EP4680343A1 - Protein-protein interaction stabilizers - Google Patents

Protein-protein interaction stabilizers

Info

Publication number
EP4680343A1
EP4680343A1 EP24771852.1A EP24771852A EP4680343A1 EP 4680343 A1 EP4680343 A1 EP 4680343A1 EP 24771852 A EP24771852 A EP 24771852A EP 4680343 A1 EP4680343 A1 EP 4680343A1
Authority
EP
European Patent Office
Prior art keywords
substituted
unsubstituted
membered
heterocycloalkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24771852.1A
Other languages
German (de)
French (fr)
Inventor
Michelle R. Arkin
Markella KONSTANTINIDOU
Christian Ottmann
Lucas Brunsveld
Emira Josien VISSER
Eline SIJBESMA
Adam R. RENSLO
Priyadarshini Jaishankar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eindhoven Technical University
University of California
University of California Berkeley
University of California San Diego UCSD
Original Assignee
Eindhoven Technical University
University of California
University of California Berkeley
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eindhoven Technical University, University of California, University of California Berkeley, University of California San Diego UCSD filed Critical Eindhoven Technical University
Publication of EP4680343A1 publication Critical patent/EP4680343A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a compound, or a pharmaceutically acceptable salt thereof having the formula: . are a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene.
  • L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O)2-, -NR 10 S(O)2-, -S(O)2NR 10 -, 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.
  • L 2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 20 -, -C(O)NR 20 -, -NR 20 C(O)-, -NR 20 C(O)O-, -OC(O)NR 20 -, -NR 20 C(O)NR 20 -, -S(O)2-, -NR 20 S(O)2-, -S(O)2NR 20 -, 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.
  • L 3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 30 -, -C(O)NR 30 -, -NR 30 C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • L 4 is –NR 40 - or -O-.
  • R 50 , R 60 , R 70 , and R 80 are independently hydrogen, halogen, -CCl3, -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, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ 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, -OCH 2 Br, -OCH 2 F, -
  • FIG.1B Chemical structure of the non-selective fragment stabilizer 917949 and key structural modifications (1-5) explored during the chemical optimization, aiming to increase the cooperativity with 14-3- 3 ⁇ /ER ⁇ and reduce the stabilization of 14-3-3 ⁇ /C-RAF.
  • FIG.1C Examples of compound evolution and crystallographic data starting from the disulfide fragment 917949 and resulting in potent and selective stabilizer 1083744.
  • FIG.1D Overview of the mass spectrometry assay (primary screening). Compound titrations were performed in the absence of peptide to determine % binding to 14-3-3 ⁇ (apo screening, D1) and then in the presence of both 14-3-3 ⁇ and peptide, as an indirect indication of stabilization (D2).
  • FIG.2A Chemical modifications (1) and (2) focused on replacing the disulfide tether with covalent warheads (i-iv) with varying linker lengths.
  • FIG.2D Crystal structures of the chloroacetamide analogs (iv) with varying linker length in complex with 14-3-3 ⁇ /ER ⁇ . Compounds are shown on the left; the C-terminus of ER ⁇ phosphopeptide is shown on the right.
  • FIG.2E Selected scaffold for further chemical optimization. [0033] FIGS.3A-3G.
  • FIG.3A Chemical modifications (3) and (4) replacing the gem- dimethyl group with cyclic, aliphatic groups and comparing ethers and anilines, aiming to increase the cooperativity with Val595 of ER ⁇ via hydrophobic, van der Waals interactions and to interact with hydrophobic residues on 14-3-3 ⁇ .
  • FIG.3B Bar graphs of mass spectrometry data at 100 nM [compound]. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. ER ⁇ data are shown in solid grey, C-RAF data with dashed lines, and apo data in black.
  • FIG.3C Bar graphs of FA compound titration EC50 values after overnight incubation.
  • FIG.3D Crystal structures of the cyclopentyl analogs 1075297 (ether) and 1075306 (aniline) with 14-3-3 ⁇ /ER ⁇ .
  • FIG.3E Crystal structures of the cyclopentyl analogs 1075297 (ether, dark grey sticks) and 1075306 (aniline, dark grey sticks) with 14-3-3 ⁇ (white surface) and C-RAF (light grey sticks).
  • FIG.3F Crystal structures of the tetrahydropyran analogs 1075305 (ether, light grey sticks) and 1075310 (aniline, dark grey sticks) with 14-3-3 ⁇ (white surface) and ER ⁇ . Interacting water molecules are shown as spheres.
  • FIG.3G Schematic representation of the preferred compound conformation with the two peptides.
  • 14-3-3 ⁇ /ER ⁇ stabilizers larger groups in X position are preferred, with an aniline group facing in the front and participating in the water network.
  • 14-3-3 ⁇ /C- RAF smaller groups, such as the cyclopentyl group in X position are preferred, with an ether group facing in the back, toward 14-3-3.
  • FIGS.4A-4K FIG.4A: Crystal structures of aniline analogs 1075310 (dark grey sticks) with a tetrahydropyran ring and 1075481 (dark grey sticks) with a piperidine ring with 14-3-3 ⁇ (white surface) and ER ⁇ (light grey sticks).
  • FIG.4B Overlay of the tetrahydropyran and piperidine ring.
  • FIG.4C Methyl groups were introduced on the tetrahydropyran ring to further enhance the hydrophobic interaction with Val595 of ER ⁇ .
  • FIG.4D Mass spectrometry bar graphs indicate that two methyl groups (compound 1080299) were well-tolerated, and binding was increased in the first measurements. Compound 1080300 with four methyl groups was weaker than the non- methylated tetrahydropyran analog.
  • FIG.4E FA bar graphs of the methylated tetrahydropyrans showed a different trend, where the presence of two methyl groups did not improve the stabilization.
  • FIG.4F Overlay of the crystal structures of 1075310, 1080299, 1080300 with 14-3-3 ⁇ (white cartoon) and ER ⁇ . Leu218 on 14-3-3 turns to make room for the methyl group.
  • FIG.4G Surface representation of crystal structure of 1080299 (dark grey) in 14-3-3 (white) and ER ⁇ (light grey). The methyl group of 1080299 fits between Leu218 and Leu222 on 14-3-3 and is also forming hydrophobic interactions with Val595 of ER ⁇ .
  • FIG.4H Modifications of the linker length of the warhead for both tetrahydropyran and piperidine analogs.
  • FIG.4J FA bar graphs, showing the same trends as the mass spectrometry data.
  • FIG.4K Crystal structures of compounds with increasing linker length (1075310, 1080267, and 1075478) in complex with 14-3-3 ⁇ /ER ⁇ . For 1075310, a hydrogen bond is formed with Asn42, whereas for 1075478, a hydrogen bond is formed with Arg41. [0035] FIGS.5A-5F.
  • FIG.5A Chemical modification (5) aimed to replace the long, flexible linkers with conformationally constrained spiro-linkers. Seven spiro-analogs were synthesized and tested, with varying linker lengths and reversed rings.
  • FIG.5B Mass spectrometry bar graphs indicate that although the spiro-linker is far from the protein-peptide interface, it can significantly affect cooperativity.
  • FIG.5C FA bar graphs of the spiro- analogs.
  • FIG.5D Crystal structures of compounds 1080265 and 1080266 (pair of small spiro-analogs with reversed rings) in complex with 14-3-3 ⁇ /ER ⁇ .
  • FIG.5E Crystal structures of compounds 1080294 and 1080295 (pair of spiro-analogs with one extra bond and reversed rings) in complex with 14-3-3 ⁇ /ER ⁇ .
  • FIG.5F Crystal structures of compounds 1080297 and 1080298 (pair of spiro-analogs with one extra -CH2- and reversed rings) in complex with 14- 3-3 ⁇ /ER ⁇ .
  • FIG 6A Combinations of 2,6-dimethyl tetrahydropyran with spiro- linkers (synergistic effect).
  • FIG.6E Overlay of the crystal structures, indicating the similar binding mode of compounds 1080299, 1083743, and 1083744.
  • FIGS.7A-7H Comparison between the optimized covalent stabilizer 1083744 and the natural product Fusicoccin-A.
  • FIG.7A Chemical structure of 1083744.
  • FIG.7B Crystal structure of 1083744 (dark grey sticks, left) with 14-3-3 ⁇ (white surface) and ⁇ R ⁇ (light grey sticks, right). Water network is depicted as black dashes.
  • FIG.7C Titration of 14-3-3 ⁇ to FAM-labeled ER ⁇ (10 nM) against varying fixed concentrations of 1083744 (between 0 and 250 ⁇ M).
  • FIG.7D Chemical structure of fusicoccin-A (FC-A).
  • FIG.7E Crystal structure of FC-A (dark grey sticks, left) with 14-3-3 ⁇ (white surface) and ⁇ R ⁇ (light grey sticks, right) (PDB ID: 4JDD); highlighting the lack of water molecules.
  • FIG.7F Titration of 14-3-3 ⁇ to FAM-labeled ER ⁇ (10 nM) against varying fixed concentrations of FC-A (between 0 and 250 ⁇ M).
  • FIGS.7G-7H ITC experiment comparing enthalpic and entropic differences between 1083744 and FC-A. Measured in two independent experiments. [0038]
  • FIG.8 Selectivity studies of compound 1083744 measured in FA protein titrations.
  • 14-3-3 ⁇ is titrated to eight different FAM-labeled peptides (ER ⁇ , CRAF, SOS1, ChREBP, p65, BRAF, USP8, and Pin1, each 10 nM) in the presence of DMSO (1%) or 1083744 (100 ⁇ M).
  • Apparent KD values are determined for the interaction of each peptide with 14-3-3 ⁇ , in the presence of DMSO or 1083744, resulting in a calculated fold- stabilization by 1083744 shown at the arrow of each graph.
  • ER ⁇ (pT594): AEGFPA(pT)V (SEQ ID NO: 2); CRAF (pS259): QRST(pS)TPNVH (SEQ ID NO: 3); SOS1 (pS1161): PRRRPE(pS)APAESS (SEQ ID NO: 5); ChREBP: RDIRLNNAIWRAWYIQYVQR (SEQ ID NO: 11); p65 (pS45): EGRSAG(pS)IPGRRS (SEQ ID NO: 4); BRAF (pS365): RDRSS(pS)APNVH (SEQ ID NO: 7); USP8 (pS719): KLKRSY(pS)SPDITQ (SEQ ID NO: 6); Pin1 (pS72): LVKHSQSRRPS(pS)WRQEK (SEQ ID NO: 9).
  • FIGS.9A-9E Overview of fragment linking approach.
  • FIG.9A Schematic and X- ray crystal structure of C42 tethered fragment 1 (dark grey sticks, left) in complex with 14-3- 3 ⁇ (N42C, C38A) (white surface) and ER ⁇ phospho-peptide (light grey sticks, right) (pdb ID: 6HMT).
  • FIG.9B Schematic and X-ray crystal structure of amidine fragment (grey sticks, left) in complex with 14-3-3 ⁇ (white surface) and p53 phospho-peptide (grey sticks, right) (pdb ID: 6S40).
  • FIG.9C Schematic of fragment linking approach taken here and crystallographic overlay of the two previously discovered fragments to show their proximity.
  • FIG.9D Structures of two fragment classes with disulfide tethered fragment 1 and benzothiophene Core A and phenyl-thiophene Core B.
  • FIG.9E X-ray crystal structure of co-soak of compound 1 and A-1 in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide.2Fo-Fc electron density map is contoured at 1 ⁇ .
  • FIGS.10A-10F Discovery of linked fragments.
  • FIG.10A Molecular structures of the different linker lengths of benzothiophene building blocks.
  • FIG.10B X-ray crystal structure of 5 (grey sticks, left) in complex with 14-3-3 ⁇ (white surface) and ER ⁇ phospho- peptide (grey sticks, right).
  • FIG.10C Crystallographic overlay of 5 with C42-tethered fragment 1, in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide.
  • FIG.10D Molecular structures of diphenyl- and phenyl-thiophene building blocks.
  • FIG.10E X-ray crystal structure of 6 in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide.
  • FIG.10F Crystallographic overlay of 6 with C42-tethered fragment 1, in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide. [0041] FIG.11.
  • FIGS.12A-12B Fluorescence anisotropy (FA) dose-response curves for the linked fragments with a cyclic group at position X containing a hydrogen bond donor or acceptor.
  • FA Fluorescence anisotropy
  • FIGS.13A-13C Characterization of stabilizing linked fragments.
  • FIG.13A FA 2D titrations with titration of 14-3-3 ⁇ to FAM-labeled ER ⁇ phospho-peptide (10 nM) against varying concentrations of 23, 24, or 25 (ranging from 0 to 500 ⁇ M).
  • FIG.13B FA with multiple doses of 24 added to ten different client peptides (10 nM each; light grey dots), or a mixture containing the peptide and 14-3-3 ⁇ (dark grey squares).
  • FIG.13C X-ray crystal structure of 24 in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide. Polar interactions are visualized as black dashes and water molecules as spheres. [0044] FIG.14.
  • FIGS.15A-15G Crystallography single soaks of amide fragments in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide.
  • FIG. 15A Soak of A-1 (PDB ID: 8BZ9).
  • FIG.15B Soak of A-2 (PDB ID: 8BZ0).
  • FIG.15C Soak of A-3 (PDB ID: 8BYZ).
  • FIG.15D Soak of B-1 (PDB ID: 8BZA).
  • FIG.15E Soak of B-2 (PDB ID: 8C4F).
  • FIGS.15F-15G Soak of B- 3 (PDB ID: 8C4F). Note that B-3 binds covalently to C38 in 14-3-3 ⁇ .
  • FIGS.16A-16F Crystallography co-soaks of benzothiophene compounds (Core A) + compound 1 in complex with 14-3-3 ⁇ and ER ⁇ phospho-peptide.
  • FIG.16A Co-soak of A- 1 + 1 (PDB ID: 8C04) overlayed with single soak of A-1.
  • FIG.16B Co-soak of A-2 + 1 (PDB ID: 8BZB) overlayed with single soak of A-2.
  • FIG.16C Co-soak of A-3 + 1 (PDB ID: 8BZQ) overlayed with single soak of A-3.
  • FIG.16D Co-soak of A-1 + 1, with distance of 3.0 ⁇ .
  • FIG.16E Co-soak of A-2 + 1, with distance of 3.9 ⁇ .
  • FIG.16F Co-soak of A-3 + 1, with distance of 2.8 ⁇ .
  • FIG.17 Crystallographic overlay of 5 with benzothiophene fragments (A-1, A-2, A-3).
  • FIGS.18A-18B Overview of biphenyl- and phenyl-thiophene linked fragments.
  • FIG.18A Fluorescence Anisotropy (FA) dose-response curves for the linked fragments.
  • FIG.18B Electron density of 6 (left, PDB ID: 8BYF) and crystallographic overlay of 6 (sticks) with the single soaks of the phenyl-thiophene fragments (B-1, B-2) in complex with 14-3-3 ⁇ (white surface) and ER ⁇ -pp.2Fo-Fc electron density map is contoured at 1 ⁇ .
  • FIGS.19A-19B Electron density of 6 (left, PDB ID: 8BYF) and crystallographic overlay of 6 (sticks) with the single soaks of the phenyl-thiophene fragments (B-1, B-2) in complex with 14-3-3 ⁇ (white surface) and ER ⁇ -pp.2Fo-Fc electron density map is contoured at 1 ⁇ .
  • FIG.19A highlights the interactions at the amidine-site, with the 14-3-3 amino-acids shown as white sticks and hydrogen bonds as black dashes.
  • FIG.19B highlights the hydrophobic interactions of the chloro-phenyl site, with the 14-3-3 amino acids shown as white sticks.
  • FIGS.20A-20C Overview of compounds 9 (FIG.20A), 10 (FIG.20B), and 11 (FIG.20C) overlaid with compound 7, as described in FIG.11.
  • Top Crystal structures complexed with 14-3-3 ⁇ and ER ⁇ -pp.
  • Bottom Fluorescence Anisotropy dose-response curves for the linked fragments.
  • FIGS.21A-21F Overview of compounds 12 (FIG.21A), 13 (FIG.21B), 14 (FIG.
  • FIGS.22A-22D Overview of compounds 6 (FIG. 22A), 19 (FIG.22B), 20 (FIG. 22C), and 21 (FIG.22D), as described in FIG.11. Left: Crystal structures complexed with 14-3-3 ⁇ (white surface) and ER ⁇ -pp. Right: Fluorescence Anisotropy (FA) dose-response curves for the linked fragments.
  • FA Fluorescence Anisotropy
  • FIGS.24A-24D Overview of compounds 26 (FIG.24A), 27 (FIG. 24B), 28 (FIG.24C), and 29 (FIG.24D) overlaid with compound 7, as described in FIG.11.
  • Left Crystal structures complexed with 14-3-3 ⁇ (white surface) and ER ⁇ -pp.
  • Right Fluorescence Anisotropy (FA) dose-response curves for the linked fragments.
  • FA Fluorescence Anisotropy
  • FIG.24F Detail of distance of the phenyl-fluoro group of 27 towards the carboxy end of ER ⁇ and K122 of 14-3-3 (black dashes).
  • FIG.25 Selectivity studies of compound 24 measured in FA compound titrations. Compound 24 is titrated to 14-3-3 ⁇ and ten different FAM-labeled peptides (10 nM). The crystal structure of 24 complexed with 14-3-3 ⁇ and ER ⁇ (top left) is overlayed with the crystal structures of the measured peptides.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C 1 -C 10 means one to ten carbons).
  • the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkenyl includes one or more double bonds.
  • An alkynyl includes one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
  • the alkylene is fully saturated.
  • the alkylene is monounsaturated.
  • the alkylene is polyunsaturated.
  • An alkenylene includes one or more double bonds.
  • An alkynylene includes one or more triple bonds.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., N, S, Si, or P
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • heteroalkynyl by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • a heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • the heteroalkyl is fully saturated.
  • the heteroalkyl is monounsaturated.
  • the heteroalkyl is polyunsaturated.
  • the term “heteroalkylene,” by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • 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)2R'- represents both -C(O)2R'- 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 -SO2R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
  • heteroalkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne.
  • the heteroalkylene is fully saturated.
  • the heteroalkylene is monounsaturated.
  • the heteroalkylene is polyunsaturated.
  • a heteroalkenylene includes one or more double bonds.
  • a heteroalkynylene includes one or more triple bonds.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings).
  • An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 CH 3 , -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, substituted or unsubstituted C 1 -C 5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
  • 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.
  • 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).
  • 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.
  • each numbered R group or L group (alternatively referred to herein as R WW or L WW wherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as R WW.1 or R LWW.1 , respectively.
  • each first substituent group (e.g., R 1.1 , R 2.1 , R 3.1 , R 4.1 , R 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 ... ... be as as may one or more substituent groups, which may alternatively be represented herein as R WW.2 .
  • each second substituent group (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2 ) may be further R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.3 ... R 100A.3 ; R L1.3 , R L2.3 , R L3.3 , R L4.3 , R L5.3 ... R L100.3 ; represented herein as R WW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R WW.3 .
  • R WW represents a substituent recited in a claim or chemical formula description herein which is openly substituted.
  • WW represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • L WW is a linker recited in a claim or chemical formula description herein which is openly substituted.
  • WW represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • each L WW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R LWW.1 ; each first substituent group, R LWW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R LWW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R LWW.3 .
  • Each first substituent group is optionally different.
  • Each second substituent group is optionally different.
  • Each third substituent group is optionally different.
  • R WW.1 is independently oxo, halogen, -CX WW.1 3 , -CHX WW.1 2 , -CH2X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 member
  • X WW.2 is independently –F, -Cl, -Br, or –I.
  • R WW.3 is independently oxo, halogen, -CX WW.3 3, -CHX WW.3 2, -CH2X WW.3 , -OCX WW.3 3 , -OCH 2 X WW.3 , -OCHX WW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C1-C8,
  • X WW.3 is independently –F, -Cl, -Br, or –I.
  • the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group, R WW.2 , may be unsubstituted or independently substituted with one or more third substituent groups, 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 , -CHX LWW.1 2 , -CH 2 X LWW.1 , -OCX LWW.1 3, -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, or or 4 to 5 membered), R LWW.2 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C5-C6), R LWW.2 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3, -CHX LWW.1 2 , -CH 2 X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -
  • X LWW.1 is independently –F, -Cl, -Br, or –I.
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3, -OCH2X LWW.2 , -OCHX LWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2, -CH2X LWW.2 , -OCX LWW.2 3, -OCH2X LWW.2 , -OCHX LWW.2 2, -CN, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-
  • X LWW.2 is independently –F, -Cl, -Br, or –I.
  • R LWW.3 is independently oxo, halogen, -CX LWW.3 3, -CHX LWW.3 2, -CH2X LWW.3 , -OCX LWW.3 3 , -OCH 2 X LWW.3 , -OCHX LWW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstit
  • X LWW.3 is independently –F, -Cl, -Br, or –I.
  • R group R WW group
  • R group is hereby defined as independently oxo, halogen, -CX WW 3, -CHX WW 2, -CH 2 X WW , -OCX WW 3 , -OCH 2 X WW , -OCHX WW 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)H, -NHC(O)
  • 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 is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, —NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO 2 -, -SO 2 NH-, R LWW.1 - substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered
  • 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.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • bioconjugate and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect.
