substituted with one or more second substituent groups denoted by R 18B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 18B.2 substituent group when an R 18B.2 substituent group is substituted, the R 18B.2 substituent group is substituted with one or more third substituent groups denoted by R 18B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 18B , R 18B.1 , R 18B.2 , and R 18B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 18B , R 18B.1 , R 18B.2 , and R 18B.3 , respectively.
  • R 19 when R 19 is substituted, R 19 is substituted with one or more first substituent groups denoted by R 19.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19.1 substituent group when an R 19.1 substituent group is substituted, the R 19.1 substituent group is substituted with one or more second substituent groups denoted by R 19.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 19.2 substituent group is substituted, the R 19.2 substituent group is substituted with one or more third substituent groups denoted by R 19.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19 , R 19.1 , R 19.2 , and R 19.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 19 , R 19.1 , R 19.2 , and R 19.3 , respectively.
  • R 19A when R 19A is substituted, R 19A is substituted with one or more first substituent groups denoted by R 19A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19A.1 substituent group when an R 19A.1 substituent group is substituted, the R 19A.1 substituent group is substituted with one or more second substituent groups denoted by R 19A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 19A.2 substituent group when an R 19A.2 substituent group is substituted, the R 19A.2 substituent group is substituted with one or more third substituent groups denoted by R 19A.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19A , R 19A.1 , R 19A.2 , and R 19A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 19A , R 19A.1 , R 19A.2 , and R 19A.3 , respectively.
  • R 19B when R 19B is substituted, R 19B is substituted with one or more first substituent groups denoted by R 19B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19B.1 substituent group when an R 19B.1 substituent group is substituted, the R 19B.1 substituent group is substituted with one or more second substituent groups denoted by R 19B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 19B.2 substituent group when an R 19B.2 substituent group is substituted, the R 19B.2 substituent group is substituted with one or more third substituent groups denoted by R 19B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19B , R 19B.1 , R 19B.2 , and R 19B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 19B , R 19B.1 , R 19B.2 , and R 19B.3 , respectively.
  • R 19A and R 19B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 19A.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19A.1 when an R 19A.1 substituent group is substituted, the R 19A.1 substituent group is substituted with one or more second substituent groups denoted by R 19A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 19A , R 19A.1 , R 19A.2 , and R 19A.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 19A , R 19A.1 , R 19A.2 , and R 19A.3 , respectively.
  • R 19A and R 19B substituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted
  • the moiety is substituted with one or more first substituent groups denoted by R 19B.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19B.1 when an R 19B.1 substituent group is substituted, the R 19B.1 substituent group is substituted with one or more second substituent groups denoted by R 19B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 19B.2 substituent group when an R 19B.2 substituent group is substituted, the R 19B.2 substituent group is substituted with one or more third substituent groups denoted by R 19B.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R 19B , R 19B.1 , R 19B.2 , and R 19B.3 have values
  • R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 19B , R 19B.1 , R 19B.2 , and R 19B.3 , respectively.
  • R L 1 when L 1 is substituted, L 1 is substituted with one or more first substituent groups denoted by R L1.1 as explained in the definitions section above in the description of“first substituent group(s)”.
  • R L1.1 substituent group when an R L1.1 substituent group is substituted, the R L1.1 substituent group is substituted with one or more second substituent groups denoted by R L1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L1.2 substituent group when an R L1.2 substituent group is substituted, the R L1.2 substituent group is substituted with one or more third substituent groups denoted by R L1.3 as explained in the definitions section above in the description of“first substituent group(s)”.
  • L 1 , R L1.1 , R L1.2 , and R L1.3 have values corresponding to the values of L WW , R LWW.1 , R LWW.2 , and R LWW.3 , respectively, as explained in the definitions section above in the description of“first substituent group(s)”, wherein L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 1 , R L1.1 , R L1.2 , and R L1.3 , respectively.
  • the compound is , wherein R 1 , R 2 , and R 4 are as described herein, including in embodiments. In embodiments, R 1 and R 4 are each independently halogen.
  • R 2 is independently C 1 -C 6 alkyl. In embodiments, R 2 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently C 3 -C 6 cycloalkyl.
  • the compound is wherein R 2 is as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • the compound is wherein R 2 is as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • the compound is wherein R 2 is as described herein, including in embodiments.
  • R 2 is independently C 1 -C 6 alkyl.
  • R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • R 2 is independently C 3 -C 6 cycloalkyl.
  • the compound is wherein R 1 and R 4 are each independently halogen.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is a compound described herein.
  • the compound, or a pharmaceutically acceptable salt thereof is the compound described herein.
  • the compound, or a pharmaceutically acceptable salt thereof is the pharmaceutically acceptable salt of a compound described herein.
  • the compound is not wherein R 1
  • R 4 are each independently halogen.
  • the compound is not
  • the compound is not
  • the compound is not
  • the compound is not .
  • the compound is not , wherein R 16 , R 17 , and R 18 are as defined herein.
  • R 1 is not–F.
  • R 4 is not–F.
  • R 1 is independently–F
  • R 4 is not–F.
  • R 1 is not–F.
  • a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition includes an effective amount of the compound.
  • the pharmaceutical composition includes a therapeutically effective amount of the compound.
  • the pharmaceutical composition includes a second agent (e.g., an anti-cancer agent).
  • the pharmaceutical composition includes a second agent in a therapeutically effective amount.
  • a method for treating cancer in a subject in need thereof including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating cancer in a subject in need thereof the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in a method of treating cancer including administering to a subject in need thereof a therapeutically effective amount of the compound, or a
  • the cancer is renal cell carcinoma, follicular lymphoma, glioblastoma, colorectal cancer, endometrial cancer, or lung cancer.
  • the cancer is renal cell carcinoma.
  • the cancer is follicular lymphoma.
  • the cancer is glioblastoma.
  • the cancer is colorectal cancer.
  • the cancer is endometrial cancer.