  • a conjugate between a first bioconjugate reactive group e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide
  • a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
  • covalent bond or linker e.g., a first linker of second linker
  • indirect e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like).
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
  • bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group e.g., –N- hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Die
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • the terms “a” or “an”, as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13.A , R 13.B , R 13.C , R 13.D , etc., wherein each of R 13.A , R 13.B , R 13.C , R 13.D , etc.
  • a group may be substituted by one or more of a number of substituents
  • substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
  • a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
  • the present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • a “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
  • 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.
  • contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
  • the terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein.
  • the agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist.
  • expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.
  • to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • a patient in need thereof is human.
  • a subject is human.
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
  • lymphoma refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved.
  • B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma.
  • Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
  • the term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
  • the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body.
  • a second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor.
  • the metastatic tumor and its cells are presumed to be similar to those of the original tumor.
  • the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells.
  • the secondary tumor in the breast is referred to a metastatic lung cancer.
  • metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors.
  • non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors.
  • metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.
  • the terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast).
  • a primary cancer site e.g., breast
  • cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.
  • visceral metastasis refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast).
  • a primary cancer site e.g., head and neck, liver, breast.
  • a primary cancer site e.g., head and neck, liver, breast
  • Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
  • administering is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
  • Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient.
  • the dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • a disease e.g., a protein associated disease, disease associated with a cellular component
  • the disease e.g., cancer
  • a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component).
  • modulating e.g., inhibiting or activating
  • aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • electrophilic as used herein refers to a chemical group that is capable of accepting electron density.
  • an “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.
  • “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.
  • isolated when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ - carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • non-naturally occurring amino acid and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • polypeptide “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids.
  • amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.
  • An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end).
  • the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
  • the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
  • that insertion will not correspond to a numbered amino acid position in the reference sequence.
  • a selected residue in a selected protein corresponds to C38 of human 14-3-3 ⁇ protein when the selected residue occupies the same essential spatial or other structural relationship as C38 of human 14-3-3 ⁇ protein.
  • the position in the aligned selected protein aligning with C38 is said to correspond to C38.
  • 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 14-3-3 ⁇ protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as C38 in the structural model is said to correspond to the C38 residue.
  • protein complex is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.
  • protein aggregate is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.
  • client protein refers to a protein that is capable of binding to another protein (e.g., a 14-3-3 protein). In embodiments, the client protein interaction with the other protein is stabilized with chemical compound as set forth herein.
  • 14-3-3 protein refers to a protein (or portion thereof) that is a member of the 14-3-3 protein family, including, but not limited to, the various human isoforms ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ / ⁇ and ⁇ ). When specified, the term can refer to a specific isoform or group of isoforms. In embodiments, the term refers to the ⁇ isoform.
  • the 14-3-3 proteins influence the function of bound phosphoserine and/or threonine phosphorylated proteins via a variety of mechanisms including sequestering them from cellular targets, controlling their enzymatic activity, relocating them or acting as adaptor molecules in mediating the association of two distinct client proteins.
  • 14-3-3 proteins regulate pathways involved in growth factor signaling and cell cycle progression.
  • the 14-3-3 protein may interact with more than 300 different partners (client proteins), including Raf kinases, heat shock proteins, oncogenes, and tumor suppressors.14- 3-3 proteins are central regulators in many biological processes and pathologies.
  • 14-3-3 binding antagonizes multiple transcription factors that act as oncogenic drivers.
  • 14-3-3 protein binds to an ER ⁇ protein, and reduces the transcriptional activity of ER ⁇ .
  • a “14-3-3 protein–ER ⁇ protein complex” is the complex formed when the 14-3-3 protein binds to an ER ⁇ protein.
  • the 14-3-3 protein is 14-3-3 ⁇ (14-3-3sigma) (e.g., Entrez 2810, UniProt P31947, RefSeq NP_006133).
  • the 14-3-3 protein is 14-3-3 ⁇ (14-3-3beta) (e.g., Entrez 7529, UniProt P31946, Q4VY19, RefSeq NP_003395).
  • the 14-3-3 protein is 14-3-3 ⁇ (14-3- 3epsilon) (e.g., Entrez 7531, UniProt P62258, RefSeq NP_006752).
  • the 14- 3-3 protein is 14-3-3 ⁇ (14-3-3eta) (e.g., Entrez 7533, UniProt Q04917, RefSeq NP_003396).
  • the 14-3-3 protein is 14-3-3 ⁇ (14-3-3gamma) (e.g., Entrez 7532, UniProt P61981, RefSeq NP_36611).
  • the 14-3-3 protein is 14-3-3 ⁇ (14-3-3tau) (e.g., Entrez 10971, UniProt P27348, RefSeq NP_006817). In embodiments, the 14-3-3 protein is 14-3-3 ⁇ (14-3-3zeta) (e.g., Entrez 7534, UniProt P63104, RefSeq NP_003397). [0176] In embodiments, the 14-3-3 protein is phosphorylated. In embodiments, the 14-3-3 client is a phosphoserine protein. In embodiments, the 14-3-3 client is a phosphothreonine protein.
  • the 14-3-3 client is a phosphorylated peptide (a phosphopeptide) derived from the 14-3-3 client protein.
  • the 14-3-3 client is a phosphorylated peptide (phosphopeptide) representing the 14-3-3 protein binding motif of the client protein.
  • estrogen receptor alpha refers to a hormone receptor activated by estrogen.
  • the term includes any recombinant or naturally-occurring form of ER ⁇ , including variants thereof that maintain ER ⁇ function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype ER ⁇ ).
  • ER ⁇ is encoded by the NR3A1 gene.
  • ER ⁇ has the amino acid sequence set forth in or corresponding to Entrez 2099, UniProt P03372, or RefSeq (protein) NP_000116.2. II.
  • Compounds [0178] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: .
  • a substituted or unsubstituted cycloalkylene e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6
  • substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (
  • L 2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 20 -, -C(O)NR 20 -, -NR 20 C(O)-, -NR 20 C(O)O-, -OC(O)NR 20 -, -NR 20 C(O)NR 20 -, -S(O)2-, -NR 20 S(O)2-, -S(O)2NR 20 -, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted), substituted or
  • L 3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 30 -, -C(O)NR 30 -, -NR 30 C(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 4 is –NR 40 - or -O-.
  • R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -C(NR 1C )NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO 2 R 1D
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2NR 2A R 2B , ⁇ NR 2C NR 2A R 2B , ⁇ ONR 2A R 2B , -NR 2C C(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -OC(O)R 2C , -OC(O)OR 2C , -C(O)NR 2A R 2B , -OC(O)NR 2A R 2B , -OR 2D , -SR 2D , -NR 2D
  • R 3 and R 4 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 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, -
  • Each R 10 , R 20 , R 30 , and R 40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -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, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2), substituted or unsubstituted heteroalkyl
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl 3 , -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1- C 8 , C
  • Each X 1 and X 2 is independently –F, -Cl, -Br, or –I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols m1, m2, v1, and v2 are independently 1 or 2.
  • the compound, or a pharmaceutically acceptable salt thereof has the formula: a or membered, 4 to 5 membered, or 5 to 6 membered);
  • L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 member
  • the compound has the formula: . Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , and R 4 are [0196] In embodiments, the compound has the formula: R 1 1 L 2 R 2 L A R 3 R 4 . Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , and [0197] In embodiments, the compound has the formula: . Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , and [0198] A person having ordinary skill in the art would understand that Ring A and Ring B together form a spirocyclic ring.
  • the spirocyclic ring is a heterocyclic spirocyclic ring. In embodiments, the spirocyclic ring is a substituted spirocyclic ring.
  • a substituted Ring A e.g., substituted cycloalkylene and/or substituted heterocycloalkylene
  • Ring A when Ring A is substituted, it is substituted with at least one substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent group. [0200] In embodiments, Ring A is a substituted or unsubstituted C 3 -C 8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, Ring A is a substituted or unsubstituted C 3 -C 8 cycloalkylene. In embodiments, Ring A is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • a substituted Ring B (e.g., substituted cycloalkylene and/or substituted heterocycloalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • Ring B when Ring B is substituted, it is substituted with at least one substituent group.
  • Ring B when Ring B is substituted, it is substituted with at least one size-limited substituent group.
  • Ring B when Ring B is substituted, it is substituted with at least one lower substituent group.
  • Ring B is a substituted or unsubstituted C 3 -C 8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, Ring B is a substituted or unsubstituted C 3 -C 8 cycloalkylene. In embodiments, Ring B is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • R 5 , R 6 , R 7 , and R 8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br,
  • the symbol z5 is an integer from 0 to 5.
  • the compound has the formula: are as described herein, [0208] In embodiments, the compound has the formula: are as described herein, [0209] In embodiments, the compound has the formula: (IIb). L 1 , L 2 , and R 1 are as described herein, including in [0210] In embodiments, the compound has the formula: z2 are as described [0211] In embodiments, the compound has the formula: (IIIa). L 1 , L 2 , R 1 , and R 2 are as described herein, [0212] In embodiments, the compound has the formula: z5 are as [0213] In embodiments, the compound has the formula: .
  • L 1 , L 2 , R 1 , and R 2 are as described herein, [0214] In embodiments, the compound has the formula: R 8 are as [0215] In embodiments, the compound has the formula: . L 1 , L 2 , R 1 , and R 2 are as described herein, [0216] In embodiments, the compound has the formula: R 2 are as described herein, [0217] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: R 4 , [0218] L 5 is –NR 90 - or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 5 is –NR 90 - or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membere
  • R 90 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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
  • L 6 is a bond or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • the symbol z5 is an integer from 0 to 4.
  • the symbol z6 is an integer from 0 to 2.
  • the compound has the formula: R 5 , [0224] In embodiments, the compound has the formula: (VIIa).
  • the compound has the formula: (R 5 ) z5 R 3 4 R 1 L 1 R (R 2 ) z2 R 3 , [0226]
  • the compound has the formula: (VIIIa).
  • the compound has the formula: (VIIIb). L 1 , L 2 , L 4 , L 5 , L 6 , R 1 , R 2 , z2, R 3 , mbodiments.
  • the compound has the formula: .
  • L 1 , L 2 , L 4 , L 5 , R 1 , R 2 , z2, R 3 , and R 4 are [0229]
  • the compound has the formula: O L 4 (VIIId).
  • L 1 , L 2 , L 4 , L 5 , R 1 , R 2 , z2, R 3 , and R 4 are [0230]
  • the compound has the formula: (VIIIe).
  • a substituted L 1 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if 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. [0233] In embodiments, L 1 is a bond. In embodiments, L 1 is -C(O)-. In embodiments, L 1 is -C(O)O-. In embodiments, L 1 is -OC(O)-. In embodiments, L 1 is -O-. In embodiments, L 1 is -S-. In embodiments, L 1 is -NR 10 -. In embodiments, L 1 is -NH-.
  • L 1 is -C(O)NR 10 -. In embodiments, L 1 is -C(O)NH-. In embodiments, L 1 is -NR 10 C(O)-. In embodiments, L 1 is -NHC(O)-. In embodiments, L 1 is -NR 10 C(O)O-. In embodiments, L 1 is -NHC(O)O-. In embodiments, L 1 is -OC(O)NR 10 -. In embodiments, L 1 is -OC(O)NH-. In embodiments, L 1 is -NR 10 C(O)NR 10 -. In embodiments, L 1 is -NHC(O)NH-. In embodiments, L 1 is -S(O) 2 -.
  • L 1 is -NR 10 S(O) 2 -. In embodiments, L 1 is -NHS(O)2-. In embodiments, L 1 is -S(O)2NR 10 -. In embodiments, L 1 is -S(O)2NH-. In embodiments, L 1 is unsubstituted C 1 -C 4 alkylene. In embodiments, L 1 is unsubstituted methylene. In embodiments, L 1 is unsubstituted ethylene. In embodiments, L 1 is unsubstituted propylene. In embodiments, L 1 is unsubstituted n-propylene. In embodiments, L 1 is unsubstituted isopropylene.
  • L 1 is unsubstituted butylene. In embodiments, L 1 is unsubstituted n-butylene. In embodiments, L 1 is unsubstituted isobutylene. In embodiments, L 1 is unsubstituted tert-butylene. In embodiments, L 1 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 1 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L 1 is unsubstituted 2 to 6 membered heteroalkylene. [0234] In embodiments, L 1 is a bond or unsubstituted C 1 -C 4 alkylene.
  • L 1 is a bond or unsubstituted methylene.
  • a substituted R 10 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 10 when R 10 is substituted, it is substituted with at least one substituent group. In embodiments, when R 10 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 10 is substituted, it is substituted with at least one lower substituent group.
  • R 10 is independently hydrogen. In embodiments, R 10 is independently unsubstituted C1-C4 alkyl. In embodiments, R 10 is independently unsubstituted methyl. In embodiments, R 10 is independently unsubstituted ethyl. In embodiments, R 10 is independently unsubstituted propyl. In embodiments, R 10 is independently unsubstituted n- propyl.
  • R 10 is independently unsubstituted isopropyl. In embodiments, R 10 is independently unsubstituted butyl. In embodiments, R 10 is independently unsubstituted n- butyl. In embodiments, R 10 is independently unsubstituted isobutyl. In embodiments, R 10 is independently unsubstituted tert-butyl.
  • a substituted L 2 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 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 L 2 is substituted, it is substituted with at least one substituent group.
  • L 2 when L 2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 2 is substituted, it is substituted with at least one lower substituent group.
  • L 2 is a bond. In embodiments, L 2 is -C(O)-. In embodiments, L 2 is -C(O)O-. In embodiments, L 2 is -OC(O)-. In embodiments, L 2 is -O-. In embodiments, L 2 is -S-. In embodiments, L 2 is –NR 20 -. In embodiments, L 2 is -NH-. In embodiments, L 2 is -C(O)NR 20 -.
  • L 2 is -C(O)NH-. In embodiments, L 2 is –NR 20 C(O)-. In embodiments, L 2 is -NHC(O)-. In embodiments, L 2 is –NR 20 C(O)O-. In embodiments, L 2 is -NHC(O)O-. In embodiments, L 2 is -OC(O)NR 20 -. In embodiments, L 2 is -OC(O)NH-. In embodiments, L 2 is –NR 20 C(O)NR 20 -. In embodiments, L 2 is -NHC(O)NH-. In embodiments, L 2 is -S(O) 2 -. In embodiments, L 2 is –NR 20 S(O) 2 -.
  • L 2 is -NHS(O)2-. In embodiments, L 2 is -S(O)2NR 20 -. In embodiments, L 2 is -S(O)2NH-. In embodiments, L 2 is unsubstituted C 1 -C 4 alkylene. In embodiments, L 2 is unsubstituted methylene. In embodiments, L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene. In embodiments, L 2 is unsubstituted isopropylene. In embodiments, L 2 is unsubstituted butylene.
  • L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted isobutylene. In embodiments, L 2 is unsubstituted tert-butylene. In embodiments, L 2 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 2 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L 2 is unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 2 .
  • L 2 is a bond, –NHC(O)-, –C(O)NH-, or substituted or unsubstituted 2 to 6 membered heteroalkylene.
  • a substituted R 20 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 20 when R 20 is substituted, it is substituted with at least one substituent group. In embodiments, when R 20 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 20 is substituted, it is substituted with at least one lower substituent group.
  • R 20 is independently hydrogen. In embodiments, R 20 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 20 is independently unsubstituted methyl. In embodiments, R 20 is independently unsubstituted ethyl. In embodiments, R 20 is independently unsubstituted propyl. In embodiments, R 20 is independently unsubstituted n- propyl.
  • R 20 is independently unsubstituted isopropyl. In embodiments, R 20 is independently unsubstituted butyl. In embodiments, R 20 is independently unsubstituted n- butyl. In embodiments, R 20 is independently unsubstituted isobutyl. In embodiments, R 20 is independently unsubstituted tert-butyl. [0242] In embodiments, -L 1 -L 2 - is a bond. In embodiments, -L 1 -L 2 - is -NHC(O)-. In embodiments, -L 1 -L 2 - is unsubstituted methylene.
  • -L 1 -L 2 - is unsubstituted ethylene. In embodiments, -L 1 -L 2 - is unsubstituted n-propylene. In embodiments, -L 1 -L 2 - is unsubstituted n-butylene. In embodiments, -L 1 -L 2 - .
  • a substituted L 3 (e.g., substituted alkylene and/or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 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.
  • when L 3 is substituted it is substituted with at least one substituent group.
  • when L 3 is substituted it is substituted with at least one size-limited substituent group.
  • L 3 when L 3 is substituted, it is substituted with at least one lower substituent group.
  • L 3 is -C(O)-. In embodiments, L 3 is -C(O)O-. In embodiments, L 3 is -OC(O)-. In embodiments, L 3 is -O-. In embodiments, L 3 is -S-. In embodiments, L 3 is –NR 30 -. In embodiments, L 3 is -NH-. In embodiments, L 3 is -C(O)NR 30 -. In embodiments, L 3 is -C(O)NH-. In embodiments, L 3 is –NR 30 C(O)-. In embodiments, L 3 is -NHC(O)-.
  • L 3 is unsubstituted C 1 -C 4 alkylene. In embodiments, L 3 is unsubstituted methylene. In embodiments, L 3 is unsubstituted ethylene. In embodiments, L 3 is unsubstituted propylene. In embodiments, L 3 is unsubstituted n-propylene. In embodiments, L 3 is unsubstituted isopropylene. In embodiments, L 3 is unsubstituted butylene. In embodiments, L 3 is unsubstituted n-butylene. In embodiments, L 3 is unsubstituted isobutylene. In embodiments, L 3 is unsubstituted tert-butylene.
  • L 3 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 3 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L 3 is unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 3 .
  • a substituted R 30 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 30 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 30 when R 30 is substituted, it is substituted with at least one substituent group.
  • R 30 when R 30 is substituted, it is substituted with at least one size-limited substituent group.
  • R 30 when R 30 is substituted, it is substituted with at least one lower substituent group.
  • R 30 is hydrogen. In embodiments, R 30 is unsubstituted C1-C4 alkyl. In embodiments, R 30 is unsubstituted methyl. In embodiments, R 30 is unsubstituted ethyl. In embodiments, R 30 is unsubstituted propyl. In embodiments, R 30 is unsubstituted n- propyl. In embodiments, R 30 is unsubstituted isopropyl. In embodiments, R 30 is unsubstituted butyl. In embodiments, R 30 is unsubstituted n-butyl.
  • R 40 when R 40 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 40 is substituted, it is substituted with at least one lower substituent group.
  • R 40 is hydrogen. In embodiments, R 40 is unsubstituted C1-C4 alkyl. In embodiments, R 40 is unsubstituted methyl. In embodiments, R 40 is unsubstituted ethyl. In embodiments, R 40 is unsubstituted propyl. In embodiments, R 40 is unsubstituted n- propyl. In embodiments, R 40 is unsubstituted isopropyl.
  • L 5 when L 5 is substituted, it is substituted with at least one substituent group. In embodiments, when L 5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 5 is substituted, it is substituted with at least one lower substituent group. [0251] In embodiments, L 5 is –NR 90 -. In embodiments, L 5 is -NH-. In embodiments, L 5 is substituted or unsubstituted heteroalkylene. In embodiments, L 5 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 5 is [0252]
  • a substituted R 90 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 90 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 90 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 90 when R 90 is substituted, it is substituted with at least one substituent group.
  • R 90 when R 90 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 90 is substituted, it is substituted with at least one lower substituent group.
  • R 90 is hydrogen. In embodiments, R 90 is unsubstituted C1-C4 alkyl. In embodiments, R 90 is unsubstituted methyl. In embodiments, R 90 is unsubstituted ethyl. In embodiments, R 90 is unsubstituted propyl. In embodiments, R 90 is unsubstituted n- propyl. In embodiments, R 90 is unsubstituted isopropyl.
  • R 90 is unsubstituted butyl. In embodiments, R 90 is unsubstituted n-butyl. In embodiments, R 90 is unsubstituted isobutyl. In embodiments, R 90 is unsubstituted tert-butyl.
  • a substituted L 6 e.g., substituted heteroarylene
  • L 6 when L 6 is substituted, it is substituted with at least one substituent group. In embodiments, when L 6 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 6 is substituted, it is substituted with at least one lower substituent group. [0255] In embodiments, L 6 is a bond. In embodiments, L 6 is a substituted or unsubstituted heteroarylene. In embodiments, L 6 is a substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 6 is a substituted or unsubstituted triazolylene. In .
  • a substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1 is substituted, it is substituted with at least one substituent group.
  • R 1 when R 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1A e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1A 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.
  • R 1A when R 1A is substituted, it is substituted with at least one substituent group. In embodiments, when R 1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) 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.
  • a substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • R 1A and R 1B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1C is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 1C is substituted, it is substituted with at least one substituent group.
  • R 1C when R 1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1D is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 1D when R 1D is substituted, it is substituted with at least one substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one lower substituent group.