  • the cancer is lung cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is melanoma. In embodiments, the cancer is breast cancer. In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is endometrial cancer. In embodiments, the cancer is non-Hodgkin lymphoma. In
  • the cancer is mantle cell lymphoma.
  • the method includes immunomodulation.
  • the method includes cancer immunotherapy.
  • a method for treating a neurodegenerative disease the method including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating a neurodegenerative disease the method including administering to a subject in need thereof an effective amount of a compound described herein.
  • the compound is included in a therapeutically effective amount.
  • the method is a method of treating nerve damage, the method including administering to a subject in need thereof an effective amount of a compound described herein.
  • the neurodegenerative disease is Huntington Disease. In embodiments, the neurodegenerative disease is Alzheimer Disease. In embodiments, the neurodegenerative disease is Parkinson’s Disease. In embodiments, the neurodegenerative disease is frontotemporal dementia. In embodiments, the method includes reducing protein aggregates (e.g., in the brain). In embodiments, the method includes reducing TDP-43 aggregates (e.g., in the brain). In embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis. In embodiments, the neurodegenerative disease is chronic traumatic encephalopathy. In embodiments, the neurodegenerative disease is traumatic brain injury (e.g., concussion).
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in a method of treating a neurodegenerative disease including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • neurodegenerative disease the use including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a method for treating a metabolic disease the method including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating a metabolic disease the method including administering to a subject in need thereof an effective amount of a compound described herein.
  • the compound is included in a therapeutically effective amount.
  • the metabolic disease is diabetes.
  • the metabolic disease is type I diabetes.
  • the metabolic disease is type II diabetes.
  • the metabolic disease is obesity.
  • the metabolic disease is metabolic syndrome.
  • the metabolic disease is a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function).
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in a method of treating a metabolic disease including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a metabolic disease the use including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a method for treating aging including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method for treating aging including administering to a subject in need thereof an effective amount of a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating aging including administering to a subject in need thereof a therapeutically effective amount of the compound, or a
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of aging, the use including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a method of extending lifespan e.g., increased 1 day, increased 2 days, increased 3 days, increased 7 days, increased 1 month, increased 6 months, increased 12 months, increased 2 years, increased 5 years, etc.
  • the method including administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of extending lifespan e.g., increased 1 day, increased 2 days, increased 3 days, increased 7 days, increased 1 month, increased 6 months, increased 12 months, increased 2 years, increased 5 years, etc.
  • administering including administering to a subject in need thereof an effective amount of a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in a method of extending lifespan (e.g., increased 1 day, increased 2 days, increased 3 days, increased 7 days, increased 1 month, increased 6 months, increased 12 months, increased 2 years, increased 5 years, etc.) or inducing longevity, including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • lifespan e.g., increased 1 day, increased 2 days, increased 3 days, increased 7 days, increased 1 month, increased 6 months, increased 12 months, increased 2 years, increased 5 years, etc.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for extending lifespan (e.g., increased 1 day, increased 2 days, increased 3 days, increased 7 days, increased 1 month, increased 6 months, increased 12 months, increased 2 years, increased 5 years, etc.) or inducing longevity, the use including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a subject in need thereof the method including administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a subject in need thereof including administering to the subject in need thereof an effective amount of a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, for use in reducing the level of activity of mTORC1 including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of activity of mTORC1, the use including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell the method including contacting a Vacuolar H + -ATPase in the cell with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell including contacting a Vacuolar H + -ATPase in the cell with a compound as described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, for use in reducing the level of activity of mTORC1 in a cell including contacting a Vacuolar H + -ATPase in the cell with the compound, or a
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of activity of mTORC1 in a cell, the use including contacting a Vacuolar H + -ATPase in the cell with the compound, or a pharmaceutically acceptable salt thereof.
  • the method includes dephosphorylation and/or nuclear
  • the method includes increasing the level of TFEB transcriptional targets in a cell or subject.
  • the method includes increasing the level of CTSA (e.g., RefSeq NM_000308.3 or RefSeq NP_000299.2), CTSB (e.g., RefSeq
  • CTSF e.g., RefSeq NM_003793.3 or RefSeq NP_003784.2
  • HEXB e.g., RefSeq NM_000521.4 or RefSeq NP_000512.2
  • CLN3 e.g., RefSeq NM_000086.2 or RefSeq NP_000077.1
  • CLCN7 e.g., RefSeq NM_001287.5 or RefSeq NP_001278.1
  • ATP6V0D1 e.g., RefSeq NM_004691.4 or RefSeq NP_004682.2
  • ATP6V0E1 e.g., RefSeq NM_003945.3 or RefSeq NP_003936.1
  • LAMP1 e.g., RefSeq NM_00556
  • the method includes increasing the level of TFE3 transcriptional targets in a cell or subject.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase the method including contacting the Vacuolar H + -ATPase with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase including contacting the Vacuolar H + -ATPase with a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in reducing the level of activity of a Vacuolar H + -ATPase including contacting contacting the Vacuolar H + -ATPase with the compound, or a pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of activity of a Vacuolar H + -ATPase, the use including contacting the Vacuolar H + -ATPase with the compound, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase protein complex the method including contacting an ATP6V1A in the Vacuolar H + - ATPase protein complex with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of a Vacuolar H + - ATPase protein complex including contacting an ATP6V1A in the Vacuolar H + - ATPase protein complex with a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, for use in reducing the level of activity of a Vacuolar H + -ATPase protein complex including contacting contacting an ATP6V1A in the Vacuolar H + -ATPase protein complex with the compound, or a pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of activity of a Vacuolar H + -ATPase protein complex, the use including contacting an ATP6V1A in the Vacuolar H + -ATPase protein complex with the compound, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell the method including contacting an ATP6V1A in the cell with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of mTORC1 in a cell including contacting an ATP6V1A in the cell with a compound as described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, for use in reducing the level of activity of mTORC1 in a cell including contacting an ATP6V1A in the cell with the compound, or a pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of activity of mTORC1 in a cell, the use including contacting an ATP6V1A in the cell with the compound, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of an ATP6V1A the method including contacting the ATP6V1A with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of an ATP6V1A the method including contacting the ATP6V1A with a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in reducing the level of activity of an ATP6V1A including contacting the ATP6V1A with the compound, or a pharmaceutically acceptable salt thereof.
  • the method includes reducing the activity of mTORC1 more than reducing the activity of mTORC2 (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9.2, 3, 4, 5, 6, 7, 8,910, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 100000, 1000000-fold more).
  • the method includes reducing the activity of mTORC1 more than reducing the activity of mTORC2 (e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9.2, 3, 4, 5, 6, 7, 8,910, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 100000, 1000000-fold more).
  • the method includes reducing the activity of mTORC1 more than reducing the activity of mTORC2 (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9.2, 3, 4, 5, 6, 7, 8,910, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 100000, 1000000-fold more).
  • the method includes reducing (e.g., reduced relative to a control) mTORC1 signaling by preventing mTORC1 localization to the lysosome.
  • the method includes modulating (e.g., preventing the formation) of the Ragulator complex. In embodiments, the method includes reducing (e.g., reduced relative to a control) mTORC1 signaling by causing an accumulation of Ragulator complex in the lysosome.
  • the method includes preventing the activation of the Ragulator complex. In embodiments, the method includes preventing the binding of mTORC1 to the Ragulator complex. In embodiments, the method includes preventing the formation of the Ragulator complex. [0482] In embodiments, the method includes inhibiting the activation of the Ragulator complex. In embodiments, the method includes inhibiting the binding of mTORC1 to the Ragulator complex. In embodiments, the method includes inhibiting the formation of the Ragulator complex. In embodiments, the method includes inhibiting the amino-acid-induced localization of mTORC1 to the lysosome. In embodiments, the method includes inhibiting the binding between the Vacuolar H + -ATPase protein complex and the Ragulator.
  • the method includes inhibiting the activity of Rag activity. In embodiments, the method includes inhibiting the GTPase activity of Rag. In embodiments, the method includes inhibiting the Rag GTPase-induced localization of mTORC1 to the lysosome. In embodiments, the method includes increased acidification of a lysosome. In embodiments, the method includes inhibiting the phosphorylation of 4EBP1. In embodiments, the method includes inhibiting the phosphorylation of S6. In embodiments, the method includes inhibiting the activity of Vacuolar H + -ATPase protein complex. In embodiments, the method includes increasing autophagy.
  • the method includes inhibiting the Rag-A/B Rag-C/D complex interaction with Raptor in mTORC1. In embodiments, the method includes inhibiting the phosphorylation of ULK1 kinase. In embodiments, the method includes increasing the nuclear translocation and/or activation of TFEB transcription factor. [0483] In an aspect is provided a method for increasing autophagy in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. [0484] In an aspect is provided a method for increasing autophagy in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in a method of increasing autophagy including administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.
  • Vacuolar H + -ATPase protein complex covalently bonded to a compound described herein, or a pharmaceutically acceptable salt thereof, which may be referred to herein as a Vacuolar H + -ATPase protein complex-compound complex.
  • a Vacuolar H + -ATPase protein complex covalently bonded to a compound described herein, which may be referred to herein as a Vacuolar H + -ATPase protein complex-compound complex.
  • the Vacuolar H + -ATPase protein complex is a human Vacuolar H + -ATPase protein complex.
  • the compound is provided in a therapeutically effective amount.
  • the compound contacts an amino acid corresponding to C277 of human ATP6V1A in the Vacuolar H + -ATPase protein complex.
  • the compound covalently binds an amino acid corresponding to C277 of human ATP6V1A in the Vacuolar H + -ATPase protein complex.
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) is covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
  • a compound e.g., compound described herein or a portion of a compound described herein.
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) is irreversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) is reversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex is covalently bonded to a portion of a compound (e.g., compound described herein).
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human
  • ATP6V1A in a human Vacuolar H + -ATPase protein complex is irreversibly covalently bonded to a portion of a compound described herein.
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex e.g., human ATP6V1A in a human Vacuolar H + - ATPase protein complex
  • the compound described herein is bonded to a cysteine residue (e.g., residue corresponding to Cys277 of human ATP6V1A) of the ATP6V1A protein (e.g., human ATP6V1A protein).
  • the ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) covalently bonded to a compound described herein is the product of a reaction between the ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) and a compound described herein.
  • a Vacuolar H + -ATPase protein complex e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex
  • the covalently bonded ATP6V1A in a Vacuolar H + -ATPase protein complex e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex
  • compound described herein are the remnants of the reactant ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) and compound, wherein each reactant now participates in the covalent bond between the ATP6V1A in a Vacuolar H + - ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) and compound.
  • the remnant of the E substitutent is a linker including a covalent bond between the ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) and the remainder of the compound described herein.
  • an ATP6V1A in a Vacuolar H + -ATPase protein complex e.g., human
  • ATP6V1A in a human Vacuolar H + -ATPase protein complex is covalently bonded to a compound described herein, the compound described herein forms a remnant of the pre- reacted compound wherein a bond connects the remnant of the compound to the remnant of the ATP6V1A in a Vacuolar H + -ATPase protein complex (e.g., human ATP6V1A in a human Vacuolar H + -ATPase protein complex) (e.g., cysteine sulfur, sulfur of amino acid
  • the ATP6V1A protein is a human ATP6V1A protein.
  • human ATP6V1A protein has a sequence described herein.
  • the compound is provided in a therapeutically effective amount.
  • the compound contacts an amino acid corresponding to C277 of human ATP6V1A.
  • the compound covalently binds an amino acid corresponding to C277 of human ATP6V1A.
  • an ATP6V1A protein e.g., human ATP6V1A
  • a compound e.g., compound described herein or a portion of a compound described herein.
  • an ATP6V1A protein (e.g., human ATP6V1A) is irreversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
  • the ATP6V1A protein (e.g., human ATP6V1A) is reversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
  • the ATP6V1A protein (e.g., human ATP6V1A) is covalently bonded to a portion of a compound (e.g., compound described herein).