  • R 1A is hydrogen. In embodiments, R 1A is unsubstituted C 1 -C 4 alkyl. In embodiments, R 1A is unsubstituted methyl. In embodiments, R 1A is unsubstituted ethyl. In embodiments, R 1A is unsubstituted propyl. In embodiments, R 1A is unsubstituted n- propyl.
  • R 1A is unsubstituted isopropyl. In embodiments, R 1A is unsubstituted butyl. In embodiments, R 1A is unsubstituted n-butyl. In embodiments, R 1A is unsubstituted isobutyl. In embodiments, R 1A is unsubstituted tert-butyl. [0263] In embodiments, R 1B is hydrogen. In embodiments, R 1B is unsubstituted C1-C4 alkyl. In embodiments, R 1B is unsubstituted methyl. In embodiments, R 1B is unsubstituted ethyl.
  • R 1B is unsubstituted propyl. In embodiments, R 1B is unsubstituted n- propyl. In embodiments, R 1B is unsubstituted isopropyl. In embodiments, R 1B is unsubstituted butyl. In embodiments, R 1B is unsubstituted n-butyl. In embodiments, R 1B is unsubstituted isobutyl. In embodiments, R 1B is unsubstituted tert-butyl. [0264] In embodiments, R 1C is hydrogen. In embodiments, R 1C is unsubstituted C 1 -C 4 alkyl.
  • R 1C is unsubstituted methyl. In embodiments, R 1C is unsubstituted ethyl. In embodiments, R 1C is unsubstituted propyl. In embodiments, R 1C is unsubstituted n- propyl. In embodiments, R 1C is unsubstituted isopropyl. In embodiments, R 1C is unsubstituted butyl. In embodiments, R 1C is unsubstituted n-butyl. In embodiments, R 1C is unsubstituted isobutyl. In embodiments, R 1C is unsubstituted tert-butyl. [0265] In embodiments, R 1D is hydrogen.
  • R 1D is unsubstituted C1-C4 alkyl. In embodiments, R 1D is unsubstituted methyl. In embodiments, R 1D is unsubstituted ethyl. In embodiments, R 1D is unsubstituted propyl. In embodiments, R 1D is unsubstituted n- propyl. In embodiments, R 1D is unsubstituted isopropyl. In embodiments, R 1D is unsubstituted butyl. In embodiments, R 1D is unsubstituted n-butyl. In embodiments, R 1D is unsubstituted isobutyl.
  • R 1D is unsubstituted tert-butyl.
  • R 1 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH 2 F,
  • R 1 is hydrogen. In embodiments, R 1 is halogen. In embodiments, R 1 is –F. In embodiments, R 1 is –Cl. In embodiments, R 1 is –Br. In embodiments, R 1 is –I. In embodiments, R 1 is -CCl 3 . In embodiments, R 1 is -CBr 3 . In embodiments, R 1 is -CF 3 . In embodiments, R 1 is -CI3. In embodiments, R 1 is -CH2Cl. In embodiments, R 1 is -CH2Br. In embodiments, R 1 is -CH 2 F. In embodiments, R 1 is -CH 2 I. In embodiments, R 1 is -CHCl 2 .
  • R 1 is -CHBr2. In embodiments, R 1 is -CHF2. In embodiments, R 1 is -CHI2. In embodiments, R 1 is –CN. In embodiments, R 1 is –OH. In embodiments, R 1 is -NH 2 . In embodiments, R 1 is –COOH. In embodiments, R 1 is -C(NR 1C )NR 1A R 1B . In embodiments, R 1 is -C(NH)NH 2 . In embodiments, R 1 is -C(NH)NHOH. In embodiments, R 1 is -C(O)NR 1A R 1B . In embodiments, R 1 is -CONH2. In embodiments, R 1 is -NO2.
  • R 1 is –SH. In embodiments, R 1 is -SO 3 H. In embodiments, R 1 is -OSO 3 H. In embodiments, R 1 is -SO 2 NH 2 . In embodiments, R 1 is ⁇ NHNH 2 . In embodiments, R 1 is ⁇ ONH 2 . In embodiments, R 1 is ⁇ NHC(O)NH 2 . In embodiments, R 1 is -NHSO 2 H. In embodiments, R 1 is -NHC(O)H. In embodiments, R 1 is -NHC(O)OH. In embodiments, R 1 is –NHOH. In embodiments, R 1 is -OCCl3. In embodiments, R 1 is -OCBr3.
  • R 1 is -OCF 3 . In embodiments, R 1 is -OCI 3 . In embodiments, R 1 is -OCH 2 Cl. In embodiments, R 1 is -OCH2Br. In embodiments, R 1 is -OCH2F. In embodiments, R 1 is -OCH 2 I. In embodiments, R 1 is -OCHCl 2 . In embodiments, R 1 is -OCHBr 2 . In embodiments, R 1 is -OCHF2. In embodiments, R 1 is -OCHI2. In embodiments, R 1 is -SF5. In embodiments, R 1 is -N 3 . In embodiments, R 1 is unsubstituted C 1 -C 4 alkyl.
  • R 1 is unsubstituted methyl. In embodiments, R 1 is unsubstituted ethyl. In embodiments, R 1 is unsubstituted propyl. In embodiments, R 1 is unsubstituted n-propyl. In embodiments, R 1 is unsubstituted isopropyl. In embodiments, R 1 is unsubstituted butyl. In embodiments, R 1 is unsubstituted n-butyl. In embodiments, R 1 is unsubstituted isobutyl. In embodiments, R 1 is unsubstituted tert-butyl. In embodiments, R 1 is unsubstituted 2 to 6 membered heteroalkyl.
  • R 1 is unsubstituted methoxy. In embodiments, R 1 is unsubstituted ethoxy. In embodiments, R 1 is unsubstituted propoxy. In embodiments, R 1 is unsubstituted n-propoxy. In embodiments, R 1 is unsubstituted isopropoxy. In embodiments, R 1 is unsubstituted butoxy. [0268] In embodiments, R 1 is substituted or unsubstituted 2 to 8 membered heteroalkyl. In is In embodiments R 1 is . In embodiments, R 1 eger from 0 to 10. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.
  • n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. [0269] In embodiments, R 1 is E. In embodiments, E is O R 11 O 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
  • substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered
  • substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered
  • substituted or unsubstituted aryl e.g., C6-C10 or phenyl
  • E is . In embodiments, E is is . In embodiments, E is is . In embodiments, E . In embodiments, E . In embodiments, E In X 11 X 11 embodiments, E . In embodiments, E . In embodiments, E . In embodiments, E . In embodiments, E . In embodiments, E . In In . O Cl [0274] In embodiments, R 1 . In embodiments, R 1 is .
  • 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 11 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 11 when R 11 is substituted, it is substituted with at least one substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one size-limited substituent group.
  • R 11 when R 11 is substituted, it is substituted with at least one lower substituent group.
  • R 11 is hydrogen. In embodiments, R 11 is unsubstituted C1-C4 alkyl. In embodiments, R 11 is unsubstituted methyl. In embodiments, R 11 is unsubstituted ethyl. In embodiments, R 11 is unsubstituted propyl. In embodiments, R 11 is unsubstituted n- propyl. In embodiments, R 11 is unsubstituted isopropyl. In embodiments, R 11 is unsubstituted butyl. In embodiments, R 11 is unsubstituted n-butyl.
  • R 11 is unsubstituted isobutyl. In embodiments, R 11 is unsubstituted tert-butyl.
  • a substituted R 12 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 12 when R 12 is substituted, it is substituted with at least one substituent group. In embodiments, when R 12 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 12 is substituted, it is substituted with at least one lower substituent group.
  • R 12 is hydrogen. In embodiments, R 12 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 12 is unsubstituted methyl. In embodiments, R 12 is unsubstituted ethyl. In embodiments, R 12 is unsubstituted propyl. In embodiments, R 12 is unsubstituted n- propyl.
  • R 12 is unsubstituted isopropyl. In embodiments, R 12 is unsubstituted butyl. In embodiments, R 12 is unsubstituted n-butyl. In embodiments, R 12 is unsubstituted isobutyl. In embodiments, R 12 is unsubstituted tert-butyl.
  • a substituted R 13 (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 13 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 13 is substituted, it is substituted with at least one substituent group.
  • R 13 when R 13 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 13 is substituted, it is substituted with at least one lower substituent group.
  • R 13 is hydrogen. In embodiments, R 13 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 13 is unsubstituted methyl. In embodiments, R 13 is unsubstituted ethyl. In embodiments, R 13 is unsubstituted propyl. In embodiments, R 13 is unsubstituted n- propyl. In embodiments, R 13 is unsubstituted isopropyl.
  • R 13 is unsubstituted butyl. In embodiments, R 13 is unsubstituted n-butyl. In embodiments, R 13 is unsubstituted isobutyl. In embodiments, R 13 is unsubstituted tert-butyl.
  • a substituted R 14 (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 14 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 14 is substituted, it is substituted with at least one substituent group.
  • R 14 when R 14 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 14 is substituted, it is substituted with at least one lower substituent group.
  • R 14 is hydrogen. In embodiments, R 14 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 14 is unsubstituted methyl. In embodiments, R 14 is unsubstituted ethyl. In embodiments, R 14 is unsubstituted propyl. In embodiments, R 14 is unsubstituted n- propyl. In embodiments, R 14 is unsubstituted isopropyl.
  • R 14 is unsubstituted butyl. In embodiments, R 14 is unsubstituted n-butyl. In embodiments, R 14 is unsubstituted isobutyl. In embodiments, R 14 is unsubstituted tert-butyl. [0283] In embodiments, R 11 , R 12 , R 13 , and R 14 are hydrogen. O , embodiments, R 1 . In embodiments, R 1 . In embodiments, O . In embodiments, R 1 is embodiments, R 1 . In embodiments, R 1 is embodiments, R 1 . In embodiments, R 1 is .
  • 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.
  • a substituted ring formed when two R 2 substituents are joined e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • a substituted R 2A (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 2A 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 2A is substituted, it is substituted with at least one substituent group.
  • R 2A when R 2A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 2B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 2B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2B 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 2B when R 2B is substituted, it is substituted with at least one substituent group. In embodiments, when R 2B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2B is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when R 2A and R 2B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • the substituted ring formed when R 2A and R 2B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when the substituted ring formed when R 2A and R 2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R 2A and R 2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 2A and R 2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 2C (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 2C 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 2C is substituted, it is substituted with at least one substituent group.
  • R 2C when R 2C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 2D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 2D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2D 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 2D when R 2D is substituted, it is substituted with at least one substituent group. In embodiments, when R 2D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2D is substituted, it is substituted with at least one lower substituent group.
  • R 2A is independently hydrogen. In embodiments, R 2A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2A is independently unsubstituted methyl. In embodiments, R 2A is independently unsubstituted ethyl. In embodiments, R 2A is independently unsubstituted propyl.
  • R 2A is independently unsubstituted n-propyl. In embodiments, R 2A is independently unsubstituted isopropyl. In embodiments, R 2A is independently unsubstituted butyl. In embodiments, R 2A is independently unsubstituted n-butyl. In embodiments, R 2A is independently unsubstituted isobutyl. In embodiments, R 2A is independently unsubstituted tert-butyl. [0293] In embodiments, R 2B is independently hydrogen. In embodiments, R 2B is independently unsubstituted C1-C4 alkyl. In embodiments, R 2B is independently unsubstituted methyl.
  • R 2B is independently unsubstituted ethyl. In embodiments, R 2B is independently unsubstituted propyl. In embodiments, R 2B is independently unsubstituted n-propyl. In embodiments, R 2B is independently unsubstituted isopropyl. In embodiments, R 2B is independently unsubstituted butyl. In embodiments, R 2B is independently unsubstituted n-butyl. In embodiments, R 2B is independently unsubstituted isobutyl. In embodiments, R 2B is independently unsubstituted tert-butyl. [0294] In embodiments, R 2C is independently hydrogen.
  • R 2C is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 2C is independently unsubstituted methyl. In embodiments, R 2C is independently unsubstituted ethyl. In embodiments, R 2C is independently unsubstituted propyl. In embodiments, R 2C is independently unsubstituted n-propyl. In embodiments, R 2C is independently unsubstituted isopropyl. In embodiments, R 2C is independently unsubstituted butyl. In embodiments, R 2C is independently unsubstituted n-butyl. In embodiments, R 2C is independently unsubstituted isobutyl.
  • R 2C is independently unsubstituted tert-butyl.
  • R 2D is independently hydrogen. In embodiments, R 2D is independently unsubstituted C1-C4 alkyl. In embodiments, R 2D is independently unsubstituted methyl. In embodiments, R 2D is independently unsubstituted ethyl. In embodiments, R 2D is independently unsubstituted propyl. In embodiments, R 2D is independently unsubstituted n-propyl. In embodiments, R 2D is independently unsubstituted isopropyl. In embodiments, R 2D is independently unsubstituted butyl.
  • R 2D is independently unsubstituted n-butyl. In embodiments, R 2D is independently unsubstituted isobutyl. In embodiments, R 2D is independently unsubstituted tert-butyl.
  • R 2 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH2F, -OCH2I, -OCHCl2,
  • R 2 is independently halogen. In embodiments, R 2 is independently –F. In embodiments, R 2 is independently –Cl. In embodiments, R 2 is independently –Br. In embodiments, R 2 is independently –I. In embodiments, R 2 is independently -CCl 3 . In embodiments, R 2 is independently -CBr3. In embodiments, R 2 is independently -CF3. In embodiments, R 2 is independently -CI 3 . In embodiments, R 2 is independently -CH 2 Cl. In embodiments, R 2 is independently -CH2Br. In embodiments, R 2 is independently -CH2F. In embodiments, R 2 is independently -CH 2 I.
  • R 2 is independently -CHCl 2 . In embodiments, R 2 is independently -CHBr2. In embodiments, R 2 is independently -CHF2. In embodiments, R 2 is independently -CHI 2 . In embodiments, R 2 is independently –CN. In embodiments, R 2 is independently –OH. In embodiments, R 2 is independently -NH2. In embodiments, R 2 is independently -C(O)R 2C , wherein R 2C is as described herein, including in embodiments. In embodiments, R 2 is independently -C(O)H. In embodiments, R 2 is independently -C(O)OR 2C , wherein R 2C is as described herein, including in embodiments. In embodiments, R 2 is independently –COOH.
  • R 2 is independently -C(O)CH3. In embodiments, R 2 is independently -CONH 2 . In embodiments, R 2 is independently -NO 2 . In embodiments, R 2 is independently –SH. In embodiments, R 2 is independently -SO3H. In embodiments, R 2 is independently -OSO 3 H. In embodiments, R 2 is independently -SO 2 NH 2 . In embodiments, R 2 is independently ⁇ NHNH2. In embodiments, R 2 is independently ⁇ ONH 2 . In embodiments, R 2 is independently ⁇ NHC(O)NH 2 . In embodiments, R 2 is independently -NHSO 2 H. In embodiments, R 2 is independently -NHC(O)H.
  • R 2 is independently -NHC(O)OH. In embodiments, R 2 is independently –NHOH. In embodiments, R 2 is independently -OCCl 3 . In embodiments, R 2 is independently -OCBr3. In embodiments, R 2 is independently -OCF3. In embodiments, R 2 is independently -OCI 3 . In embodiments, R 2 is independently -OCH 2 Cl. In embodiments, R 2 is independently -OCH2Br. In embodiments, R 2 is independently -OCH2F. In embodiments, R 2 is independently -OCH 2 I. In embodiments, R 2 is independently -OCHCl 2 . In embodiments, R 2 is independently -OCHBr2. In embodiments, R 2 is independently -OCHF2.
  • R 2 is independently -OCHI 2 . In embodiments, R 2 is independently -SF 5 . In embodiments, R 2 is independently -N3. 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.
  • R 2 is independently unsubstituted n-butyl. In embodiments, R 2 is independently unsubstituted isobutyl. In embodiments, R 2 is independently unsubstituted tert-butyl. In embodiments, R 2 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 2 is independently unsubstituted methoxy. In embodiments, R 2 is independently unsubstituted ethoxy. In embodiments, R 2 is independently unsubstituted propoxy. In embodiments, R 2 is independently unsubstituted n-propoxy. In embodiments, R 2 is independently unsubstituted isopropoxy.
  • R 2 is independently unsubstituted butoxy.
  • R 2 is independently halogen, -CX 2 3, -C(O)R 2C , -C(O)OR 2C , -OR 2D , substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 2 is independently –Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3.
  • z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3.
  • z2 is 4. In embodiments, z2 is 5. [0300]
  • a substituted R 3 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 3 when R 3 is substituted, it is substituted with at least one substituent group. In embodiments, when R 3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is hydrogen. In embodiments, R 3 is halogen. In embodiments, R 3 is –F. In embodiments, R 3 is –Cl. In embodiments, R 3 is –Br. In embodiments, R 3 is –I. In embodiments, R 3 is -CCl3. In embodiments, R 3 is -CBr3. In embodiments, R 3 is -CF3. In embodiments, R 3 is -CI 3 .
  • R 3 is -CH 2 Cl. In embodiments, R 3 is -CH 2 Br. In embodiments, R 3 is -CH2F. In embodiments, R 3 is -CH2I. In embodiments, R 3 is -CHCl2. In embodiments, R 3 is -CHBr 2 . In embodiments, R 3 is -CHF 2 . In embodiments, R 3 is -CHI 2 . In embodiments, R 3 is –CN. In embodiments, R 3 is –OH. In embodiments, R 3 is -NH2. In embodiments, R 3 is –COOH. In embodiments, R 3 is -CONH 2 . In embodiments, R 3 is -NO 2 . In embodiments, R 3 is –SH.
  • R 3 is -SO3H. In embodiments, R 3 is -OSO3H. In embodiments, R 3 is -SO2NH2. In embodiments, R 3 is ⁇ NHNH2. In embodiments, R 3 is ⁇ ONH2. In embodiments, R 3 is ⁇ NHC(O)NH2. In embodiments, R 3 is -NHSO2H. In embodiments, R 3 is -NHC(O)H. In embodiments, R 3 is -NHC(O)OH. In embodiments, R 3 is –NHOH. In embodiments, R 3 is -OCCl 3 . In embodiments, R 3 is -OCBr 3 . In embodiments, R 3 is -OCF3. In embodiments, R 3 is -OCI3.
  • R 3 is -OCH2Cl. In embodiments, R 3 is -OCH2Br. In embodiments, R 3 is -OCH2F. In embodiments, R 3 is -OCH2I. In embodiments, R 3 is -OCHCl2. In embodiments, R 3 is -OCHBr2. In embodiments, R 3 is -OCHF2. In embodiments, R 3 is -OCHI2. In embodiments, R 3 is -SF5. In embodiments, R 3 is -N3. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl.
  • R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted isobutyl. In embodiments, R 3 is unsubstituted tert-butyl. In embodiments, R 3 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 3 is unsubstituted methoxy. In embodiments, R 3 is unsubstituted ethoxy.
  • R 3 is unsubstituted propoxy. In embodiments, R 3 is unsubstituted n-propoxy. In embodiments, R 3 is unsubstituted isopropoxy. In embodiments, R 3 is unsubstituted butoxy. In embodiments, R 3 is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R 3 is substituted or unsubstituted cyclopropyl. In embodiments, R 3 is substituted or unsubstituted cyclobutyl. In embodiments, R 3 is substituted or unsubstituted cyclopentyl. In embodiments, R 3 is substituted or unsubstituted cyclohexyl.
  • R 3 is substituted or unsubstituted cycloheptyl. In embodiments, R 3 is substituted or unsubstituted cyclooctyl. In embodiments, R 3 is substituted or unsubstituted phenyl.
  • 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.
  • R 4 is hydrogen. In embodiments, R 4 is halogen. In embodiments, R 4 is –F. In embodiments, R 4 is –Cl. In embodiments, R 4 is –Br. In embodiments, R 4 is –I. In embodiments, R 4 is –CCl 3 . In embodiments, R 4 is –CBr 3 . In embodiments, R 4 is –CF 3 . In embodiments, R 4 is –CI 3 . In embodiments, R 4 is -CH 2 Cl.
  • R 4 is -CH 2 Br. In embodiments, R 4 is -CH 2 F. In embodiments, R 4 is -CH 2 I. In embodiments, R 4 is -CHCl 2 . In embodiments, R 4 is -CHBr 2 . In embodiments, R 4 is -CHF 2 . In embodiments, R 4 is -CHI 2 . In embodiments, R 4 is –CN. In embodiments, R 4 is –OH. In embodiments, R 4 is -NH 2 . In embodiments, R 4 is –COOH. In embodiments, R 4 is -CONH 2 . In embodiments, R 4 is -NO 2 . In embodiments, R 4 is –SH.
  • R 4 is –SO 3 H. In embodiments, R 4 is –OSO 3 H. In embodiments, R 4 is -SO 2 NH 2 . In embodiments, R 4 is ⁇ NHNH 2 . In embodiments, R 4 is ⁇ ONH 2 . In embodiments, R 4 is ⁇ NHC(O)NH 2 . In embodiments, R 4 is -NHSO 2 H. In embodiments, R 4 is -NHC(O)H. In embodiments, R 4 is -NHC(O)OH. In embodiments, R 4 is –NHOH. In embodiments, R 4 is –OCCl 3 . In embodiments, R 4 is –OCBr 3 . In embodiments, R 4 is –OCF3.