  • the ATP6V1A protein (e.g., human ATP6V1A) is irreversibly covalently bonded to a portion of a compound described herein.
  • the ATP6V1A protein (e.g., human ATP6V1A) is reversibly covalently bonded to a portion of a compound described herein.
  • the compound described herein is bonded to a cysteine residue (e.g., residue corresponding to Cys277 of human ATP6V1A) of the ATP6V1A protein (e.g., human ATP6V1A).
  • the ATP6V1A protein covalently bonded to a compound described herein is the product of a reaction between the ATP6V1A protein and a compound described herein.
  • the covalently bonded ATP6V1A protein and compound described herein are the remnants of the reactant ATP6V1A protein and compound, wherein each reactant now participates in the covalent bond between the ATP6V1A protein and or compound.
  • the remnant of the E substitutent is a linker including a covalent bond between the ATP6V1A protein and the remainder of the compound described herein.
  • Embodiment P A compound having the formula:
  • Ring A is a phenyl or 5 to 6 membered heteroaryl
  • Ring B is a phenyl or 5 to 6 membered heteroaryl
  • L 1 is independently a bond, -S(O) 2 -, -N(R 5 )-, -O-, -S-, -C(O)-, -C(O)N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 )C(O)NH-, -NHC(O)N(R 5 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 5 is independently hydrogen
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 , -NH C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene;
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -
  • Embodiment P3 The compound of embodiment P1, having the formula:
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene;
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -
  • Embodiment P4 The compound of one of embodiments P1 to P3, wherein R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,
  • Embodiment P5. The compound of one of embodiments P1 to P3, wherein R 1 is independently halogen.
  • Embodiment P6 The compound of one of embodiments P1 to P3, wherein R 1 is -F.
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI
  • Embodiment P8 The compound of one of embodiments P1 to P6, wherein R 4 is independently halogen.
  • Embodiment P9 The compound of one of embodiments P1 to P6, wherein R 4 is -F.
  • Embodiment P10 The compound of one of embodiments P1 to P9, wherein L 1 is independently -S(O) 2 -, -NH-, or substituted or unsubstituted 5 to 6 membered
  • Embodiment P11 The compound of one of embodiments P1 to P9, wherein L 1 is independently -S(O) 2 -, -NH-, unsubstituted pyrrolidinylene, unsubstituted piperidinylene, or unsubstituted piperazinylene.
  • Embodiment P12 The compound of one of embodiments P1 to P9, wherein L 1 is independently -NH-.
  • Embodiment P13 The compound of one of embodiments P1 to P12 wherein E is
  • R 16 is independently hydrogen, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -CN,
  • R 17 is independently hydrogen, halogen, -CX 17 3 , -CHX 17 2 , -CH 2 X 17 , -CN, -SO n17 R 17A , -SO v17 NR 17A R 17B , -NH NR 17A R 17B , -ONR 17A R 17B , -NHC(O)NHNR 17A R 17B ,
  • R 18 is independently hydrogen, halogen, -CX 18 3 , -CHX 18 2 , -CH 2 X 18 , -CN, -SO n18 R 18A , -SO v18 NR 18A R 18B , -NH NR 18A R 18B , -ONR 18A R 18B , -NHC(O)NHNR 18A R 18B ,
  • R 19 is independently hydrogen, halogen, -CX 19 3 , -CHX 19 2 , -CH 2 X 19 , -CN, -SO n19 R 19A , -SO v19 NR 19A R 19B , -NH NR 19A R 19B , -ONR 19A R 19B , -NHC(O)NHNR 19A R 19B ,
  • R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are independently
  • R 16A and R 16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 17A and R 17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • Embodiment P15 The compound of one of embodiments P1 to P14, wherein the
  • Embodiment P16 A pharmaceutical composition comprising a compound of one of embodiments P1 to P15 and a pharmaceutically acceptable excipient.
  • Embodiment P17 A method for treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P15.
  • Embodiment P18 The method of embodiment P17, wherein said cancer is renal cell carcinoma, follicular lymphoma, glioblastoma, colorectal cancer, endometrial, or lung cancer.
  • Embodiment P19 Embodiment P19.
  • a method of reducing the level of activity of mTORC1 in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments P1 to P15.
  • Embodiment P20 A method of reducing the level of activity of mTORC1 in a cell, the method comprising contacting a Vacuolar H + -ATPase protein complex in said cell with a compound of one of embodiments P1 to P15.
  • Embodiment P21 A method of reducing the level of activity of mTORC1 in a cell, the method comprising contacting an ATP6V1A in said cell with a compound of one of embodiments P1 to P15.
  • Embodiment P22 A method of reducing the level of activity of a Vacuolar H + - ATPase protein complex, the method comprising contacting an ATP6V1A in the Vacuolar H + -ATPase protein complex with a compound of one of embodiments P1 to P15. VII. Additional embodiments
  • Embodiment 1 A compound, or a pharmaceutically acceptable salt thereof, having the formula:
  • Ring A is a phenyl or 5 to 6 membered heteroaryl
  • Ring B is a phenyl or 5 to 6 membered heteroaryl
  • L 1 is independently a bond, -S(O) 2 -, -N(R 5 )-, -O-, -S-, -C(O)-, -C(O)N(R 5 )-,
  • R 5 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent -L 1 -R 1 substituents may optionally be joined to form a substituted or
  • R 2 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl,
  • R 1A , R 1B , R 1C , and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 ,
  • -CF 3 -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NH NH 2 , -ONH 2 ,
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-,
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br,
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br,
  • Embodiment 3 The compound of embodiment 1, having the formula:
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-,
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br,
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-,
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br,
  • L 1 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)NH-, -NHC(O)-,
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br,
  • Embodiment 6 The compound of one of embodiments 1, 4, and 5, wherein R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3
  • Embodiment 7 The compound of one of embodiments 1, 4, and 5, wherein R 3 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , or -CI 3 .
  • Embodiment 8. The compound of one of embodiments 1, 4, and 5, wherein R 3 is independently–Br or -CF 3 .
  • R 1 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 ,
  • Embodiment 10 The compound of one of embodiments 1 to 8, wherein R 1 is independently halogen.
  • Embodiment 11 The compound of one of embodiments 1 to 8, wherein R 1 is independently -F.
  • R 4 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NH C(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 ,
  • Embodiment 13 The compound of one of embodiments 1 to 11, wherein R 4 is independently halogen.
  • Embodiment 14 The compound of one of embodiments 1 to 11, wherein R 4 is independently -F.
  • Embodiment 15 The compound of one of embodiments 1 to 14, wherein L 1 is independently -S(O) 2 -, -NH-, or substituted or unsubstituted 5 to 6 membered
  • Embodiment 16 The compound of one of embodiments 1 to 14, wherein L 1 is independently -S(O) 2 -, -NH-, unsubstituted pyrrolidinylene, unsubstituted piperidinylene, or unsubstituted piperazinylene.
  • Embodiment 17 The compound of one of embodiments 1 to 14, wherein L 1 is independently -NH-.
  • Embodiment 18 The compound of one of embodiments 1 to 17, wherein
  • R 16 is independently hydrogen, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 ,
  • R 17 is independently hydrogen, halogen, -CX 17 3, -CHX 17 2, -CH 2 X 17 , -CN,
  • R 18 is independently hydrogen, halogen, -CX 18 3 , -CHX 18 2 , -CH 2 X 18 , -CN,
  • R 19 is independently hydrogen, halogen, -CX 19 3 , -CHX 19 2 , -CH 2 X 19 , -CN,
  • R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are independently
  • R 16A and R 16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 17A and R 17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • Embodiment 20 The compound of one of embodiments 1 to 17, wherein E is
  • Embodiment 21 The compound of one of embodiments 1 to 3, wherein the
  • Embodiment 22 A pharmaceutical composition comprising a compound of one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, and a
  • Embodiment 23 A method for treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Embodiment 24 The method of embodiment 23, wherein said cancer is renal cell carcinoma, follicular lymphoma, glioblastoma, colorectal cancer, endometrial cancer, or lung cancer.
  • Embodiment 25 Embodiment 25.
  • a method of reducing the level of activity of mTORC1 in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Embodiment 26 A method of reducing the level of activity of mTORC1 in a cell, the method comprising contacting a Vacuolar H + -ATPase protein complex in said cell with a compound of one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Embodiment 28 A method of reducing the level of activity of a Vacuolar H + - ATPase protein complex, the method comprising contacting an ATP6V1A in the Vacuolar H + -ATPase protein complex with a compound of one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Example 1 Covalent targeting of the vacuolar H + -ATPase enhances cellular clearance through inhibition of lysosomal mTORC1 signaling
  • Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis.
  • a major route for activating autophagy involves inhibition of the mTORC1 kinase, but selective and complete mTORC1 inhibition remains beyond the reach of current mTORC1-targeting compounds.
  • EN6 a small-molecule in vivo activator of autophagy that covalently and selectively targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which mediates mTORC1 activation at the lysosome.
  • EN6-mediated ATP6V1A modification impairs mTORC1 lysosomal recruitment via the Rag guanosine triphosphatases, activates autophagy and increases lysosomal acidification. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in an autophagy-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling. [0547] Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations.
  • mTORC1 rapamycin complex 1
  • mTORC1 phosphorylates and inhibits a master switch for autophagosome formation, the ULK1 kinase (5,6).
  • mTORC1 blocks the nuclear translocation and activation of the TFEB transcription factors, which functions as a‘master regulator’ of catabolism by coordinately promoting the expression of genes required for autophagosome formation and lysosomal function (5-9).
  • pharmacological activators of autophagy can be beneficial in both cell and animal models of these diseases, by both degrading intracytoplasmic aggregates and by preventing associated cell death (12-15).
  • agents have been discovered that either inhibit or activate autophagy, many of these compounds do not possess the required specificity to activate autophagy in a selective manner, either due to off-target effects or due to multiple functions of a specific target.
  • the allosteric mTORC1 inhibitor, rapamycin results in the relatively specific inhibition of mTORC1 by causing its binding to FK506-binding protein 1A (FKBP1A).
  • rapamycin is an incomplete mTORC1 inhibitor; most notably it largely fails at blocking mTORC1-dependent inhibitory phosphorylation of ULK1 and TFEB and at triggering their pro-catabolic programs.
  • rapamycin-based drugs Rostyroxine-based drugs
  • the recently developed‘ATP-competitive’ compounds block the kinase activity of mTOR toward virtually all substrates. The higher potency and broader range of ATP-competitive mTOR inhibitors has led to promising results in cancer clinical trials;
  • Akt signaling which is an essential survival signal for neuronal cells (19-22).
  • the limitations of current mTOR inhibitors thus create an urgent need to identify new targets that could lead to selective activation of autophagy while avoiding unacceptable toxicities.
  • mTORC1 needs to translocate to the lysosome membrane (5,6).
  • Nutrients primarily amino acids, directly regulate the lysosomal recruitment of mTORC1 by modulating the nucleotide state of the Rag GTPases.
  • the Rags assemble as obligate heterodimers composed of RagA or RagB (which are highly similar to each other) associated with RagC or RagD, and are tethered to the lysosomal membrane by the pentameric
  • Ragulator complex composed of the LAMTOR1-5 proteins (23-25).
  • the Rag GTPases become active by adopting a nucleotide state in which Rag-A/B is GTP-loaded and Rag-C/D is GDP-loaded, and mediate the lysosomal attachment of mTORC1 by directly interacting with the mTORC1 subunit Raptor (23-25).
  • v-ATPase vacuolar H+ ATPase
  • v-ATPase vacuolar H+ ATPase
  • the v-ATPase forms a physical supercomplex with Ragulator and the Rag GTPases, and its integrity and activity are essential for lysosomal mTORC1 recruitment in response to amino acids (28-31).