  • R 4 is –OCI3. In embodiments, R 4 is -OCH2Cl. In embodiments, R 4 is -OCH 2 Br. In embodiments, R 4 is -OCH 2 F. In embodiments, R 4 is -OCH2I. In embodiments, R 4 is -OCHCl2. In embodiments, R 4 is -OCHBr2. In embodiments, R 4 is -OCHF 2 . In embodiments, R 4 is -OCHI 2 . In embodiments, R 4 is -SF 5 . In embodiments, R 4 is –N3. In embodiments, R 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is unsubstituted methyl.
  • R 4 is unsubstituted ethyl. In embodiments, R 4 is unsubstituted propyl. In embodiments, R 4 is unsubstituted n-propyl. In embodiments, R 4 is unsubstituted isopropyl. In embodiments, R 4 is unsubstituted butyl. In embodiments, R 4 is unsubstituted n-butyl. In embodiments, R 4 is unsubstituted isobutyl. In embodiments, R 4 is unsubstituted tert-butyl. In embodiments, R 4 is unsubstituted 2 to 6 membered heteroalkyl.
  • R 4 is unsubstituted methoxy. In embodiments, R 4 is unsubstituted ethoxy. In embodiments, R 4 is unsubstituted propoxy. In embodiments, R 4 is unsubstituted n-propoxy. In embodiments, R 4 is unsubstituted isopropoxy. In embodiments, R 4 is unsubstituted butoxy.
  • a substituted ring formed when R 3 and R 4 substituents are joined is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R 3 and R 4 substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 3 and R 4 when the substituted ring formed when R 3 and R 4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R 3 and R 4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 3 and R 4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0305] In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted C 3 -C 8 heterocycloalkyl.
  • R 3 and R 4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted cyclopropyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted cyclobutyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted cyclopentyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted cyclohexyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted cycloheptyl.
  • R 3 and R 4 combine to form a substituted or unsubstituted cyclooctyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted tetrahydropyranyl. In embodiments, R 3 and R 4 combine to form a substituted or unsubstituted piperidinyl. In embodiments, R 3 and R 4 combine to In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to .
  • R 3 and R 4 combine to . In embodiments, R 3 and R 4 combine to .
  • a substituted R 5 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • a substituted R 5 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 5 when R 5 is substituted, it is substituted with at least one substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one lower substituent group. [0307] In embodiments, R 5 is halogen. In embodiments, R 5 is –F. In embodiments, R 5 is –Cl. In embodiments, R 5 is –Br. In embodiments, R 5 is –I. In embodiments, R 5 is –CCl3. In embodiments, R 5 is –CBr 3 . In embodiments, R 5 is –CF 3 . In embodiments, R 5 is –CI 3 .
  • R 5 is -CH2Cl. In embodiments, R 5 is -CH2Br. In embodiments, R 5 is -CH2F. In embodiments, R 5 is -CH 2 I. In embodiments, R 5 is -CHCl 2 . In embodiments, R 5 is -CHBr 2 . In embodiments, R 5 is -CHF2. In embodiments, R 5 is -CHI2. In embodiments, R 5 is –CN. In embodiments, R 5 is –OH. In embodiments, R 5 is -NH 2 . In embodiments, R 5 is –COOH. In embodiments, R 5 is -CONH2. In embodiments, R 5 is -NO2. In embodiments, R 5 is –SH.
  • R 5 is –SO 3 H. In embodiments, R 5 is –OSO 3 H. In embodiments, R 5 is -SO 2 NH 2 . In embodiments, R 5 is ⁇ NHNH 2 . In embodiments, R 5 is ⁇ ONH 2 . In embodiments, R 5 is ⁇ NHC(O)NH 2 . In embodiments, R 5 is -NHSO 2 H. In embodiments, R 5 is -NHC(O)H. In embodiments, R 5 is -NHC(O)OH. In embodiments, R 5 is –NHOH. In embodiments, R 5 is –OCCl3. In embodiments, R 5 is –OCBr3. In embodiments, R 5 is –OCF3.
  • R 5 is –OCI 3 . In embodiments, R 5 is -OCH 2 Cl. In embodiments, R 5 is -OCH2Br. In embodiments, R 5 is -OCH2F. In embodiments, R 5 is -OCH2I. In embodiments, R 5 is -OCHCl 2 . In embodiments, R 5 is -OCHBr 2 . In embodiments, R 5 is -OCHF2. In embodiments, R 5 is -OCHI2. In embodiments, R 5 is -SF5. In embodiments, R 5 is –N 3 . In embodiments, R 5 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 5 is unsubstituted methyl.
  • R 5 is unsubstituted ethyl. In embodiments, R 5 is unsubstituted propyl. In embodiments, R 5 is unsubstituted n-propyl. In embodiments, R 5 is unsubstituted isopropyl. In embodiments, R 5 is unsubstituted butyl. In embodiments, R 5 is unsubstituted n-butyl. In embodiments, R 5 is unsubstituted isobutyl. In embodiments, R 5 is unsubstituted tert-butyl. In embodiments, R 5 is unsubstituted 2 to 6 membered heteroalkyl.
  • R 5 is unsubstituted methoxy. In embodiments, R 5 is unsubstituted ethoxy. In embodiments, R 5 is unsubstituted propoxy. In embodiments, R 5 is unsubstituted n- propoxy. In embodiments, R 5 is unsubstituted isopropoxy. In embodiments, R 5 is unsubstituted butoxy. [0308] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5.
  • a substituted R 6 (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 6 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 6 is substituted, it is substituted with at least one substituent group.
  • R 6 when R 6 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 6 is substituted, it is substituted with at least one lower substituent group.
  • R 6 is halogen. In embodiments, R 6 is –F. In embodiments, R 6 is –Cl. In embodiments, R 6 is –Br. In embodiments, R 6 is –I. In embodiments, R 6 is –CCl3. In embodiments, R 6 is –CBr 3 . In embodiments, R 6 is –CF 3 . In embodiments, R 6 is –CI 3 . In embodiments, R 6 is -CH2Cl. In embodiments, R 6 is -CH2Br.
  • R 6 is -CH2F. In embodiments, R 6 is -CH 2 I. In embodiments, R 6 is -CHCl 2 . In embodiments, R 6 is -CHBr 2 . In embodiments, R 6 is -CHF2. In embodiments, R 6 is -CHI2. In embodiments, R 6 is –CN. In embodiments, R 6 is –OH. In embodiments, R 6 is -NH 2 . In embodiments, R 6 is –COOH. In embodiments, R 6 is -CONH2. In embodiments, R 6 is -NO2. In embodiments, R 6 is –SH. In embodiments, R 6 is –SO 3 H. In embodiments, R 6 is –OSO 3 H.
  • R 6 is -SO2NH2. In embodiments, R 6 is ⁇ NHNH2. In embodiments, R 6 is ⁇ ONH2. In embodiments, R 6 is ⁇ NHC(O)NH 2 . In embodiments, R 6 is -NHSO 2 H. In embodiments, R 6 is -NHC(O)H. In embodiments, R 6 is -NHC(O)OH. In embodiments, R 6 is –NHOH. In embodiments, R 6 is –OCCl3. In embodiments, R 6 is –OCBr3. In embodiments, R 6 is –OCF3. In embodiments, R 6 is –OCI 3 . In embodiments, R 6 is -OCH 2 Cl.
  • R 6 is -OCH2Br. In embodiments, R 6 is -OCH2F. In embodiments, R 6 is -OCH2I. In embodiments, R 6 is -OCHCl2. In embodiments, R 6 is -OCHBr2. In embodiments, R 6 is -OCHF2. In embodiments, R 6 is -OCHI2. In embodiments, R 6 is –SF5. In embodiments, R 6 is –N3. In embodiments, R 6 is unsubstituted C1-C4 alkyl. In embodiments, R 6 is unsubstituted methyl. In embodiments, R 6 is unsubstituted ethyl. In embodiments, R 6 is unsubstituted propyl.
  • R 6 is unsubstituted n-propyl. In embodiments, R 6 is unsubstituted isopropyl. In embodiments, R 6 is unsubstituted butyl. In embodiments, R 6 is unsubstituted n-butyl. In embodiments, R 6 is unsubstituted isobutyl. In embodiments, R 6 is unsubstituted tert-butyl.
  • a substituted R 7 (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 7 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 7 is substituted, it is substituted with at least one substituent group.
  • R 7 when R 7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 7 is substituted, it is substituted with at least one lower substituent group.
  • R 7 is halogen. In embodiments, R 7 is –F. In embodiments, R 7 is –Cl. In embodiments, R 7 is –Br. In embodiments, R 7 is –I. In embodiments, R 7 is –CCl 3 . In embodiments, R 7 is –CBr3. In embodiments, R 7 is –CF3. In embodiments, R 7 is –CI3. In embodiments, R 7 is -CH 2 Cl. In embodiments, R 7 is -CH 2 Br.
  • R 7 is -CH 2 F. In embodiments, R 7 is -CH2I. In embodiments, R 7 is -CHCl2. In embodiments, R 7 is -CHBr2. In embodiments, R 7 is -CHF 2 . In embodiments, R 7 is -CHI 2 . In embodiments, R 7 is –CN. In embodiments, R 7 is –OH. In embodiments, R 7 is -NH2. In embodiments, R 7 is –COOH. In embodiments, R 7 is -CONH 2 . In embodiments, R 7 is -NO 2 . In embodiments, R 7 is –SH. In embodiments, R 7 is –SO3H. In embodiments, R 7 is –OSO3H.
  • R 7 is -SO2NH2. In embodiments, R 7 is ⁇ NHNH2. In embodiments, R 7 is ⁇ ONH2. In embodiments, R 7 is ⁇ NHC(O)NH2. In embodiments, R 7 is -NHSO2H. In embodiments, R 7 is -NHC(O)H. In embodiments, R 7 is -NHC(O)OH. In embodiments, R 7 is –NHOH. In embodiments, R 7 is –OCCl 3 . In embodiments, R 7 is –OCBr 3 . In embodiments, R 7 is –OCF 3 . In embodiments, R 7 is –OCI3. In embodiments, R 7 is -OCH2Cl.
  • R 7 is -OCH2Br. In embodiments, R 7 is -OCH2F. In embodiments, R 7 is -OCH2I. In embodiments, R 7 is -OCHCl2. In embodiments, R 7 is -OCHBr2. In embodiments, R 7 is -OCHF2. In embodiments, R 7 is -OCHI2. In embodiments, R 7 is –SF5. In embodiments, R 7 is –N3. In embodiments, R 7 is unsubstituted C1-C4 alkyl. In embodiments, R 7 is unsubstituted methyl. In embodiments, R 7 is unsubstituted ethyl. In embodiments, R 7 is unsubstituted propyl.
  • R 7 is unsubstituted n-propyl. In embodiments, R 7 is unsubstituted isopropyl. In embodiments, R 7 is unsubstituted butyl. In embodiments, R 7 is unsubstituted n-butyl. In embodiments, R 7 is unsubstituted isobutyl. In embodiments, R 7 is unsubstituted tert-butyl.
  • a substituted R 8 (e.g., substituted alkyl, 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 8 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 8 is substituted, it is substituted with at least one substituent group.
  • R 8 when R 8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one lower substituent group.
  • R 8 is halogen. In embodiments, R 8 is –F. In embodiments, R 8 is –Cl. In embodiments, R 8 is –Br. In embodiments, R 8 is –I. In embodiments, R 8 is –CCl3. In embodiments, R 8 is –CBr 3 . In embodiments, R 8 is –CF 3 . In embodiments, R 8 is –CI 3 . In embodiments, R 8 is -CH2Cl. In embodiments, R 8 is -CH2Br.
  • R 8 is -CH2F. In embodiments, R 8 is -CH 2 I. In embodiments, R 8 is -CHCl 2 . In embodiments, R 8 is -CHBr 2 . In embodiments, R 8 is -CHF2. In embodiments, R 8 is -CHI2. In embodiments, R 8 is –CN. In embodiments, R 8 is –OH. In embodiments, R 8 is -NH 2 . In embodiments, R 8 is –COOH. In embodiments, R 8 is -CONH2. In embodiments, R 8 is -NO2. In embodiments, R 8 is –SH. In embodiments, R 8 is –SO 3 H. In embodiments, R 8 is –OSO 3 H.
  • R 8 is -SO 2 NH 2 . In embodiments, R 8 is ⁇ NHNH 2 . In embodiments, R 8 is ⁇ ONH 2 . In embodiments, R 8 is ⁇ NHC(O)NH 2 . In embodiments, R 8 is -NHSO 2 H. In embodiments, R 8 is -NHC(O)H. In embodiments, R 8 is -NHC(O)OH. In embodiments, R 8 is –NHOH. In embodiments, R 8 is –OCCl3. In embodiments, R 8 is –OCBr3. In embodiments, R 8 is –OCF3. In embodiments, R 8 is –OCI3. In embodiments, R 8 is -OCH2Cl.
  • R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.1 , R 1A.2 , and R 1A.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
  • R 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 2.1 when two R 2 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 2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2.1 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 2A when R 2A is substituted, R 2A is substituted with one or more first substituent groups denoted by R 2A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.1 substituent group when an R 2A.1 substituent group is substituted, the R 2A.1 substituent group is substituted with one or more second substituent groups denoted by R 2A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.2 substituent group when an R 2A.2 substituent group is substituted, the R 2A.2 substituent group is substituted with one or more third substituent groups denoted by R 2A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A , R 2A.1 , R 2A.2 , and R 2A.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 2A , R 2A.1 , R 2A.2 , and R 2A.3 , respectively.
  • R 2B when R 2B is substituted, R 2B is substituted with one or more first substituent groups denoted by R 2B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.1 substituent group when an R 2B.1 substituent group is substituted, the R 2B.1 substituent group is substituted with one or more second substituent groups denoted by R 2B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.2 substituent group when an R 2B.2 substituent group is substituted, the R 2B.2 substituent group is substituted with one or more third substituent groups denoted by R 2B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B , R 2B.1 , R 2B.2 , and R 2B.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 2B , R 2B.1 , R 2B.2 , and R 2B.3 , respectively.
  • R 2A and R 2B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 2A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.1 when an R 2A.1 substituent group is substituted, the R 2A.1 substituent group is substituted with one or more second substituent groups denoted by R 2A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.2 substituent group when an R 2A.2 substituent group is substituted, the R 2A.2 substituent group is substituted with one or more third substituent groups denoted by R 2A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.1 , R 2A.2 , and R 2A.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 2A.1 , R 2A.2 , and R 2A.3 , respectively.
  • R 2A and R 2B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 2B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.1 substituent group when an R 2B.1 substituent group is substituted, the R 2B.1 substituent group is substituted with one or more second substituent groups denoted by R 2B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.2 substituent group when an R 2B.2 substituent group is substituted, the R 2B.2 substituent group is substituted with one or more third substituent groups denoted by R 2B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.1 , R 2B.2 , and R 2B.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 2B.1 , R 2B.2 , and R 2B.3 , respectively.
  • R 2C when R 2C is substituted, R 2C is substituted with one or more first substituent groups denoted by R 2C.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2C.1 substituent group when an R 2C.1 substituent group is substituted, the R 2C.1 substituent group is substituted with one or more second substituent groups denoted by R 2C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2C.2 substituent group when an R 2C.2 substituent group is substituted, the R 2C.2 substituent group is substituted with one or more third substituent groups denoted by R 2C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2C , R 2C.1 , R 2C.2 , and R 2C.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 2C , R 2C.1 , R 2C.2 , and R 2C.3 , respectively.
  • R 2D when R 2D is substituted, R 2D is substituted with one or more first substituent groups denoted by R 2D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2D.1 when an R 2D.1 substituent group is substituted, the R 2D.1 substituent group is substituted with one or more second substituent groups denoted by R 2D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2D.2 substituent group when an R 2D.2 substituent group is substituted, the R 2D.2 substituent group is substituted with one or more third substituent groups denoted by R 2D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2D , R 2D.1 , R 2D.2 , and R 2D.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 2D , R 2D.1 , R 2D.2 , and R 2D.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)”. In embodiments, 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 3 and R 4 substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R 3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3.1 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)”.
  • R 3.2 substituent group when an R 3.2 substituent group is substituted, the R 3.2 substituent group is substituted with one or more third substituent groups denoted by R 3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3.1 , R 3.2 , and R 3.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 3.1 , R 3.2 , and R 3.3 , respectively.
  • R 3 and R 4 substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), 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 first substituent groups
  • R 4.2 second substituent groups
  • 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 4.1 , R 4.2 , and R 4.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 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 8 , R 8.1 , R 8.2 , and R 8.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 8 , R 8.1 , R 8.2 , and R 8.3 , respectively.
  • R 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 70.1 substituent group when an R 70.1 substituent group is substituted, the R 70.1 substituent group is substituted with one or more second substituent groups denoted by R 70.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 70.2 substituent group is substituted, the R 70.2 substituent group is substituted with one or more third substituent groups denoted by R 70.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 80 , R 80.1 , R 80.2 , and R 80.3 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 80 , R 80.1 , R 80.2 , and R 80.3 , respectively.
  • R 90 when R 90 is substituted, R 90 is substituted with one or more first substituent groups denoted by R 90.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L3.1 substituent group when an R L3.1 substituent group is substituted, the R L3.1 substituent group is substituted with one or more second substituent groups denoted by R L3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L3.2 substituent group when an R L3.2 substituent group is substituted, the R L3.2 substituent group is substituted with one or more third substituent groups denoted by R L3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • L 6 , R L6.1 , R L6.2 , and R L6.3 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 6 , R L6.1 , R L6.2 , and R L6.3 , respectively.
  • the compound has the formula: O
  • the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VII), (VIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including all embodiments thereof.
  • IV. Methods of use [0366] In an aspect is provided a method of treating a 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, or a pharmaceutically acceptable salt thereof.
  • the cancer is an estrogen receptor positive cancer.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is endometrial cancer.
  • the cancer is uterine cancer.
  • the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), or (Vb), including all embodiments thereof.
  • the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VII), (VIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including all embodiments thereof.
  • a method of increasing the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject including administering to the subject a compound, or a pharmaceutically acceptable salt thereof, having the formula:
  • W is O or NH.
  • R 50 , R 60 , R 70 , and R 80 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OC
  • the method includes administering to the subject a compound, or a pharmaceutically acceptable salt thereof, having the formula: [0373]
  • W is O.
  • W is NH.
  • a substituted R 50 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • W is NH.
  • a substituted R 50 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 50 when R 50 is substituted, it is substituted with at least one substituent group. In embodiments, when R 50 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 50 is substituted, it is substituted with at least one lower substituent group.
  • R 50 is hydrogen. In embodiments, R 50 is halogen. In embodiments, R 50 is –F. In embodiments, R 50 is –Cl. In embodiments, R 50 is –Br. In embodiments, R 50 is –I. In embodiments, R 50 is –CCl 3 . In embodiments, R 50 is –CBr 3 . In embodiments, R 50 is –CF3.
  • R 50 is –CI3. In embodiments, R 50 is -CH2Cl. In embodiments, R 50 is -CH 2 Br. In embodiments, R 50 is -CH 2 F. In embodiments, R 50 is -CH 2 I. In embodiments, R 50 is -CHCl2. In embodiments, R 50 is -CHBr2. In embodiments, R 50 is -CHF 2 . In embodiments, R 50 is -CHI 2 . In embodiments, R 50 is –CN. In embodiments, R 50 is –OH. In embodiments, R 50 is -NH2. In embodiments, R 50 is –COOH. In embodiments, R 50 is -CONH 2 . In embodiments, R 50 is -NO 2 .
  • R 50 is –SH. In embodiments, R 50 is –SO3H. In embodiments, R 50 is –OSO3H. In embodiments, R 50 is -SO 2 NH 2 . In embodiments, R 50 is ⁇ NHNH 2 . In embodiments, R 50 is ⁇ ONH 2 . In embodiments, R 50 is ⁇ NHC(O)NH2. In embodiments, R 50 is -NHSO2H. In embodiments, R 50 is -NHC(O)H. In embodiments, R 50 is -NHC(O)OH. In embodiments, R 50 is –NHOH. In embodiments, R 50 is –OCCl 3 . In embodiments, R 50 is –OCBr 3 .
  • R 50 is –OCF3. In embodiments, R 50 is –OCI3. In embodiments, R 50 is -OCH2Cl. In embodiments, R 50 is -OCH 2 Br. In embodiments, R 50 is -OCH 2 F. In embodiments, R 50 is -OCH 2 I. In embodiments, R 50 is -OCHCl2. In embodiments, R 50 is -OCHBr2. In embodiments, R 50 is -OCHF 2 . In embodiments, R 50 is -OCHI 2 . In embodiments, R 50 is -SF 50 . In embodiments, R 50 is –N3. In embodiments, R 50 is unsubstituted C1-C4 alkyl.
  • R 50 is unsubstituted methyl. In embodiments, R 50 is unsubstituted ethyl. In embodiments, R 50 is unsubstituted propyl. In embodiments, R 50 is unsubstituted n-propyl. In embodiments, R 50 is unsubstituted isopropyl. In embodiments, R 50 is unsubstituted butyl. In embodiments, R 50 is unsubstituted n-butyl. In embodiments, R 50 is unsubstituted isobutyl. In embodiments, R 50 is unsubstituted tert-butyl.