  • v-ATPase represents a prime target for discovery of small molecules that may simultaneously block mTORC1 activation and enhance autophagic function.
  • chemoproteomics and covalent ligand screening we have discovered a small-molecule activator of autophagy that acts through covalently targeting a unique regulatory cysteine on ATP6V1A, resulting in the complete and selective inactivation of mTORC1 and enhanced cellular clearance of toxic protein aggregates.
  • EN6 The primary site of EN6 was identified as cysteine 277 (C277) of ATP6V1A, the catalytic subunit of the lysosomal v- ATPase (FIG.2B). This site showed an isotopic light-to-heavy (control-to-EN6-treated) ratio of >50 indicating high target engagement of this site compared to other targets.
  • EN6 displaces iodoacetamide-rhodamine (IA-rhodamine) labeling from recombinant human ATP6V1A protein with an IC 50 of 1.7 mM (FIG.2C).
  • v-ATPase interacts with Ragulator-Rags to enable amino acid-dependent recruitment of mTORC1 to the lysosome (28,42). Consistent with an inhibitory mechanism towards this pathway, EN6 treatment completely abrogated amino acid-induced mTORC1 recruitment to LAMP2-positive lysosomes (FIG.3E).
  • amino acids modulate the interaction of FLAG-tagged Ragulator subunit p14 with the v-ATPase (FIG.4A).
  • EN6 decreased the overall binding between the v-ATPase and Ragulator, and rendered this interaction insensitive to amino acids (FIG.4A).
  • TDP43 Tar-binding protein 43
  • EN6-mediated clearance of TDP-43 aggregates was lysosome- and v-ATPase-dependent, as it was prevented by co-treatment with bafilomycin A1 (FIG.5A, FIG.5B).
  • bafilomycin A1 FIG.5A, FIG.5B
  • EN6 is capable of clearing toxic protein aggregates in an autophagy-dependent manner.
  • Three mice cohorts were injected intraperitoneally with vehicle, rapamycin or EN6, and analyzed after 4 hours.
  • mTORC1 signaling was significantly impaired across the heart, kidney, and skeletal muscle, as demonstrated by reduced phosphorylation of S6, whereas autophagy was strongly activated, as shown by heightened LC3BII levels (FIGS.6A-6C).
  • EN6 was somewhat less potent than rapamycin in shutting down p-S6, it was significantly more effective than rapamycin at inhibiting phosphorylation of 4EBP1, consistent with our data in cell lines (FIG.6A).
  • EN6 functions as a complete and selective mTORC1 inhibitor both in cells and in vivo.
  • rapalogues pharmacological modulators of autophagy that mostly act through directly targeting the kinase function mTORC1, such as with rapalogues and ATP-competitive inhibitors. While both rapalogues and ATP-competitive mTORC1 inhibitors have potential therapeutic activity, their clinical utility is hampered by their incomplete mTORC1 inhibition (rapalogues) and concomitant inhibition of mTORC2 (ATP competitors) (44-47). Chronic exposure to rapalogues also inhibits mTORC2, leading to metabolic dysregulation (48,49).
  • EN6 shows promising cellular and in vivo activity
  • this covalent ligand is an early hit that still requires further medicinal chemistry efforts to optimize potency, selectivity, and in vivo bioavailability and efficacy.
  • isoTOP-ABPP studies here show that C277 of ATP6V1A is one of the primary and most highly engaged targets of EN6 in cells
  • EN6 may possess additional off-targets that either exhibit lower degree of engagement or act through reversible interactions.
  • Development of an alkyne-functionalized EN6 probe will aid in future assessment of EN6 selectivity and provide a foundation for additional medicinal chemistry, target engagement, and screening efforts to identify improved ligands against this site.
  • MEF cells stably expressing GFP-LC3-RFP- LC3DG were plated on 96-well plates (Corning; 3904) at 30,000 cells/well and allowed to grow in complete medium overnight. The cells were then incubated with covalent ligands (50 ⁇ M or at indicated concentrations), rapamycin (100 nM), Torin 1 (250 nM) or DMSO solvent control in complete medium (100 ⁇ L) for 24 h.
  • the medium was aspirated and the cells were fixed with 4% paraformaldehyde in PBS (100 ⁇ L) for 10 min, washed with PBS (100 ⁇ L) and assayed in PBS (100 ⁇ L) by SpectraMax i3 (Molecular Devices).
  • GFP fluorescence was measured with excitation and emission at 488 ⁇ 9 nm and 514 ⁇ 15 nm respectively, while RFP fluorescence was measured with excitation and emission at 584 ⁇ 9 nm and 612 ⁇ 15 nm respectively.
  • HEK293A cells stably expressing GFP-LC3-RFP-LC3DG before they were seeded, 96-well plates were coated with fibronectin in PBS (5 ⁇ g/mL, 75 ⁇ L/well) for 1 h at 37 o C. The solution was then aspirated, and cells were plated at 30,000 cells/well, allowed to grow in complete medium overnight, treated and assayed with the same protocol as described above for MEF cells.
  • solutions were aspirated after treatment with the compounds, and the cells were fixed and stained by Hoechst 33342 (13.3 ⁇ g/mL) in formalin (100 ⁇ L) for 15 min.
  • IsoTOP-ABPP chemoproteomic studies IsoTOP-ABPP studies were done as previously reported (35,36). Cells were lysed by probe sonication in PBS and protein concentrations were measured by BCA assay (54). For in situ experiments, cells were treated for 90 min with either DMSO vehicle or covalently-acting small molecule (from 1000X DMSO stock) before cell collection and lysis.
  • proteome samples diluted in PBS 4 mg of proteome per biological replicate
  • a DMSO vehicle or covalently-acting small-molecule for 30 min at room temperature.
  • Proteomes were subsequently labeled with IA-alkyne labeling (100 mM) for 1 h at room temperature.