  • R 60 when R 60 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 60 is substituted, it is substituted with at least one lower substituent group.
  • R 60 is hydrogen. In embodiments, R 60 is halogen. In embodiments, R 60 is –F. In embodiments, R 60 is –Cl. In embodiments, R 60 is –Br. In embodiments, R 60 is –I. In embodiments, R 60 is –CCl3. In embodiments, R 60 is –CBr3. In embodiments, R 60 is –CF3. In embodiments, R 60 is –CI3. In embodiments, R 60 is -CH2Cl.
  • R 60 is -CH2Br. In embodiments, R 60 is -CH2F. In embodiments, R 60 is -CH2I. In embodiments, R 60 is -CHCl2. In embodiments, R 60 is -CHBr2. In embodiments, R 60 is -CHF 2 . In embodiments, R 60 is -CHI 2 . In embodiments, R 60 is –CN. In embodiments, R 60 is –OH. In embodiments, R 60 is -NH2. In embodiments, R 60 is –COOH. In embodiments, R 60 is -CONH 2 . In embodiments, R 60 is -NO 2 . In embodiments, R 60 is –SH. In embodiments, R 60 is –SO3H.
  • R 60 is –OSO3H. In embodiments, R 60 is -SO2NH2. In embodiments, R 60 is ⁇ NHNH2. In embodiments, R 60 is ⁇ ONH2. In embodiments, R 60 is ⁇ NHC(O)NH2. In embodiments, R 60 is -NHSO2H. In embodiments, R 60 is -NHC(O)H. In embodiments, R 60 is -NHC(O)OH. In embodiments, R 60 is –NHOH. In embodiments, R 60 is –OCCl 3 . In embodiments, R 60 is –OCBr 3 . In embodiments, R 60 is –OCF3. In embodiments, R 60 is –OCI3.
  • R 60 is -OCH2Cl. In embodiments, R 60 is -OCH 2 Br. In embodiments, R 60 is -OCH 2 F. In embodiments, R 60 is -OCH 2 I. In embodiments, R 60 is -OCHCl2. In embodiments, R 60 is -OCHBr2. In embodiments, R 60 is -OCHF 2 . In embodiments, R 60 is -OCHI 2 . In embodiments, R 60 is –SF 5 . In embodiments, R 60 is –N3. In embodiments, R 60 is unsubstituted C1-C4 alkyl. In embodiments, R 60 is unsubstituted methyl. In embodiments, R 60 is unsubstituted ethyl.
  • R 60 is unsubstituted propyl. In embodiments, R 60 is unsubstituted n-propyl. In embodiments, R 60 is unsubstituted isopropyl. In embodiments, R 60 is unsubstituted butyl. In embodiments, R 60 is unsubstituted n-butyl. In embodiments, R 60 is unsubstituted isobutyl. In embodiments, R 60 is unsubstituted tert-butyl.
  • a substituted R 70 (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 70 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 70 is substituted, it is substituted with at least one substituent group.
  • R 70 when R 70 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 70 is substituted, it is substituted with at least one lower substituent group.
  • R 70 is hydrogen. In embodiments, R 70 is halogen. In embodiments, R 70 is –F. In embodiments, R 70 is –Cl. In embodiments, R 70 is –Br. In embodiments, R 70 is –I. In embodiments, R 70 is –CCl3. In embodiments, R 70 is –CBr3. In embodiments, R 70 is –CF3. In embodiments, R 70 is –CI3. In embodiments, R 70 is -CH2Cl.
  • R 70 is -OCH2Cl. In embodiments, R 70 is -OCH 2 Br. In embodiments, R 70 is -OCH 2 F. In embodiments, R 70 is -OCH 2 I. In embodiments, R 70 is -OCHCl2. In embodiments, R 70 is -OCHBr2. In embodiments, R 70 is -OCHF 2 . In embodiments, R 70 is -OCHI 2 . In embodiments, R 70 is –SF 5 . In embodiments, R 70 is –N3. In embodiments, R 70 is unsubstituted C1-C4 alkyl. In embodiments, R 70 is unsubstituted methyl. In embodiments, R 70 is unsubstituted ethyl.
  • R 70 is unsubstituted propyl. In embodiments, R 70 is unsubstituted n-propyl. In embodiments, R 70 is unsubstituted isopropyl. In embodiments, R 70 is unsubstituted butyl. In embodiments, R 70 is unsubstituted n-butyl. In embodiments, R 70 is unsubstituted isobutyl. In embodiments, R 70 is unsubstituted tert-butyl.
  • R 80 is –OSO3H. In embodiments, R 80 is -SO2NH2. In embodiments, R 80 is ⁇ NHNH2. In embodiments, R 80 is ⁇ ONH2. In embodiments, R 80 is ⁇ NHC(O)NH2. In embodiments, R 80 is -NHSO2H. In embodiments, R 80 is -NHC(O)H. In embodiments, R 80 is -NHC(O)OH. In embodiments, R 80 is –NHOH. In embodiments, R 80 is –OCCl 3 . In embodiments, R 80 is –OCBr 3 . In embodiments, R 80 is –OCF3. In embodiments, R 80 is –OCI3.
  • R 80 is unsubstituted propyl. In embodiments, R 80 is unsubstituted n-propyl. In embodiments, R 80 is unsubstituted isopropyl. In embodiments, R 80 is unsubstituted butyl. In embodiments, R 80 is unsubstituted n-butyl. In embodiments, R 80 is unsubstituted isobutyl. In embodiments, R 80 is unsubstituted tert-butyl. [0382] In embodiments, R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted C1-C4 alkyl.
  • R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted methyl.
  • the compound is a compound described herein.
  • the compound has the formula: O O Cl N O O the has the formula: .
  • the compound has the formula: .
  • the compound has the .
  • the compound has the In embodiments, the compound has the .
  • the compound has the has the .
  • the compound has the odiments, the compound has the .
  • the in a subject is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50- , 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by about 1.5-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3- 3 protein–ER ⁇ protein complex in a subject is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by about 25-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by about 1000-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ER ⁇ protein complex in a subject is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by at least 10-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein– ER ⁇ protein complex in a subject is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a subject is increased by at least 1000-fold relative to a control (e.g., absence of the compound).
  • a method of increasing the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, having the formula: R 2 , embodiments.
  • the method includes contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, having the formula:
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound).
  • a control e.g., absence of the compound.
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ER ⁇ protein complex in a cell is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 10-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ER ⁇ protein complex in a cell is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by about 250-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ER ⁇ protein complex in a cell is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 10-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ER ⁇ protein complex in a cell is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 250-fold relative to a control (e.g., absence of the compound).
  • the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ER ⁇ protein complex in a cell is increased by at least 1000-fold relative to a control (e.g., absence of the compound).
  • a method of forming a 14-3-3 protein–ER ⁇ protein– compound complex including combining a 14-3-3 protein, an ER ⁇ protein, and a compound, or a pharmaceutically acceptable salt thereof, in a reaction vessel, cell, or organism, thereby forming the 14-3-3 protein–ER ⁇ protein–compound complex bound together noncovalently; wherein the compound has the formula:
  • the compound has the formula: [0393] In an aspect is provided a method of stabilizing a 14-3-3 protein–ER ⁇ protein complex, the method including contacting the 14-3-3 protein–ER ⁇ protein complex with a compound, or a pharmaceutically acceptable salt thereof, thereby stabilizing the 14-3-3 protein–ER ⁇ protein complex; wherein the compound has the formula: R 2 , embodiments. [0394] In embodiments, the compound has the formula:
  • the stabilizing occurs in a cell. In embodiments, the stabilizing occurs in an organism. In embodiments, the stabilizing occurs in a cell in an organism. [0396] In embodiments, the compound binds to C38 of the 14-3-3 ⁇ (e.g., human 14-3-3 ⁇ ) protein. In embodiments, the compound binds covalently to C38 of the 14-3-3 ⁇ (e.g., human 14-3-3 ⁇ ) protein. V. Embodiments [0397] Embodiment P1.
  • Embodiment P2 The compound of embodiment P1, having the formula: . of embodiment P1, having the formula: R 1 L 2 2 L 1 R A R 3 R 4 H . P1, having the formula: . of embodiments P1 to P4, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Embodiment P7 The compound of one of embodiments P1 to P6, wherein , R 2 is halogen.
  • Embodiment P9 The compound of one of embodiments P1 to P7, wherein R 2 is -Cl.
  • Embodiment P10 The compound of one of embodiments P1 to P9, wherein R 3 and R 4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • Embodiment P11 The compound of one of embodiments P1 to P9, wherein R 3 and R 4 combine to form a substituted or unsubstituted tetrahydropyranyl.
  • Embodiment P1 to P1 1 2 wherein L is a bond or unsubstituted C 1 -C 4 alkylene.
  • Embodiment P14 The compound of one of embodiments P1 to P12, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment P15 The compound of one of embodiments P1 to P14, wherein L 2 is a bond.
  • Embodiment P16 The compound of one of embodiments P1 to P15, wherein R 1 is E.
  • Embodiment P17 The compound of embodiment P16, wherein E is O R 11
  • Embodiment P18 The compound of embodiment P17, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment P19 The compound of one of embodiments P1 to P16, wherein R 1 is O Cl .
  • L 2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 20 -, -C(O)NR 20 -, -NR 20 C(O)-, -NR 20 C(O)O-, -OC(O)NR 20 -, -NR 20 C(O)NR 20 -, -S(O) 2 -, -NR 20 S(O) 2 -, -S(O) 2 NR 20 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene;
  • Embodiment P22 The compound of embodiment P21, having the formula: (IIb).
  • Embodiment P24 The compound of embodiment P21, having the formula: . of embodiment P21, having the formula: . is halogen.
  • Embodiment P27 The compound of one of embodiments P21 to P25, wherein R 2 is -Cl.
  • Embodiment P28 The compound of one of embodiments P21 to P27, wherein L 1 is a bond or unsubstituted C1-C4 alkylene.
  • Embodiment P29 The compound of one of embodiments P21 to P27, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment P30 The compound of one of embodiments P21 to P29, wherein L 2 is a bond.
  • Embodiment P31 The compound of one of embodiments P21 to P30, wherein R 1 is E.
  • Embodiment P32 The compound of embodiment P31, wherein E is
  • Embodiment P33 The compound of embodiment P32, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment P34 The compound of one of embodiments P21 to P30, wherein R 1 . P35.
  • the compound of embodiment P21 having the formula: , [0 3 ] mbod ment 36. p armaceut ca compos t on compr s ng t e compound of one of embodiments P1 to P35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment P37 Embodiment P37.
  • Ring A and Ring B are independently a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; W is O or NH; L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene, substituted or unsub
  • Embodiment P41 A method of increasing the level of a 14-3-3 protein–ER ⁇ protein complex in a cell, said method comprising contacting the cell with a compound, or a salt thereof, having the formula: Ring A and Ring B are independently a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene, substituted or un
  • Embodiment P46 The method of one of embodiments P40 to P44, wherein R 3 and R 4 combine to form a substituted or unsubstituted tetrahydropyranyl.
  • Embodiment P47 The method of one of embodiments P40 to P44, wherein R 3 and . one of embodiments P40 to P41, wherein W is O.
  • Embodiment P49 The method of one of embodiments P40 to P41, wherein W is NH.
  • Embodiment P50 The method of one of embodiments P40 to P41 and P48 to P49, wherein R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment P51 The method of one of embodiments P40 to P41 and P48 to P49, wherein R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted methyl.
  • Embodiment P52 The method of one of embodiments P40 to P51, wherein R 2 is independently halogen.
  • Embodiment P53 Embodiment P53.
  • Embodiment P54 The method of one of embodiments P40 to P53, wherein z2 is 1.
  • Embodiment P55 The method of one of embodiments P40 to P54, wherein L 1 is a bond or unsubstituted C1-C4 alkylene.
  • Embodiment P56 The method of one of embodiments P40 to P54, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment P57 The method of one of embodiments P40 to P56, wherein L 2 is a bond.
  • Embodiment P58 The method of one of embodiments P40 to P57, wherein R 1 is E.
  • Embodiment P59 The method of embodiment P58, wherein E is O R 11
  • R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH 2 F, -OCH
  • Embodiment P60 The method of embodiment P59, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment P61 The method of one of embodiments P40 to P58, wherein R 1 is O .
  • Embodiment 1 A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkylene,
  • Embodiment 2 The compound of embodiment 1, having the formula: . of embodiment 1, having the formula: R 1 2 1 L R 2 L . 1, having the formula: c). e of embodiments 1 to 4, wherein Ring A is a substituted or unsubstituted C 3 -C 8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Embodiment 6 The compound of one of embodiments 1 to 5, wherein Ring B is a substituted or unsubstituted C 3 -C 8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Embodiment 9 The compound of one of embodiments 1 to 6, wherein , R 2 is halogen.
  • Embodiment 9. The compound of one of embodiments 1 to 7, wherein R 2 is -Cl.
  • Embodiment 10. The compound of one of embodiments 1 to 9, wherein R 3 and R 4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • Embodiment 11. The compound of one of embodiments 1 to 9, wherein R 3 and R 4 combine to form a substituted or unsubstituted tetrahydropyranyl.
  • Embodiment 12. The compound of one of embodiments 1 to 9, wherein R 3 and .
  • Embodiment 14 The compound of one of embodiments 1 to 12, wherein L 1 is a bond or unsubstituted C1-C4 alkylene.
  • Embodiment 15 The compound of one of embodiments 1 to 14, wherein L 2 is a bond.
  • Embodiment 16 The compound of one of embodiments 1 to 15, wherein R 1 is E.
  • Embodiment 18 The compound of embodiment 17, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment 19 The compound of one of embodiments 1 to 16, wherein R 1 is O Cl .
  • armaceutically acceptable salt thereof having the formula: - -, - , - -, - , - , - , - , - -, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, 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;
  • L 2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 20 -
  • Embodiment 22 The compound of embodiment 21, having the formula: (IIb). (IIIa).
  • Embodiment 24 The compound of embodiment 21, having the formula: ). d of embodiment 21, having the formula: . is halogen.
  • Embodiment 27 The compound of one of embodiments 21 to 25, wherein R 2 is -Cl.
  • Embodiment 28 The compound of one of embodiments 21 to 27, wherein L 1 is a bond or unsubstituted C1-C4 alkylene.
  • Embodiment 29 The compound of one of embodiments 21 to 27, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment 30 The compound of one of embodiments 21 to 27, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment 31 The compound of one of embodiments 21 to 30, wherein R 1 is E.
  • Embodiment 32 The compound of embodiment 31, wherein E is O R 11
  • Embodiment 33 The compound of embodiment 32, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment 34 The compound of one of embodiments 21 to 30, wherein R 1 is . 35.
  • L 2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 20 -, -C(O)NR 20
  • Embodiment 37 The compound of embodiment 36, having the formula: (VIIa). bodiment 36, having the formula: (VIIIa). embodiment 36, having the formula: (VIIIb). embodiment 36, having the formula: . 36, having the formula: O . 36, having the formula: (VIIIe). embodiment 36, having the formula: R 3 R 4 (R 2 ) L 5 z2 . 36 to 43, wherein L 4 is -O-.
  • Embodiment 45 The compound of one of embodiments 36 to 43, wherein L 4 is -NH-.
  • Embodiment 46 Embodiment 46.
  • Embodiment 47 The compound of one of embodiments 36 and 38 to 45, wherein L 5 is –NH- or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment 47 The compound of one of embodiments 36 and 38 to 45, .
  • R 2 is independently halogen, -CX 2 3, -C(O)R 2C , -C(O)OR 2C , -OR 2D , substituted or unsubstituted C1- C 4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • Embodiment 49 Embodiment 49.
  • Embodiment 50 The compound of one of embodiments 36 to 47, wherein R 2 is independently –Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3.
  • Embodiment 50 The compound of one of embodiments 36 to 47, wherein z2 is 0.
  • Embodiment 51 The compound of one of embodiments 36 to 49, wherein z2 is 1.
  • Embodiment 52 The compound of one of embodiments 36 to 49, wherein z2 is 2.
  • Embodiment 53 The compound of one of embodiments 36 to 52, wherein R 3 and R 4 are independently unsubstituted C1-C4 alkyl.
  • Embodiment 54 The compound of one of embodiments 36 to 52, wherein R 3 and R 4 are independently unsubstituted C1-C4 alkyl.
  • Embodiment 55 The compound of one of embodiments 36 to 52, wherein R 3 and R 4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • Embodiment 56 The compound of one of embodiments 36 to 52, wherein R 3 and R 4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • Embodiment 57 The compound of one of embodiments 36 to 52, wherein R 3 and R 4 combine to form: NH 2 . 57, wherein L 1 is a bond.
  • Embodiment 59 The compound of one of embodiments 36 to 58, wherein L 2 is a bond.
  • Embodiment 60 The compound of one of embodiments 36 to 59, wherein R 1 is -C(NR 1C )NR 1A R 1B or -C(O)NR 1A R 1B .
  • Embodiment 61 The compound of one of embodiments 36 to 59, wherein R 1 is -C(NH)NH 2 , -C(NH)NHOH, or –C(O)NH 2 .
  • Embodiment 62 The compound of one of embodiments 36 to 59, wherein R 1 is -C(NH)NH2.
  • Embodiment 63 Embodiment 63.
  • Embodiment 64 A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof.
  • Embodiment 65 The method of embodiment 64, wherein the cancer is an estrogen receptor positive cancer.
  • Embodiment 66 The method of embodiment 64, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.
  • Embodiment 67 A method of increasing the level of a 14-3-3 protein–ER ⁇ protein complex in a subject, said method comprising administering to said subject a compound, or a pharmaceutically acceptable salt thereof, having the formula:
  • W is O or NH;
  • L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted
  • Embodiment 68 A method of increasing the level of a 14-3-3 protein–ER ⁇ protein complex in a cell, said method comprising contacting the cell with a compound, or a salt thereof, having the formula: substituted or unsubstituted heterocycloalkylene; L 1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -NR 10 C(O)O-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -S(O) 2 -, -NR 10 S(O) 2 -, -S(O) 2 NR 10 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene
  • Embodiment 69 The method of one of embodiments 67 to 68, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Embodiment 70 The method of one of embodiments 67 to 69, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Embodiment 71 Embodiment 71.
  • Embodiment 73 The method of one of embodiments 67 to 71, wherein R 3 and R 4 combine to form a substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl.
  • Embodiment 74 The method of one of embodiments 67 to 71, wherein R 3 and NH 2 , W is O.
  • Embodiment 76 The method of one of embodiments 67 to 68, wherein W is NH.
  • Embodiment 77 The method of one of embodiments 67 to 68 and 75 to 76, wherein R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment 78 Embodiment 78.
  • Embodiment 80 The method of one of embodiments 67 to 68 and 75 to 76, wherein R 50 , R 60 , R 70 , and R 80 are independently hydrogen or unsubstituted methyl.
  • Embodiment 79 The method of one of embodiments 67 to 78, wherein R 2 is independently halogen, -CX 2 3, -C(O)R 2C , -C(O)OR 2C , -OR 2D , substituted or unsubstituted C1- C 4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • Embodiment 80 Embodiment 80.
  • Embodiment 81 The method of one of embodiments 67 to 78, wherein R 2 is independently -Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3.
  • Embodiment 81 The method of one of embodiments 67 to 78, wherein z2 is 0.
  • Embodiment 82 The method of one of embodiments 67 to 80, wherein z2 is 1.
  • Embodiment 83 The method of one of embodiments 67 to 80, wherein z2 is 2.
  • Embodiment 84 The method of one of embodiments 67 to 78, wherein z2 is 2.
  • Embodiment 85 The method of one of embodiments 67 to 82, wherein L 1 is a bond or unsubstituted C 1 -C 4 alkylene.
  • Embodiment 85 The method of one of embodiments 67 to 82, wherein L 1 is a bond or unsubstituted methylene.
  • Embodiment 86 The method of one of embodiments 67 to 85, wherein L 2 is a bond.
  • Embodiment 87 The method of one of embodiments 67 to 86, wherein R 1 is E.
  • Embodiment 88 Embodiment 88.
  • E is O R 11 -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted al
  • Embodiment 89 The method of embodiment 88, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen.
  • Embodiment 90 The method of one of embodiments 67 to 87, wherein R 1 is O Cl .
  • Embodiment 92 The method of one of embodiments 67 to 86, wherein R 1 is -C(NH)NH2, -C(NH)NHOH, or –C(O)NH2.
  • Embodiment 93 Embodiment 93.
  • Embodiment 94 The method of one of embodiments 67 to 68, wherein the compound has the formula: O O Cl Cl
  • PPIs are considered particularly difficult targets for small molecules, due to the large, usually hydrophobic, surfaces, the lack of suitable deep pockets and the difficulty in identifying new chemical matter to target them (4).
  • modulation of PPIs has emerged as an attractive strategy both in chemical biology and drug discovery (5-7).
  • chemical biology the inhibition or stabilization of specific PPIs allows the study of complex networks and the dissection of certain functions.
  • drug discovery induced proximity of PPI, as with molecular glue and PROTAC degraders, have successfully provided an alternative approach for targeting “undruggable” protein targets (8-10).
  • hub proteins that have the ability to interact with numerous protein clients, typically via intrinsically disordered regions and post-translational modifications (11-13).
  • the extensive interactome of hub proteins provides tremendous potential for drug discovery, but at the same time raises the question of selective targeting, since the underlying biology might be intertwined and the molecular recognition principles within a hub protein’s PPI network are potentially based on similar chemical motifs.
  • 14-3-3 is a dimeric hub protein that binds to its clients via their phospho-serine or phospho-threonine sites and upon binding creates order in these disordered client regions (17,18).14-3-3 is involved in the regulation of transcription factors, cell signaling, cell cycle progression, signal-transduction pathways, and protein stability (19-24). In humans, 14-3-3 is present via seven highly conserved isoforms with seemingly overlapping functions (23,26).
  • the sigma ( ⁇ ) isoform is often associated with the role of tumor suppressor (27- 29), and there is evidence of downregulation or degradation in certain types of cancer (30- 32).
  • the sigma isoform has a native cysteine residue in the central binding channel that accommodates the phosphorylated client protein (position Cys38).
  • this cysteine can be used as a handle for selective targeting of 14-3-3 ⁇ .
  • ER ⁇ estrogen-receptor alpha
  • ER ⁇ In breast cancer treatments, blocking the function of ER ⁇ is a well- established strategy and includes small molecules that bind to the ligand-binding pocket of ER ⁇ . However, inhibition of ER ⁇ in this manner often leads to the development of resistance (33,34).
  • An alternative approach for modulating ER ⁇ function could be the stabilization of the interaction between 14-3-3 and ER ⁇ , since 14-3-3 is a known negative regulator of ER ⁇ (25).14-3-3 binds at the extreme C-terminus of the receptor via the recognition of the penultimate threonine (ER ⁇ -T594). As a result, at a cellular level, cell growth and receptor/DNA interactions are modulated (25).
  • a crystallography-based fragment screen identified amidine fragments, that although weak stabilizers, selectively bound to 14-3-3/p53-peptide or 14-3- 3/TAZ-peptide complexes (36).
  • a second crystallography screen identified aldehyde- containing fragments that targeted a conserved lysine residue on 14-3-3 in close proximity to the client protein binding-site and stabilized the 14-3-3/p65 complex (37).
  • Disulfide tethering (38,39) has been applied both to engineered cysteine residues and the native cysteine of the 14-3-3 ⁇ isoform to identify fragment stabilizers of 14-3-3/ER ⁇ (40).
  • Disulfide tethering can be used to target 14-3-3/client interactions with diverse shapes and binding modes.
  • the native cysteine (Cys38) at the periphery of the peptide- binding groove on 14-3-3 ⁇ (FIG.1A) was targeted with a library consisting of ⁇ 1600 disulfide fragments and both client-selective and general stabilizing fragments were identified.
  • a non-selective disulfide fragment (917949) was able to stabilize both 14-3-3/ ⁇ R ⁇ and 14-3-3/C-RAF peptide complexes.
  • the disulfide fragment showed preferential stabilization for C-RAF (38-fold stabilization for C-RAF and 4-fold stabilization for ER ⁇ at 100 ⁇ compound), the crystal structures showed a similar binding mode with both clients.
  • Modifications (3) and (4), at the protein – peptide interface focused on optimizing the substituents in close proximity to the client peptides (protein/peptide interface), aiming to increase cooperativity and selectivity via specific interactions with the client of 14-3-3.
  • the last modification (5) was the rigidification of the linkers, aiming to “lock” the compounds’ conformations, resulting in the best stabilizer of the series, compound 1083744.
  • Representative examples of the compound evolution and their cocrystal structures with 14-3-3 ⁇ /ER ⁇ are shown in FIG.1C.
  • Two orthogonal assays were developed for screening.
  • the 1C-chloroacetamide warhead was selected, since it showed most consistency in the mass spectrometry and FA assays (FIG.2E).
  • the linker length we focused on the potential effect of the warhead reactivity in stabilization.
  • the more reactive ⁇ -chloroketone analog (1074203) was synthesized and tested.
  • the compound showed remarkably faster kinetics, however this correlated with increased binding with 14-3-3 in the absence of peptides, thus significantly lacking cooperativity for the PPI.
  • the compound was considered a “neutral binder” in the mass spectrometry assay.
  • compound 1083744 showed remarkable selectivity for 14-3-3/ER ⁇ (115- fold stabilization at 100 ⁇ M compound) compared to the other clients (fold-stabilization varied from 0 to 15-fold).
  • An overlay with the other peptides indicates the lack of favorable interactions and shape complementarity (FIG.8).
  • FC-A Fusicoccin-A
  • 1083744 is forming polar interactions both with 14-3-3 and ER ⁇ via the water network, whereas FC-A forms hydrogen bonds with Asp215 and Lys122 directly (FIG.
  • Example 2 Experimental procedures for Example 1 [0583] Protein expression and purification [0584] The 14-3-3 ⁇ isoform (full-length for mass spectrometry and fluorescence anisotropy assays, ⁇ C for crystallography) with an N-terminal His6 tag was expressed in Rosetta TM 2(DE3)pLysS competent E. coli (Novagen) from a pPROEX HTb expression vector.
  • the His6-tagged protein was purified by Ni-affinity chromatography (Ni-NTA Agarose, Invitrogen) (Wash buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 1 mM TCEP; Elution buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 500 mM imidazole, 1 mM TCEP) and analyzed for purity by SDS-PAGE and Q-Tof LC/MS.
  • Ni-NTA Agarose, Invitrogen Wash buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 1 mM TCEP
  • Elution buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 500 mM imidazole, 1 mM TCEP Elution buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 500 mM imidazole,
  • the protein was buffer exchanged (Storage buffer 25 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP) and concentrated to ⁇ 16 mg/mL and aliquotsflash-frozen for storage at ⁇ 80 °C.
  • the ⁇ C variant was truncated at the C-terminus after T231 to enhance crystallization and after the first Ni- affinity chromatography column, the construct was treated with TEV protease to cleave of the His6 tag during dialysis (25 mM HEPES, pH 7.5, 200 mM NaCl, 5% glycerol, 10 mM MgCl2, 250 ⁇ M TCEP) overnight at 4 °C.
  • Sequences were as follows: Ac- KYYITGEAEGFPA ⁇ pT ⁇ V-COOH (SEQ ID NO: 1) (ER ⁇ -pp), Ac-RQRST ⁇ pS ⁇ TPNVH- CONH 2 (CRAF pS259-pp). Peptides for X-ray crystallography and fluorescein-labeled peptides were purchased from GenScript Biotech Corp. Sequences were: Ac- or 5-FAM- AEGFPA ⁇ pT ⁇ V-COOH (SEQ ID NO: 2) (8mer ER ⁇ -pp) and QRST ⁇ pS ⁇ TPNVH-CONH 2 (SEQ ID NO: 3) (CRAF pS259-pp).
  • K d values of the fluorescently labeled peptides for 14-3- 3 ⁇ are 2 ⁇ M for ER ⁇ and 10 ⁇ M for C-RAF.
  • LC-MS dose response assays [0588] Mass spectrometry dose response assays were performed on a Waters Acquity UPLC/ Xevo G2-XS Q-Tof mass spectrometer. A Waters UPLC Protein BEH-C4 Column (300 ⁇ , 1.7 ⁇ m, 2.1 mm x 50 mm) was used to desalt the samples prior to application on the mass spectrometer.
  • Fluorescence anisotropy measurements [0590] Fluorescein-labeled peptides (5-FAM), 14-3-3 ⁇ FL protein, the compounds (50 mM stock solution in DMSO) were diluted in buffer (10 mM HEPES, pH 7.5, 150 mM NaCl, 0.1% Tween20, 1 mg/mL Bovine Serum Albumin (BSA; Sigma-Aldrich).
  • DMSO in the assay was always 1%.
  • Dilution series of 14-3-3 proteins or compounds were made in black, round-bottom 384-microwell plates (Corning) in a final sample volume of 10 ⁇ L in triplicates.
  • Compound titrations were made by titrating the compound in a 2-fold dilution series (starting at 500 or 1000 ⁇ M) to a mix of fluorescein-labeled peptide (10 nM) and 14-3- 3 ⁇ (concentration at EC 20 value of the protein-peptide complex; 1 ⁇ M for ER ⁇ and 5 ⁇ M for C-RAF). Fluorescence anisotropy measurements were performed directly and after overnight incubation at room temperature.
  • Protein titrations were made by titrating 14-3-3 ⁇ in a 2-fold dilution series (starting at 300 ⁇ M) to a mix of fluorescein-labeled peptide (10 nM) and DMSO or compound (100 ⁇ M). Fluorescence anisotropy measurements were performed after overnight incubation at room temperature. [0593] Protein 2D titrations were made by titrating 14-3-3 ⁇ in a 2-fold dilution series (starting at 300 ⁇ M) to a mix of fluorescein-labeled peptide (10 nM) against varying fixed concentrations of compound (2-fold dilution, starting at 250 ⁇ M), or DMSO.
  • Fluorescence anisotropy measurements were performed after overnight incubation at room temperature. [0594] Fluorescence anisotropy values were measured using a Tecan Infinite F500 plate reader (filter set lex: 485 ⁇ 20 nm, lem: 535 ⁇ 25 nm; mirror: Dichroic 510; flashes: 20; integration time: 50 ms; settle time: 0 ms; gain: 55; and Z-position: calculated from well). Wells containing only FAM-peptide were used to set as G-factor at 35 mP. Data reported are at endpoint. EC50 and apparent Kd values were obtained from fitting the data with a four- parameter logistic model (4PL) in GraphPad Prism 7 for Windows.
  • 4PL four- parameter logistic model
  • DMSO or compound concentrations were matched in the cell and syringe till 500 ⁇ M of compound and 1% DMSO.
  • Samples were degassed at 450 mmHg, 10 minutes prior to measurement. Measurements were performed on an Affinity ITC LV (TA instruments), with injection size set to 2 ⁇ L, stirring speed of 150 rpm and temperature at 25 °C. The data was processed and analyzed with NanoAnalyze v3.11. The baseline was manually inspected and corrected, after which a blank constant model was fitted to correct for the heat of injection. Subsequently, an independent model was fitted, which the NanoAnalyze software uses to report the thermodynamic binding properties reported in this paper.
  • the complex was set up for sitting- drop crystallization after overnight incubation at 4 °C, in a custom crystallization liquor (0.095 M HEPES (pH 7.1, 7.3, 7.5, 7.7), 0.19 M CaCl 2 , 24-29 % PEG 400 and 5% (v/v) glycerol). Crystals grew within 10 – 14 days at 4 °C. Crystals were fished and flash-cooled in liquid nitrogen.
  • X-ray diffraction (XRD) data were collected at either an in-house system Rigaku Micromax-003 (Rigaku, Europe, Kemsing Sevenoaks, UK) equipped with an Dectris Pilatus 200K detector, the Deutsche Elektronen-Synchrotron (DESY) Petra III beamline P11, Hamburg, Germany, the European Synchrotron Radiation Facility (ESRF Grenoble, France, beamline ID23-2, ID30A-1/MASSIF-1 or beamline ID30B/MAD) or at Diamond Light Source (DLS) (Oxfordshire, United Kingdom, beamline I03).
  • the images were created using the PyMOL Molecular Graphics System (Schrödinger LLC, version 2.2.3).
  • the structures were deposited in the protein data bank (PDB) with IDs: 8AV7 (1074202 non-covalent), 8AWG (1074202 covalent), 8AXE (1074210), 8ANF (1074359), 8ARO (1080291), 8AI0 (1080268), 8ARX (1074378), 8ARZ (1076406), 8AT9 (1080269), 8AXU (1075297 - ER ⁇ ), 8ATR (1075297 – C-RAF), 8AZE (1075306 – ER ⁇ ), 8ATS (1075306 – C-RAF), 8AV8 (1075300), 8ALR (1080272), 8ARY (1080273), 8ALV (1076403), 8AV3 (1075299), 8ALT (1075311), 8AV4 (1075305), 8ALW (1075310), 8AM7 (1076397), 8AS1 (1076398), 8ATP (107548
  • TFA (370 ⁇ l, 4.8 mmol, 20 equiv) was added dropwise. Stirring at 0 o C for 30 min, then rt for 2 h. Solvents were removed under reduced pressure and the obtained TFA salt was used directly in the next step.
  • Procedure G The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 o C, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 o C for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat.
  • TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 o C, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 o C for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 o C, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 o C for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • Procedure G The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 o C, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 o C for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO 3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure.
  • the reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H 2 O – CH 3 CN + 0.05% formic acid, gradient 30-100% CH 3 CN in H 2 O, 20 min total).
  • the amine HCl salt (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 o C for 30 min, then rt for 2 h. The reaction mixture was diluted with sat. NH 4 Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total).
  • tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride 159 (1 mmol, 1.0 equiv) was dissolved in 5 ml dry DCM. DIPEA (3 equiv, 3 mmol) was added. The reaction mixture was cooled at 0 o C and chloroacetyl chloride 25 (1.2 equiv, 1.2 mmol) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO 3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure.
  • the amine HCl salt (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H 2 O – CH 3 CN + 0.05% formic acid, gradient 30-100% CH 3 CN in H 2 O, 20 min total).
  • the reaction mixture was diluted with sat. NH 4 Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure.
  • the obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step.
  • the obtained product was suspended in 1.5 ml HCl/dioxane (4N) for Boc-deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step.
  • the HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv) was added. The reaction mixture was cooled at 0 o C and chloroacetyl chloride 25 (1.2 equiv) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH 3 CN in H 2 O, 20 min total).
  • the obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step.
  • the obtained product was suspended in 1.5 ml HCl/dioxane (4 N) for Boc-deprotection. Stirring rt for 3h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step.
  • the HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv) was added. The reaction mixture was cooled at 0 o C and chloroacetyl chloride 25 (1.2 equiv) was added slowly. Stirring rt for 4 h.
  • a Reagents and conditions (a) tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (169), chloroacetyl chloride (25), DIPEA, DCM, 0 o C to rt, 4 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 o C to rt, 2 h. [0901] Procedure A. Tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 169 (1 mmol, 1 equiv) was dissolved in 5 ml dry DCM.

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Abstract

Described herein, inter alia, are stabilizers of protein-protein interactions and methods of using the same.

Description

PATENT Attorney Docket No.: 048536-763001WO PROTEIN-PROTEIN INTERACTION STABILIZERS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/452,329, filed March 15, 2023, and U.S. Provisional Application No.63/526,918, filed July 14, 2023, which are incorporated herein by reference in their entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (048536- 763001WO_Sequence_Listing_ST26.xml; Size: 22,292 bytes; and Date of Creation: March 6, 2024) is hereby incorporated by reference in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0003] This invention was made with government support under R01 GM147696 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0004] The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. For hub proteins, such as 14-3-3, that interact with hundreds of other proteins, the identification of suitable starting points for stabilizing specific interactions can be challenging. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY [0005] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: . are a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene. [0007] L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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. [0008] L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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. [0009] L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0010] L4 is –NR40- or -O-. [0011] R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E. [0012] E is an electrophilic moiety. [0013] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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. [0014] The symbol z2 is an integer from 0 to 5. [0015] R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. [0016] Each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0017] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0018] Each X1 and X2 is independently –F, -Cl, -Br, or –I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols m1, m2, v1, and v2 are independently 1 or 2. [0019] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: [0020] R5, R6, R7, and R8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbol z5 is an integer from 0 to 5. [0021] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: R6 [0022] L5 is –NR90- or substituted or unsubstituted heteroalkylene. [0023] R90 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0024] L6 is a bond or substituted or unsubstituted heteroarylene. [0025] The symbol z5 is an integer from 0 to 4. The symbol z6 is an integer from 0 to 2. [0026] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0027] In an aspect is provided a method of treating a 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, or a pharmaceutically acceptable salt thereof. [0028] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–ERα protein complex in a subject, the method including administering to the subject a compound, or a pharmaceutically acceptable salt thereof, having the formula: z2, [0029] W is O or NH. R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0030] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–ERα protein complex in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, having the formula: R2, embodiments. BRIEF DESCRIPTION OF THE DRAWINGS [0031] FIGS.1A-1E. FIG.1A: The binding groove of 14-3-3σ (grey surface). The position of the native cysteine (Cys38) is indicated in dark grey. FIG.1B: Chemical structure of the non-selective fragment stabilizer 917949 and key structural modifications (1-5) explored during the chemical optimization, aiming to increase the cooperativity with 14-3- 3σ/ERα and reduce the stabilization of 14-3-3σ/C-RAF. FIG.1C: Examples of compound evolution and crystallographic data starting from the disulfide fragment 917949 and resulting in potent and selective stabilizer 1083744. FIG.1D: Overview of the mass spectrometry assay (primary screening). Compound titrations were performed in the absence of peptide to determine % binding to 14-3-3σ (apo screening, D1) and then in the presence of both 14-3-3σ and peptide, as an indirect indication of stabilization (D2). Compounds that showed % bound D2>D1 were classified as stabilizers, whereas compounds for which % bound did not change significantly between D1 and D2 were classified as neutral binders. FIG.1E: Overview of the fluorescence anisotropy assay (confirmatory assay). Compound titrations were performed in the presence of 14-3-3σ (1 µM for ERα, 5 μΜ for C-RAF) and FAM-labeled peptides (10 nM). In the case of stabilizers, a dose-dependent increase in anisotropy was observed. No significant increase was observed for neutral binders. [0032] FIGS.2A-2E. FIG.2A: Chemical modifications (1) and (2) focused on replacing the disulfide tether with covalent warheads (i-iv) with varying linker lengths. FIG.2B: Mass spectrometry dose-response curves for the chloroacetamides (iv) with varying linker length (n = 0 – 3) after overnight incubation with 14-3-3σ/ΕRα and 14-3-3σ/C-RAF. Bar graphs of the mass spectrometry data at 100 nM compound concentration (1:1 ratio with the protein concentration), including the apo binding (plotted in black). FIG.2C: Fluorescence anisotropy (FA) dose-response curves for the chloroacetamides with varying linker length (n = 0 – 3) after overnight incubation with 14-3-3σ/ΕRα and 14-3-3σ/C-RAF. Bar graphs of FA compound titration EC50 values. FIG.2D: Crystal structures of the chloroacetamide analogs (iv) with varying linker length in complex with 14-3-3σ/ERα. Compounds are shown on the left; the C-terminus of ERα phosphopeptide is shown on the right. FIG.2E: Selected scaffold for further chemical optimization. [0033] FIGS.3A-3G. FIG.3A: Chemical modifications (3) and (4) replacing the gem- dimethyl group with cyclic, aliphatic groups and comparing ethers and anilines, aiming to increase the cooperativity with Val595 of ERα via hydrophobic, van der Waals interactions and to interact with hydrophobic residues on 14-3-3σ. FIG.3B: Bar graphs of mass spectrometry data at 100 nM [compound]. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. ERα data are shown in solid grey, C-RAF data with dashed lines, and apo data in black. FIG.3C: Bar graphs of FA compound titration EC50 values after overnight incubation. ERα data are shown in solid grey, and C-RAF data with dashed lines. FIG.3D: Crystal structures of the cyclopentyl analogs 1075297 (ether) and 1075306 (aniline) with 14-3-3σ/ERα. FIG.3E: Crystal structures of the cyclopentyl analogs 1075297 (ether, dark grey sticks) and 1075306 (aniline, dark grey sticks) with 14-3-3σ (white surface) and C-RAF (light grey sticks). FIG.3F: Crystal structures of the tetrahydropyran analogs 1075305 (ether, light grey sticks) and 1075310 (aniline, dark grey sticks) with 14-3-3σ (white surface) and ERα. Interacting water molecules are shown as spheres. FIG.3G: Schematic representation of the preferred compound conformation with the two peptides. For 14-3-3σ/ERα stabilizers, larger groups in X position are preferred, with an aniline group facing in the front and participating in the water network. For 14-3-3σ/C- RAF, smaller groups, such as the cyclopentyl group in X position are preferred, with an ether group facing in the back, toward 14-3-3. [0034] FIGS.4A-4K. FIG.4A: Crystal structures of aniline analogs 1075310 (dark grey sticks) with a tetrahydropyran ring and 1075481 (dark grey sticks) with a piperidine ring with 14-3-3σ (white surface) and ERα (light grey sticks). Both the hydrogen bond acceptor and hydrogen bond donor are able to maintain the interactions with the water network (black dashed lines). FIG.4B: Overlay of the tetrahydropyran and piperidine ring. FIG.4C: Methyl groups were introduced on the tetrahydropyran ring to further enhance the hydrophobic interaction with Val595 of ERα. FIG.4D: Mass spectrometry bar graphs indicate that two methyl groups (compound 1080299) were well-tolerated, and binding was increased in the first measurements. Compound 1080300 with four methyl groups was weaker than the non- methylated tetrahydropyran analog. FIG.4E: FA bar graphs of the methylated tetrahydropyrans showed a different trend, where the presence of two methyl groups did not improve the stabilization. FIG.4F: Overlay of the crystal structures of 1075310, 1080299, 1080300 with 14-3-3σ (white cartoon) and ERα. Leu218 on 14-3-3 turns to make room for the methyl group. FIG.4G: Surface representation of crystal structure of 1080299 (dark grey) in 14-3-3 (white) and ERα (light grey). The methyl group of 1080299 fits between Leu218 and Leu222 on 14-3-3 and is also forming hydrophobic interactions with Val595 of ERα. FIG.4H: Modifications of the linker length of the warhead for both tetrahydropyran and piperidine analogs. FIG.4I: Mass spectrometry bar graphs of tetrahydropyran and piperidine analogs with linker length n=1-3. FIG.4J: FA bar graphs, showing the same trends as the mass spectrometry data. FIG.4K: Crystal structures of compounds with increasing linker length (1075310, 1080267, and 1075478) in complex with 14-3-3σ/ERα. For 1075310, a hydrogen bond is formed with Asn42, whereas for 1075478, a hydrogen bond is formed with Arg41. [0035] FIGS.5A-5F. FIG.5A: Chemical modification (5) aimed to replace the long, flexible linkers with conformationally constrained spiro-linkers. Seven spiro-analogs were synthesized and tested, with varying linker lengths and reversed rings. FIG.5B: Mass spectrometry bar graphs indicate that although the spiro-linker is far from the protein-peptide interface, it can significantly affect cooperativity. FIG.5C: FA bar graphs of the spiro- analogs. FIG.5D: Crystal structures of compounds 1080265 and 1080266 (pair of small spiro-analogs with reversed rings) in complex with 14-3-3σ/ERα. FIG.5E: Crystal structures of compounds 1080294 and 1080295 (pair of spiro-analogs with one extra bond and reversed rings) in complex with 14-3-3σ/ERα. FIG.5F: Crystal structures of compounds 1080297 and 1080298 (pair of spiro-analogs with one extra -CH2- and reversed rings) in complex with 14- 3-3σ/ERα. [0036] FIGS.6A-6E. FIG 6A: Combinations of 2,6-dimethyl tetrahydropyran with spiro- linkers (synergistic effect). FIG.6B: Mass spectrometry bar graphs of compounds 1080299, 1083743, and 1083744 binding to 14-3-3σ in absence and presence of the ERα peptide and at different time points. FIG.6C: FA bar graphs of the same analogs. For compound 1083744, the EC50 value at t=0 is plotted in dashed lines. FIG.6D: Crystal structures (2Fo-Fc, 1σ) of compounds 1080299, 1083743, and 1083744 in complex with 14-3-3σ/ERα. Compound 1080299 with a linear linker is forming a hydrogen bond with Asn42, whereas compound 1083744 with a spiro-linker forms a hydrogen bond with Arg41. FIG.6E: Overlay of the crystal structures, indicating the similar binding mode of compounds 1080299, 1083743, and 1083744. [0037] FIGS.7A-7H. Comparison between the optimized covalent stabilizer 1083744 and the natural product Fusicoccin-A. FIG.7A: Chemical structure of 1083744. FIG.7B: Crystal structure of 1083744 (dark grey sticks, left) with 14-3-3σ (white surface) and ΕRα (light grey sticks, right). Water network is depicted as black dashes. FIG.7C: Titration of 14-3-3σ to FAM-labeled ERα (10 nM) against varying fixed concentrations of 1083744 (between 0 and 250 µM). FIG.7D: Chemical structure of fusicoccin-A (FC-A). FIG.7E: Crystal structure of FC-A (dark grey sticks, left) with 14-3-3σ (white surface) and ΕRα (light grey sticks, right) (PDB ID: 4JDD); highlighting the lack of water molecules. FIG.7F: Titration of 14-3-3σ to FAM-labeled ERα (10 nM) against varying fixed concentrations of FC-A (between 0 and 250 µM). FIGS.7G-7H: ITC experiment comparing enthalpic and entropic differences between 1083744 and FC-A. Measured in two independent experiments. [0038] FIG.8. Selectivity studies of compound 1083744 measured in FA protein titrations. 