  • CuAAC was used by sequential addition of tris(2-carboxyethyl)phosphine (1 mM, Sigma), tris[(1- benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (34 mM, Sigma), copper (II) sulfate (1 mM, Sigma), and biotin-linker-azide—the linker functionalized with a TEV protease recognition sequence as well as an isotopically light or heavy valine for treatment of control or treated proteome, respectively.
  • proteomes were precipitated by centrifugation at 6500 x g, washed in ice-cold methanol, combined in a 1:1 control/treated ratio, washed again, then denatured and resolubilized by heating in 1.2% SDS/PBS to 80 °C for 5 minutes.
  • Insoluble components were precipitated by centrifugation at 6500 x g and soluble proteome was diluted in 5 mL 0.2% SDS/PBS. Labeled proteins were bound to avidin-agarose beads (170 ml resuspended beads/sample, Thermo Pierce) while rotating overnight at 4 °C. Bead- linked proteins were enriched by washing three times each in PBS and water, then
  • Peptides were diluted in water and acidified with formic acid (1.2 M, Spectrum) and prepared for analysis. [0571] Mass spectrometry analysis. Peptides from all chemoproteomic experiments were pressure-loaded onto a 250 mm inner diameter fused silica capillary tubing packed with 4 cm of Aqua C18 reverse-phase resin (Phenomenex # 04A-4299) which was previously equilibrated on an Agilent 600 series HPLC using gradient from 100% buffer A to 100% buffer B over 10 min, followed by a 5 min wash with 100% buffer B and a 5 min wash with 100% buffer A.
  • Aqua C18 reverse-phase resin Phenomenex # 04A-4299
  • Heated capillary temperature was set to 200 °C and the nanospray voltage was set to 2.75 kV.
  • Data were extracted in the form of MS1 and MS2 files using Raw Extractor 1.9.9.2 (The Scripps Research Institute) and searched against the Uniprot human database using ProLuCID search methodology in IP2 v.3 (Integrated Proteomics Applications, Inc.) (55). Cysteine residues were searched with a static modification for carboxyaminomethylation (+57.02146) and up to two differential modifications for methionine oxidation and either the light or heavy TEV tags (+464.28596 or +470.29977, respectively). Peptides were required to have at least one tryptic end and to contain the TEV modification.
  • ProLUCID data was filtered through DTASelect to achieve a peptide false-positive rate below 5%. Only those probe-modified peptides that were evident across all two out of three biological replicates were interpreted for their isotopic light to heavy ratios. Those probe-modified peptides that showed ratios >4 were further analyzed as potential targets of the covalently-acting small- molecule. For modified peptides with ratios >4, we filtered these hits for peptides were present in all three biological replicates. For those probe-modified peptide ratios >4, only those peptides with 3 ratios >4 were interpreted, and otherwise replaced with the lowest ratio.
  • lentiviral plasmids and packaging plasmids were transfected into HEK293T cells using PEI transfection method. Viral supernatant was collected 48 hours after transfection and filtered with 0.45 mm filter. The viruses were further concentrated using Lenti-X Concentrator (Clontech, 631231) according to the manufacturer’s instructions. Target cells were plated in 6-well or 10 cm plates with 8 mg/mL polybrene (Millipore, TR-1003-G) and incubated with virus containing media. 24 hours later, the media was changed to fresh media containing 2 mg/mL puromycin
  • Covalent ligand library The synthesis and characterization of the covalent ligands screened here have been previously reported (33-37,59). Compounds starting with“EN” were purchased from Enamine LLC. [0577] Antibodies and reagents for biological experiments.
  • Goat anti-rabbit IgG superclonal secondary antibody-Alexa Fluor 647 was from Thermo Fisher Scientific.
  • IRDye® 800CW Goat anti-Rabbit IgG H + L; 926-32211 was from Li-Cor.
  • Recombinant human ATP6V1A protein (ab132441) was from Abcam; Tetramethylrhodamine-5-iodoacetamide dihydroiodide (6222) was from Setareh Biotech.; Normal goat serum (10%; 50062Z), Hoechst 33342 (H3570) and LysoSensor Yellow/Blue DND-160 (L7545) were from Thermo Fisher Scientific.
  • DMEM Dulbecco's Modified Eagle’s Medium
  • FBS fetal bovine serum
  • Sequencing grade modified trypsin was from Promega.
  • Amino acid starvation and stimulation Sub-confluent cells were rinsed and incubated with RPMI without amino acids supplemented with 2% dialyzed FBS for 50 min, as described (27). Stimulation with amino acids (concentration as in RPMI) was performed for 10 min. Where drug treatment was performed, cells were incubated during the 50 min starvation period and the 10 min stimulation period.
  • Western blotting and immunoprecipitation was performed.
  • Cells were washed twice with ice-cold phosphate-buffered saline (PBS) and lysed in lysis buffer (1% Triton X-100, 10 mM b- glycerol phosphate, 10 mM sodium pyrophosphate, 4 mM EDTA, 40 mM HEPES at pH 7.4, and 1 tablet of EDTA-free protease inhibitors per 50 mL). Cell lysates were cleared by centrifugation in a microcentrifuge at 17,000 g for 10 minutes at 4 °C.
  • lysis buffer 1% Triton X-100, 10 mM b- glycerol phosphate, 10 mM sodium pyrophosphate, 4 mM EDTA, 40 mM HEPES at pH 7.4, and 1 tablet of EDTA-free protease inhibitors per 50 mL.
  • HEK293T cells stably expressing Flag-tagged proteins were lysed as above and 30 mL of a well-mixed 50% slurry of anti-FLAG M2 Affinity Gel (Sigma A2220) was added to each lysate (1 mg/mL) and incubated at 4 °C in a shaker for 1 hour.
  • Immunoprecipitates were washed four times, three times with lysis buffer and once with lysis buffer containing 400 mM NaCl. Immunoprecipitated proteins were denatured by addition of 50 mL of sample buffer and heating to 95 °C for 5 minutes, resolved by SDS-PAGE, and analyzed by immunoblotting.
  • the cells were then incubated with EN6 (at indicated concentrations), Torin 1 (250 nM) or DMSO control for indicated time intervals. After aspiration of the solution, the cells were washed with PBS (350 ⁇ L) and fixed with methanol for 15 min at -20 o C. The cells were rinsed three times with PBS (350 ⁇ L each), and incubated with PBS containing 5% normal goat serum and 0.3% Triton X-100 (300 ⁇ L) for 1 h.
  • EN6 at indicated concentrations
  • Torin 1 250 nM
  • DMSO control DMSO control
  • the cells were washed three times with PBS (350 ⁇ L each) and stained with Hoechst 33342 (5 ⁇ g/mL) in PBS in dark at room temperature for 15 min. After washing with PBS three times (350 ⁇ L each), the cells were imaged in PBS by Zeiss laser scanning microscope (LSM) 710 with a 20 ⁇ or 63 ⁇ oil-immersion objective lens.
  • LSM Zeiss laser scanning microscope
  • Hoechst 33342 was excited with a 405 nm diode laser, and emission was collected on a META detector between 410 and 587 nm.
  • Alexa Fluor 647 was excited with a 633 nm HeNe laser, and emission was collected on a META detector between 638 and 755 nm.
  • HEK-293T or Hela cells were seeded on fibronectin-coated glass coverslips and allowed to attach overnight. On the following day, cells were subjected to either amino acid starvation and stimulation with or without drug incubation and fixed in 4% paraformaldehyde (PFA) for 15 minutes at room temperature. The coverslips were rinsed twice with PBS and cells were permeabilized with 0.1% (w/v) saponin in PBS for 10 minutes.
  • PFA paraformaldehyde
  • the slides were incubated with primary antibodies in 5% normal donkey serum (Jackson ImmunoResearch, 017-000-121) for 1 hour at room temperature, rinsed four times with PBS, and incubated with fluorophore conjugated secondary antibodies derived from goat or donkey (Life Technologies, diluted 1:400 in 5% normal donkey serum) for 1 hour at room
  • HEK293A cells were plated on fibronectin-coated (5 ⁇ g/mL) 8-well Lab Tek borosilicate chambered coverglass slides (Nunc) at 40,000 cells/well and allowed to grow in complete medium overnight.
  • the cells were then incubated with DMSO control, EN6 (50 ⁇ M), bafilomycin A1 (0.2 ⁇ M), or a mixture of EN6 and bafilomycin A1 (50 and 0.2 ⁇ M respectively) at 37 o C for 4 h. After that, LysoSensor DND-160 (2 ⁇ M final concentration) was added to the solution and the cells were stained at 37 o C for 5 min. The solution was then replaced by DPBS and the live cells were imaged by Zeiss LSM 880 with a 40 ⁇ water-immersion objective lens.
  • the ratiometric images, F yellow / F blue were generated by Ratio Plus plugin of ImageJ. For quantification, a threshold value was set as background and the average intensity of the whole image was measured by ImageJ. All experiments were performed in triplicate, and statistical analyses were performed with a two-tailed Student’s t-test (MS Excel).
  • RNA extraction and quantitative RT-PCR were performed using AurumTM Total RNA Mini Kit (Bio-rad) and reverse transcription was performed from 1 mg total RNAs using iScriptTM Reverse Transcription for RT-qPCR (Bio-rad) according to manufacturer’s instruction. All real-time qPCR(qRT-PCR) analyses were performed using StepOnePlus machine (Applied Biosystems) with SsoAdbancedTM
  • the cells were incubated with DMSO control, isopropylthio-b-galactoside (IPTG; 50 ⁇ M), a mixture of EN6 (25 ⁇ M) and IPTG (50 ⁇ M), or a mixture of EN6 (25 ⁇ M), IPTG (50 ⁇ M) and bafilomycin A1 (0.2 ⁇ M) at 37 o C for 7 h.
  • IPTG isopropylthio-b-galactoside
  • EN6 25 ⁇ M
  • IPTG IPTG
  • bafilomycin A1 0.2 ⁇ M
  • the cells were imaged in PBS by Zeiss laser scanning microscope (LSM) 710 with a 20 ⁇ or 63 ⁇ oil-immersion objective lens.
  • LSM Zeiss laser scanning microscope
  • Hoechst 33342 was excited with a 405 nm diode laser, and emission was collected on a META detector between 410 and 483 nm.
  • GFP was excited with a 488 nm Ar laser, and emission was collected on a META detector between 493 and 598 nm.
  • Image analysis was performed by use of ImageJ. A threshold was first set for selection of GFP-TDP-43 aggregate, and a region of interest (ROI) was created over a single cell.
  • ROI region of interest
  • mice were euthanized, and tissues were harvested and lysed in lysis buffer (1% Triton X-100, 10 mM b- glycerol phosphate, 10 mM sodium pyrophosphate, 4 mM EDTA, 40 mM HEPES at pH 7.4, and 1 tablet of EDTA-free protease inhibitors per 50 ml) at 4 o C for 30 min.
  • lysis buffer 1% Triton X-100, 10 mM b- glycerol phosphate, 10 mM sodium pyrophosphate, 4 mM EDTA, 40 mM HEPES at pH 7.4, and 1 tablet of EDTA-free protease inhibitors per 50 ml
  • the lysates were cleared by centrifugation in a microcentrifuge at 21,130 g for 10 minutes at 4°C and protein concentration of supernatant was determined by BCA assay (Thermo Fisher Scientific).
  • the lysates was then diluted to 1.5 mg/mL, mixed with 4 x sample buffer, heated at 95 °C for 5 minutes, resolved by precast 4-20% TGX gels, and analyzed by immunoblotting.
  • Antibodies were obtained from various commercial sources and dilutions were prepared per

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Abstract

L'invention concerne, entre autres, des composés et des méthodes utiles pour produire une augmentation de l'autophagie.<i />
PCT/US2020/013158 2019-01-11 2020-01-10 Inhibiteurs de mtorc1 pour activer l'autophagie Ceased WO2020146779A1 (fr)

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