14-3-3σ is titrated to eight different FAM-labeled peptides (ERα, CRAF, SOS1, ChREBP, p65, BRAF, USP8, and Pin1, each 10 nM) in the presence of DMSO (1%) or 1083744 (100 µM). Apparent KD values (stated in each legend) are determined for the interaction of each peptide with 14-3-3σ, in the presence of DMSO or 1083744, resulting in a calculated fold- stabilization by 1083744 shown at the arrow of each graph. The crystal structure of 1083744 complexed with 14-3-3σ and ERα (top left) is overlayed with the crystal structures of the measured peptides (CRAF (4FJ3), SOS1 (6Y44), ChREBP (4GNT), p65 (6QHL), BRAF (6NYB), USP8 (6F09) and Pin1 (7AOG)). Sequences shown: ERα (pT594): AEGFPA(pT)V (SEQ ID NO: 2); CRAF (pS259): QRST(pS)TPNVH (SEQ ID NO: 3); SOS1 (pS1161): PRRRPE(pS)APAESS (SEQ ID NO: 5); ChREBP: RDIRLNNAIWRAWYIQYVQR (SEQ ID NO: 11); p65 (pS45): EGRSAG(pS)IPGRRS (SEQ ID NO: 4); BRAF (pS365): RDRSS(pS)APNVH (SEQ ID NO: 7); USP8 (pS719): KLKRSY(pS)SPDITQ (SEQ ID NO: 6); Pin1 (pS72): LVKHSQSRRPS(pS)WRQEK (SEQ ID NO: 9). [0039] FIGS.9A-9E. Overview of fragment linking approach. FIG.9A: Schematic and X- ray crystal structure of C42 tethered fragment 1 (dark grey sticks, left) in complex with 14-3- 3σ (N42C, C38A) (white surface) and ERα phospho-peptide (light grey sticks, right) (pdb ID: 6HMT). FIG.9B: Schematic and X-ray crystal structure of amidine fragment (grey sticks, left) in complex with 14-3-3σ (white surface) and p53 phospho-peptide (grey sticks, right) (pdb ID: 6S40). FIG.9C: Schematic of fragment linking approach taken here and crystallographic overlay of the two previously discovered fragments to show their proximity. FIG.9D: Structures of two fragment classes with disulfide tethered fragment 1 and benzothiophene Core A and phenyl-thiophene Core B. FIG.9E: X-ray crystal structure of co-soak of compound 1 and A-1 in complex with 14-3-3σ and ERα phospho-peptide.2Fo-Fc electron density map is contoured at 1σ. [0040] FIGS.10A-10F. Discovery of linked fragments. FIG.10A: Molecular structures of the different linker lengths of benzothiophene building blocks. FIG.10B: X-ray crystal structure of 5 (grey sticks, left) in complex with 14-3-3σ (white surface) and ERα phospho- peptide (grey sticks, right). FIG.10C: Crystallographic overlay of 5 with C42-tethered fragment 1, in complex with 14-3-3σ and ERα phospho-peptide. FIG.10D: Molecular structures of diphenyl- and phenyl-thiophene building blocks. FIG.10E: X-ray crystal structure of 6 in complex with 14-3-3σ and ERα phospho-peptide. FIG.10F: Crystallographic overlay of 6 with C42-tethered fragment 1, in complex with 14-3-3σ and ERα phospho-peptide. [0041] FIG.11. Overview SAR optimization of linked fragments. If the control (no 14-3-3 protein) also shows an increase in anisotropy, the EC50 value is indicated with a ~ sign. An asterisk (*) indicates that the molecule was crystallized. [0042] FIGS.12A-12B. FIG.12A: Fluorescence anisotropy (FA) dose-response curves for the linked fragments with a cyclic group at position X containing a hydrogen bond donor or acceptor. Compounds are titrated into FAM-labeled ERα phospho-peptide (10 nM; light grey dots) or to a mixture of FAM-labeled ERα phospho-peptide (10 nM) and 14-3-3γ (1 µM; dark grey squares). FIG.12B: X-ray crystal structures of 22, 23, 24, and 25, in complex with 14- 3-3σ and ERα phospho-peptide. Hydrogen bonds are visualized by black dashes and water molecules as spheres. [0043] FIGS.13A-13C. Characterization of stabilizing linked fragments. FIG.13A: FA 2D titrations with titration of 14-3-3γ to FAM-labeled ERα phospho-peptide (10 nM) against varying concentrations of 23, 24, or 25 (ranging from 0 to 500 µM). FIG.13B: FA with multiple doses of 24 added to ten different client peptides (10 nM each; light grey dots), or a mixture containing the peptide and 14-3-3γ (dark grey squares). FIG.13C: X-ray crystal structure of 24 in complex with 14-3-3σ and ERα phospho-peptide. Polar interactions are visualized as black dashes and water molecules as spheres. [0044] FIG.14. Structures of fragments with Core A the benzothiophene core and Core B the phenylthiophene-core. [0045] FIGS.15A-15G. Crystallography single soaks of amide fragments in complex with 14-3-3σ and ERα phospho-peptide. FIG. 15A: Soak of A-1 (PDB ID: 8BZ9). FIG.15B: Soak of A-2 (PDB ID: 8BZ0). FIG.15C: Soak of A-3 (PDB ID: 8BYZ). FIG.15D: Soak of B-1 (PDB ID: 8BZA). FIG.15E: Soak of B-2 (PDB ID: 8C4F). FIGS.15F-15G: Soak of B- 3 (PDB ID: 8C4F). Note that B-3 binds covalently to C38 in 14-3-3σ. [0046] FIGS.16A-16F. Crystallography co-soaks of benzothiophene compounds (Core A) + compound 1 in complex with 14-3-3σ and ERα phospho-peptide. FIG.16A: Co-soak of A- 1 + 1 (PDB ID: 8C04) overlayed with single soak of A-1. FIG.16B: Co-soak of A-2 + 1 (PDB ID: 8BZB) overlayed with single soak of A-2. FIG.16C: Co-soak of A-3 + 1 (PDB ID: 8BZQ) overlayed with single soak of A-3. FIG.16D: Co-soak of A-1 + 1, with distance of 3.0 Å. FIG.16E: Co-soak of A-2 + 1, with distance of 3.9 Å. FIG.16F: Co-soak of A-3 + 1, with distance of 2.8 Å. [0047] FIG.17. Crystallographic overlay of 5 with benzothiophene fragments (A-1, A-2, A-3). Electron density of 5 (left, PDB ID: 8BYG) and crystallographic overlay of 5 with the single soaks of the benzothiophene fragments, or with the co-soaks of the benzothiophene fragments + compound 1. Complexed with 14-3-3σ (white surface) and ERα-pp.2Fo-Fc electron density map is contoured at 1σ. [0048] FIGS.18A-18B. Overview of biphenyl- and phenyl-thiophene linked fragments. FIG.18A: Fluorescence Anisotropy (FA) dose-response curves for the linked fragments. Compounds are titrated into FAM-labeled ERα phospho-peptide (10 nM) (light grey dots) or into a mixture of FAM-labeled ERα phospho-peptide (10 nM) / 14-3-3γ (1 µM) (dark grey squares). FIG.18B: Electron density of 6 (left, PDB ID: 8BYF) and crystallographic overlay of 6 (sticks) with the single soaks of the phenyl-thiophene fragments (B-1, B-2) in complex with 14-3-3σ (white surface) and ERα-pp.2Fo-Fc electron density map is contoured at 1σ. [0049] FIGS.19A-19B. Crystal structure of 6 in complex with 14-3-3σ and ERα phospho- peptide. FIG.19A highlights the interactions at the amidine-site, with the 14-3-3 amino-acids shown as white sticks and hydrogen bonds as black dashes. FIG.19B highlights the hydrophobic interactions of the chloro-phenyl site, with the 14-3-3 amino acids shown as white sticks. [0050] FIGS.20A-20C. Overview of compounds 9 (FIG.20A), 10 (FIG.20B), and 11 (FIG.20C) overlaid with compound 7, as described in FIG.11. Top: Crystal structures complexed with 14-3-3σ and ERα-pp. Bottom: Fluorescence Anisotropy dose-response curves for the linked fragments. Compounds are titrated into FAM-labeled ERα phospho- peptide (10 nM) (light grey dots) or into a mixture of FAM-labeled ERα phospho-peptide (10 nM) / 14-3-3γ (1 µM) ( dark grey squares). In the upper left corner, the density is depicted of each compound with their corresponding PDB ID (8BYY, 8BXI, 8BXM). 2Fo-Fc electron density map is contoured at 1σ. [0051] FIGS.21A-21F. Overview of compounds 12 (FIG.21A), 13 (FIG.21B), 14 (FIG. 21C), 15 (FIG.21D), 16 (FIG.21E), and 17 (FIG.21F) overlaid with compound 6, as described in FIG.11. Top: Crystal structures complexed with 14-3-3σ (white surface) and ERα phospho-peptide. Bottom: Fluorescence Anisotropy (FA) dose-response curves for the linked fragments. Compounds are titrated into FAM-labeled ERα phospho-peptide (10 nM) (light grey dots) or into a mixture of FAM-labeled ERα phospho-peptide (10 nM) / 14-3-3γ (1 µM) (dark grey squares). In the upper left corner, the density is depicted of each compound with their corresponding PDB ID (8BX3, 8BWJ, 8BX4, 8BYO, 8BWZ, 8BX0). 2Fo-Fc electron density map is contoured at 1σ. [0052] FIGS.22A-22D. Overview of compounds 6 (FIG. 22A), 19 (FIG.22B), 20 (FIG. 22C), and 21 (FIG.22D), as described in FIG.11. Left: Crystal structures complexed with 14-3-3σ (white surface) and ERα-pp. Right: Fluorescence Anisotropy (FA) dose-response curves for the linked fragments. Compounds are titrated into FAM-labeled ERα phospho- peptide (10 nM) (light grey dots) or into a mixture of FAM-labeled ERα phospho-peptide (10 nM) / 14-3-3γ (1 µM) (dark grey squares). In the upper left corner, the density is depicted of each compound with their corresponding PDB ID (8BYF, 8BYE, 8BYD, 8BYB). 2Fo-Fc electron density map is contoured at 1σ. [0053] FIG.23. Crystallographic electron density of compounds described in FIG.11: 22 (8BXS), 23 (8C0K), 24 (8BWX) and 25 (8BYC). 2Fo-Fc electron density map is contoured at 1σ. [0054] FIGS.24A-24F. FIGS.24A-24D: Overview of compounds 26 (FIG.24A), 27 (FIG. 24B), 28 (FIG.24C), and 29 (FIG.24D) overlaid with compound 7, as described in FIG.11. Left: Crystal structures complexed with 14-3-3σ (white surface) and ERα-pp. Right: Fluorescence Anisotropy (FA) dose-response curves for the linked fragments. Compounds are titrated into FAM-labeled ERα phospho-peptide (10 nM) (light grey dots) or into a mixture of FAM-labeled ERα phospho-peptide (10 nM) / 14-3-3γ (1 µM) (dark grey squares). In the upper left corner, the density is depicted of each compound with their corresponding PDB ID (8BXQ, 8BXO, 8BXN, 8BY9). 2Fo-Fc electron density map is contoured at 1σ. FIG.24E: Details of crystal structure of 26, 28, and 27 in complex with 14-3-3σ (white surface) and ERα phospho-peptide. Hydrogen bonds are depicted as black dashes and water molecules as spheres. FIG.24F: Detail of distance of the phenyl-fluoro group of 27 towards the carboxy end of ERα and K122 of 14-3-3 (black dashes). [0055] FIG.25. Selectivity studies of compound 24 measured in FA compound titrations. Compound 24 is titrated to 14-3-3γ and ten different FAM-labeled peptides (10 nM). The crystal structure of 24 complexed with 14-3-3σ and ERα (top left) is overlayed with the crystal structures of the measured peptides. (CRAF (4FJ3), p65 (6QHL), SOS1 (6Y44), USP8 (6F09), BRAF (6NYB), FOXO (6QZR), PIN1 (7AOG), EXOS (2O02), ChREBP (4GNT)). DETAILED DESCRIPTION I. Definitions [0056] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0057] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0058] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds. [0059] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds. [0060] 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. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)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. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated. [0061] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds. [0062] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated. [0063] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings. [0064] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings. [0065] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings. [0066] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0067] The term “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. [0068] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0069] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0070] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0071] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0072] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: . [0073] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted. [0074] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0075] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). [0076] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0077] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0078] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. [0079] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0080] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0081] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 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: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 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: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0082] A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0083] A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. [0084] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0085] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0086] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0087] In embodiments, 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 heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, 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). [0088] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted 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. [0089] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted 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. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. [0090] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0091] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0092] In a recited claim or chemical formula description herein, 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. [0093] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1 may be substituted with one or more first substituent groups denoted by R1.1, R2 may be substituted with one or more first substituent groups denoted by R2.1, R3 may be substituted with one or more first substituent groups denoted by R3.1, R4 may be substituted with one or more first substituent groups denoted by R4.1, R5 may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100 that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1A may be substituted with one or more first substituent groups denoted by R1A.1, R2A may be substituted with one or more first substituent groups denoted by R2A.1, R3A may be substituted with one or more first substituent groups denoted by R3A.1, R4A may be substituted with one or more first substituent groups denoted by R4A.1, R5A may be substituted with one or more first substituent groups denoted by R5A.1 and the like up to or exceeding an R100A may be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1 may be substituted with one or more first substituent groups denoted by RL1.1, L2 may be substituted with one or more first substituent groups denoted by RL2.1, L3 may be substituted with one or more first substituent groups denoted by RL3.1, L4 may be substituted with one or more first substituent groups denoted by RL4.1, L5 may be substituted with one or more first substituent groups denoted by RL5.1 and the like up to or exceeding an L100 which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWW or LWW wherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1 or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1 … R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1 … R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1 … RL100.1) may be … … be as as may one or more substituent groups, which may alternatively be represented herein as RWW.2. [0094] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2 … R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2 … R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2 … RL100.2) may be further R1A.3, R2A.3, R3A.3, R4A.3, R5A.3 … R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3 … RL100.3; represented herein as RWW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.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. [0095] Thus, as used herein, RWW 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.). Likewise, LWW is a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWW is phenyl, the said phenyl group is optionally substituted by one or more RWW.1 groups as defined herein below, e.g., when RWW.1 is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2 is optionally substituted by one or more RWW.3. By way of example when the RWW group is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to: . [0096] oxo, - - - -OCXWW.1 3, -OCH2XWW.1, -OCHXWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.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), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-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), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.1 is independently oxo, halogen, -CXWW.1 3, -CHXWW.1 2, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1 is independently –F, -Cl, -Br, or –I. [0097] RWW.2 is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.2 3, -OCH2XWW.2, -OCHXWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.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), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-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), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2 is independently oxo, halogen, -CXWW.2 3, -CHXWW.2 2, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2 is independently –F, -Cl, -Br, or –I. [0098] RWW.3 is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.3 3, -OCH2XWW.3, -OCHXWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3 is independently –F, -Cl, -Br, or –I. [0099] Where two different RWW substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWW substituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2 and RWW.3 refers to the designated number of one of the two different RWW substituents. For example, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100A.1, RWW.2 is R100A.2, and RWW.3 is R100A.3. Alternatively, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100B.1, RWW.2 is R100B.2, and RWW.3 is R100B.3. RWW.1, RWW.2 and RWW.3 in this paragraph are as defined in the preceding paragraphs. [0100] RLWW.1 is independently oxo, halogen, -CXLWW.1 3, -CHXLWW.1 2, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, or or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-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), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.1 is independently oxo, halogen, -CXLWW.13, -CHXLWW.1 2, -CH2XLWW.1, -OCXLWW.1 3, -OCH2XLWW.1, -OCHXLWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1 is independently –F, -Cl, -Br, or –I. [0101] RLWW.2 is independently oxo, halogen, -CXLWW.2 3, -CHXLWW.2 2, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.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), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-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), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2 is independently oxo, halogen, -CXLWW.2 3, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2 is independently –F, -Cl, -Br, or –I. [0102] RLWW.3 is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.3 3, -OCH2XLWW.3, -OCHXLWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3 is independently –F, -Cl, -Br, or –I. [0103] In the event that any R group recited in a claim or chemical formula description set forth herein (RWW substituent) is not specifically defined in this disclosure, then that R group (RWW group) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW 3, -OCH2XWW, -OCHXWW 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-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), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-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), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW is independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3 are as defined above. [0104] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWW substituent) is not explicitly defined, then that L group (LWW group) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2 and RLWW.3 are as defined above. [0105] 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. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0106] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0107] 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. [0108] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. [0109] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. [0110] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. [0111] 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. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. [0112] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0113] As used herein, the terms “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. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –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). In embodiments, 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). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). [0114] Useful 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 Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex. [0115] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group. [0116] “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. [0117] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0118] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13 and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency. [0119] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. [0120] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0121] Thus, 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. [0122] 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. [0123] In addition to salt forms, 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. Additionally, 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. [0124] 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. [0125] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant. [0126] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). [0127] 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. [0128] 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 degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment. [0129] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0130] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables). [0131] “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. [0132] 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). In some embodiments 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. [0133] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. [0134] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist. [0135] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, 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). Thus, 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. [0136] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. [0137] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition. [0138] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.). [0139] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. [0140] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human. [0141] “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. In some embodiments, 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). In embodiments, the disease is a cancer (e.g., breast cancer, ovarian cancer, endometrial cancer, or uterine cancer). [0142] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. [0143] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [0144] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma. [0145] 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. [0146] 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. [0147] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0148] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast. [0149] The terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin. [0150] The term “visceral metastasis” refer to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs. [0151] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug. [0152] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-1581Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra, 225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT/US2015/022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. [0153] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-158Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra, and 225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu. [0154] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0155] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0156] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value. [0157] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0158] 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. [0159] In some embodiments, 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. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. [0160] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. 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, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient. The dose administered to a patient, 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. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. [0161] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or 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). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. [0162] The term “aberrant” as used herein 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. [0163] 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 “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond. [0164] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density. [0165] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. 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. [0166] The term “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, γ- 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 α 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. The terms “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. [0167] 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. [0168] The terms “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. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. [0169] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). 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. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence. [0170] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. [0171] 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. For example, a selected residue in a selected protein corresponds to C38 of human 14-3-3 ^ protein when the selected residue occupies the same essential spatial or other structural relationship as C38 of human 14-3-3 ^ protein. In some embodiments, where a selected protein is aligned for maximum homology with the human 14-3-3 ^ protein, the position in the aligned selected protein aligning with C38 is said to correspond to C38. Instead of a primary sequence alignment, 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 14-3-3 ^ protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as C38 in the structural model is said to correspond to the C38 residue. [0172] The term “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. [0173] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes. [0174] The term “client protein” as used herein refers to a protein that is capable of binding to another protein (e.g., a 14-3-3 protein). In embodiments, the client protein interaction with the other protein is stabilized with chemical compound as set forth herein. [0175] The term “14-3-3 protein” as used herein refers to a protein (or portion thereof) that is a member of the 14-3-3 protein family, including, but not limited to, the various human isoforms (β, γ, ε, ζ, η, ^/θ and σ). When specified, the term can refer to a specific isoform or group of isoforms. In embodiments, the term refers to the σ isoform. In embodiments, the 14-3-3 proteins influence the function of bound phosphoserine and/or threonine phosphorylated proteins via a variety of mechanisms including sequestering them from cellular targets, controlling their enzymatic activity, relocating them or acting as adaptor molecules in mediating the association of two distinct client proteins. Thus, in embodiments, 14-3-3 proteins regulate pathways involved in growth factor signaling and cell cycle progression. The 14-3-3 protein may interact with more than 300 different partners (client proteins), including Raf kinases, heat shock proteins, oncogenes, and tumor suppressors.14- 3-3 proteins are central regulators in many biological processes and pathologies. In embodiments, 14-3-3 binding antagonizes multiple transcription factors that act as oncogenic drivers. In embodiments, 14-3-3 protein binds to an ERα protein, and reduces the transcriptional activity of ERα. A “14-3-3 protein–ERα protein complex” is the complex formed when the 14-3-3 protein binds to an ERα protein. In embodiments, the 14-3-3 protein is 14-3-3σ (14-3-3sigma) (e.g., Entrez 2810, UniProt P31947, RefSeq NP_006133). In embodiments, the 14-3-3 protein is 14-3-3β (14-3-3beta) (e.g., Entrez 7529, UniProt P31946, Q4VY19, RefSeq NP_003395). In embodiments, the 14-3-3 protein is 14-3-3ε (14-3- 3epsilon) (e.g., Entrez 7531, UniProt P62258, RefSeq NP_006752). In embodiments, the 14- 3-3 protein is 14-3-3η (14-3-3eta) (e.g., Entrez 7533, UniProt Q04917, RefSeq NP_003396). In embodiments, the 14-3-3 protein is 14-3-3 ^ (14-3-3gamma) (e.g., Entrez 7532, UniProt P61981, RefSeq NP_36611). In embodiments, the 14-3-3 protein is 14-3-3τ (14-3-3tau) (e.g., Entrez 10971, UniProt P27348, RefSeq NP_006817). In embodiments, the 14-3-3 protein is 14-3-3ζ (14-3-3zeta) (e.g., Entrez 7534, UniProt P63104, RefSeq NP_003397). [0176] In embodiments, the 14-3-3 protein is phosphorylated. In embodiments, the 14-3-3 client is a phosphoserine protein. In embodiments, the 14-3-3 client is a phosphothreonine protein. In embodiments, the 14-3-3 client is a phosphorylated peptide (a phosphopeptide) derived from the 14-3-3 client protein. In embodiments, the 14-3-3 client is a phosphorylated peptide (phosphopeptide) representing the 14-3-3 protein binding motif of the client protein. [0177] The term “estrogen receptor alpha”, “ERα”, or “NR3A1” refers to a hormone receptor activated by estrogen. The term includes any recombinant or naturally-occurring form of ERα, including variants thereof that maintain ERα function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype ERα). In embodiments, ERα is encoded by the NR3A1 gene. In embodiments, ERα has the amino acid sequence set forth in or corresponding to Entrez 2099, UniProt P03372, or RefSeq (protein) NP_000116.2. II. Compounds [0178] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: . a substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0180] L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0181] L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0182] L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). [0183] L4 is –NR40- or -O-. [0184] R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or E. [0185] E is an electrophilic moiety. [0186] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0187] The symbol z2 is an integer from 0 to 5. [0188] R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or 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). [0189] Each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0190] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0191] Each X1 and X2 is independently –F, -Cl, -Br, or –I. [0192] The symbols n1 and n2 are independently an integer from 0 to 4. [0193] The symbols m1, m2, v1, and v2 are independently 1 or 2. [0194] In embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the formula: a or membered, 4 to 5 membered, or 5 to 6 membered); L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered); L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); the symbol z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6) or 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); each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); each X1 and X2 is independently –F, -Cl, -Br, or –I; the symbols n1 and n2 are independently an integer from 0 to 4; and the symbols m1, m2, v1, and v2 are independently 1 or 2. [0195] In embodiments, the compound has the formula: . Ring A, Ring B, L1, L2, R1, R2, R3, and R4 are [0196] In embodiments, the compound has the formula: R1 1 L2 R2 L A R3 R4 . Ring A, Ring B, L1, L2, R1, R2, R3, and [0197] In embodiments, the compound has the formula: . Ring A, Ring B, L1, L2, R1, R2, R3, and [0198] A person having ordinary skill in the art would understand that Ring A and Ring B together form a spirocyclic ring. In embodiments, the spirocyclic ring is a heterocyclic spirocyclic ring. In embodiments, the spirocyclic ring is a substituted spirocyclic ring. [0199] In embodiments, a substituted Ring A (e.g., substituted cycloalkylene and/or substituted heterocycloalkylene) is substituted with at least one substituent group, size- limited substituent group, or lower substituent group; wherein if the substituted Ring A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when Ring A is substituted, it is substituted with at least one substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent group. [0200] In embodiments, Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, Ring A is a substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, Ring A is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0201] In embodiments, a substituted Ring B (e.g., substituted cycloalkylene and/or substituted heterocycloalkylene) is substituted with at least one substituent group, size- limited substituent group, or lower substituent group; wherein if the substituted Ring B 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 Ring B is substituted, it is substituted with at least one substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one lower substituent group. [0202] In embodiments, Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, Ring B is a substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, Ring B is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
is . In embodiments, is . In thereof, having the formula: [0205] R5, R6, R7, and R8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0206] The symbol z5 is an integer from 0 to 5. [0207] In embodiments, the compound has the formula: are as described herein, [0208] In embodiments, the compound has the formula: are as described herein, [0209] In embodiments, the compound has the formula: (IIb). L1, L2, and R1 are as described herein, including in [0210] In embodiments, the compound has the formula: z2 are as described [0211] In embodiments, the compound has the formula: (IIIa). L1, L2, R1, and R2 are as described herein, [0212] In embodiments, the compound has the formula: z5 are as [0213] In embodiments, the compound has the formula: . L1, L2, R1, and R2 are as described herein, [0214] In embodiments, the compound has the formula: R8 are as [0215] In embodiments, the compound has the formula: . L1, L2, R1, and R2 are as described herein, [0216] In embodiments, the compound has the formula: R2 are as described herein, [0217] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: R4, [0218] L5 is –NR90- or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). [0219] R90 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0220] L6 is a bond or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0221] The symbol z5 is an integer from 0 to 4. [0222] The symbol z6 is an integer from 0 to 2. [0223] In embodiments, the compound has the formula: R5, [0224] In embodiments, the compound has the formula: (VIIa). L1, L2, L4, R1, R2, z2, R3, and [0225] In embodiments, the compound has the formula: (R5)z5 R3 4 R1 L1 R (R2)z2 R3, [0226] In embodiments, the compound has the formula: (VIIIa). L1, L2, L4, L5, L6, R1, R2, z2, R3, [0227] In embodiments, the compound has the formula: (VIIIb). L1, L2, L4, L5, L6, R1, R2, z2, R3, mbodiments. [0228] In embodiments, the compound has the formula: . L1, L2, L4, L5, R1, R2, z2, R3, and R4 are [0229] In embodiments, the compound has the formula: O L4 (VIIId). L1, L2, L4, L5, R1, R2, z2, R3, and R4 are [0230] In embodiments, the compound has the formula: (VIIIe). L1, L2, L4, L5, R1, R2, z2, R3, and [0231] In embodiments, the compound has the formula: R3 R4 (R2)z2 N L5 [0232] In embodiments, a substituted L1 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L1 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 L1 is substituted, it is substituted with at least one substituent group. In embodiments, when L1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1 is substituted, it is substituted with at least one lower substituent group. [0233] In embodiments, L1 is a bond. In embodiments, L1 is -C(O)-. In embodiments, L1 is -C(O)O-. In embodiments, L1 is -OC(O)-. In embodiments, L1 is -O-. In embodiments, L1 is -S-. In embodiments, L1 is -NR10-. In embodiments, L1 is -NH-. In embodiments, L1 is -C(O)NR10-. In embodiments, L1 is -C(O)NH-. In embodiments, L1 is -NR10C(O)-. In embodiments, L1 is -NHC(O)-. In embodiments, L1 is -NR10C(O)O-. In embodiments, L1 is -NHC(O)O-. In embodiments, L1 is -OC(O)NR10-. In embodiments, L1 is -OC(O)NH-. In embodiments, L1 is -NR10C(O)NR10-. In embodiments, L1 is -NHC(O)NH-. In embodiments, L1 is -S(O)2-. In embodiments, L1 is -NR10S(O)2-. In embodiments, L1 is -NHS(O)2-. In embodiments, L1 is -S(O)2NR10-. In embodiments, L1 is -S(O)2NH-. In embodiments, L1 is unsubstituted C1-C4 alkylene. In embodiments, L1 is unsubstituted methylene. In embodiments, L1 is unsubstituted ethylene. In embodiments, L1 is unsubstituted propylene. In embodiments, L1 is unsubstituted n-propylene. In embodiments, L1 is unsubstituted isopropylene. In embodiments, L1 is unsubstituted butylene. In embodiments, L1 is unsubstituted n-butylene. In embodiments, L1 is unsubstituted isobutylene. In embodiments, L1 is unsubstituted tert-butylene. In embodiments, L1 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L1 is unsubstituted 2 to 6 membered heteroalkylene. [0234] In embodiments, L1 is a bond or unsubstituted C1-C4 alkylene. In embodiments, L1 is a bond or unsubstituted methylene. [0235] In embodiments, a substituted R10 (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 R10 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 R10 is substituted, it is substituted with at least one substituent group. In embodiments, when R10 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10 is substituted, it is substituted with at least one lower substituent group. [0236] In embodiments, R10 is independently hydrogen. In embodiments, R10 is independently unsubstituted C1-C4 alkyl. In embodiments, R10 is independently unsubstituted methyl. In embodiments, R10 is independently unsubstituted ethyl. In embodiments, R10 is independently unsubstituted propyl. In embodiments, R10 is independently unsubstituted n- propyl. In embodiments, R10 is independently unsubstituted isopropyl. In embodiments, R10 is independently unsubstituted butyl. In embodiments, R10 is independently unsubstituted n- butyl. In embodiments, R10 is independently unsubstituted isobutyl. In embodiments, R10 is independently unsubstituted tert-butyl. [0237] In embodiments, a substituted L2 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L2 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 L2 is substituted, it is substituted with at least one substituent group. In embodiments, when L2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L2 is substituted, it is substituted with at least one lower substituent group. [0238] In embodiments, L2 is a bond. In embodiments, L2 is -C(O)-. In embodiments, L2 is -C(O)O-. In embodiments, L2 is -OC(O)-. In embodiments, L2 is -O-. In embodiments, L2 is -S-. In embodiments, L2 is –NR20-. In embodiments, L2 is -NH-. In embodiments, L2 is -C(O)NR20-. In embodiments, L2 is -C(O)NH-. In embodiments, L2 is –NR20C(O)-. In embodiments, L2 is -NHC(O)-. In embodiments, L2 is –NR20C(O)O-. In embodiments, L2 is -NHC(O)O-. In embodiments, L2 is -OC(O)NR20-. In embodiments, L2 is -OC(O)NH-. In embodiments, L2 is –NR20C(O)NR20-. In embodiments, L2 is -NHC(O)NH-. In embodiments, L2 is -S(O)2-. In embodiments, L2 is –NR20S(O)2-. In embodiments, L2 is -NHS(O)2-. In embodiments, L2 is -S(O)2NR20-. In embodiments, L2 is -S(O)2NH-. In embodiments, L2 is unsubstituted C1-C4 alkylene. In embodiments, L2 is unsubstituted methylene. In embodiments, L2 is unsubstituted ethylene. In embodiments, L2 is unsubstituted propylene. In embodiments, L2 is unsubstituted n-propylene. In embodiments, L2 is unsubstituted isopropylene. In embodiments, L2 is unsubstituted butylene. In embodiments, L2 is unsubstituted n-butylene. In embodiments, L2 is unsubstituted isobutylene. In embodiments, L2 is unsubstituted tert-butylene. In embodiments, L2 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L2 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L2 is unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L2 . [0239] In embodiments, L2 is a bond, –NHC(O)-, –C(O)NH-, or substituted or unsubstituted 2 to 6 membered heteroalkylene. [0240] In embodiments, a substituted R20 (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 R20 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 R20 is substituted, it is substituted with at least one substituent group. In embodiments, when R20 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20 is substituted, it is substituted with at least one lower substituent group. [0241] In embodiments, R20 is independently hydrogen. In embodiments, R20 is independently unsubstituted C1-C4 alkyl. In embodiments, R20 is independently unsubstituted methyl. In embodiments, R20 is independently unsubstituted ethyl. In embodiments, R20 is independently unsubstituted propyl. In embodiments, R20 is independently unsubstituted n- propyl. In embodiments, R20 is independently unsubstituted isopropyl. In embodiments, R20 is independently unsubstituted butyl. In embodiments, R20 is independently unsubstituted n- butyl. In embodiments, R20 is independently unsubstituted isobutyl. In embodiments, R20 is independently unsubstituted tert-butyl. [0242] In embodiments, -L1-L2- is a bond. In embodiments, -L1-L2- is -NHC(O)-. In embodiments, -L1-L2- is unsubstituted methylene. In embodiments, -L1-L2- is unsubstituted ethylene. In embodiments, -L1-L2- is unsubstituted n-propylene. In embodiments, -L1-L2- is unsubstituted n-butylene. In embodiments, -L1-L2- . [0243] In embodiments, a substituted L3 (e.g., substituted alkylene and/or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L3 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 L3 is substituted, it is substituted with at least one substituent group. In embodiments, when L3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L3 is substituted, it is substituted with at least one lower substituent group. [0244] In embodiments, L3 is -C(O)-. In embodiments, L3 is -C(O)O-. In embodiments, L3 is -OC(O)-. In embodiments, L3 is -O-. In embodiments, L3 is -S-. In embodiments, L3 is –NR30-. In embodiments, L3 is -NH-. In embodiments, L3 is -C(O)NR30-. In embodiments, L3 is -C(O)NH-. In embodiments, L3 is –NR30C(O)-. In embodiments, L3 is -NHC(O)-. In embodiments, L3 is unsubstituted C1-C4 alkylene. In embodiments, L3 is unsubstituted methylene. In embodiments, L3 is unsubstituted ethylene. In embodiments, L3 is unsubstituted propylene. In embodiments, L3 is unsubstituted n-propylene. In embodiments, L3 is unsubstituted isopropylene. In embodiments, L3 is unsubstituted butylene. In embodiments, L3 is unsubstituted n-butylene. In embodiments, L3 is unsubstituted isobutylene. In embodiments, L3 is unsubstituted tert-butylene. In embodiments, L3 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3 is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L3 is unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3 . [0245] In embodiments, a substituted R30 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 R30 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 R30 is substituted, it is substituted with at least one substituent group. In embodiments, when R30 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R30 is substituted, it is substituted with at least one lower substituent group. [0246] In embodiments, R30 is hydrogen. In embodiments, R30 is unsubstituted C1-C4 alkyl. In embodiments, R30 is unsubstituted methyl. In embodiments, R30 is unsubstituted ethyl. In embodiments, R30 is unsubstituted propyl. In embodiments, R30 is unsubstituted n- propyl. In embodiments, R30 is unsubstituted isopropyl. In embodiments, R30 is unsubstituted butyl. In embodiments, R30 is unsubstituted n-butyl. In embodiments, R30 is unsubstituted isobutyl. In embodiments, R30 is unsubstituted tert-butyl. [0247] In embodiments, L4 is –NR40-. In embodiments, L4 is -NH-. In embodiments, L4 is -O-. [0248] In embodiments, a substituted R40 (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 R40 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 R40 is substituted, it is substituted with at least one substituent group. In embodiments, when R40 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R40 is substituted, it is substituted with at least one lower substituent group. [0249] In embodiments, R40 is hydrogen. In embodiments, R40 is unsubstituted C1-C4 alkyl. In embodiments, R40 is unsubstituted methyl. In embodiments, R40 is unsubstituted ethyl. In embodiments, R40 is unsubstituted propyl. In embodiments, R40 is unsubstituted n- propyl. In embodiments, R40 is unsubstituted isopropyl. In embodiments, R40 is unsubstituted butyl. In embodiments, R40 is unsubstituted n-butyl. In embodiments, R40 is unsubstituted isobutyl. In embodiments, R40 is unsubstituted tert-butyl. [0250] In embodiments, a substituted L5 (e.g., substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L5 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 L5 is substituted, it is substituted with at least one substituent group. In embodiments, when L5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L5 is substituted, it is substituted with at least one lower substituent group. [0251] In embodiments, L5 is –NR90-. In embodiments, L5 is -NH-. In embodiments, L5 is substituted or unsubstituted heteroalkylene. In embodiments, L5 is substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L5 is –(unsubstituted C1-C4 alkylene)-N(R90)-, wherein each R90 is as described herein, including in embodiments. In embodiments, L5 is –CH2-NH-, wherein each R90 is as described herein, including in embodiments. In embodiments, L5 is –N(R90)-(unsubstituted C1-C4 alkylene)-N(R90)-, wherein each R90 is as described herein, including in embodiments. In embodiments, L5 . In embodiments, L5 is [0252] In embodiments, a substituted R90 (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 R90 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 R90 is substituted, it is substituted with at least one substituent group. In embodiments, when R90 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R90 is substituted, it is substituted with at least one lower substituent group. [0253] In embodiments, R90 is hydrogen. In embodiments, R90 is unsubstituted C1-C4 alkyl. In embodiments, R90 is unsubstituted methyl. In embodiments, R90 is unsubstituted ethyl. In embodiments, R90 is unsubstituted propyl. In embodiments, R90 is unsubstituted n- propyl. In embodiments, R90 is unsubstituted isopropyl. In embodiments, R90 is unsubstituted butyl. In embodiments, R90 is unsubstituted n-butyl. In embodiments, R90 is unsubstituted isobutyl. In embodiments, R90 is unsubstituted tert-butyl. [0254] In embodiments, a substituted L6 (e.g., substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L6 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 L6 is substituted, it is substituted with at least one substituent group. In embodiments, when L6 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L6 is substituted, it is substituted with at least one lower substituent group. [0255] In embodiments, L6 is a bond. In embodiments, L6 is a substituted or unsubstituted heteroarylene. In embodiments, L6 is a substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L6 is a substituted or unsubstituted triazolylene. In . [0256] In embodiments, a substituted R1 (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 R1 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 R1 is substituted, it is substituted with at least one substituent group. In embodiments, when R1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1 is substituted, it is substituted with at least one lower substituent group. [0257] In embodiments, a substituted R1A (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 R1A 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 R1A is substituted, it is substituted with at least one substituent group. In embodiments, when R1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1A is substituted, it is substituted with at least one lower substituent group. [0258] In embodiments, a substituted R1B (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 R1B 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 R1B is substituted, it is substituted with at least one substituent group. In embodiments, when R1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1B is substituted, it is substituted with at least one lower substituent group. [0259] In embodiments, a substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0260] In embodiments, a substituted R1C (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 R1C 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 R1C is substituted, it is substituted with at least one substituent group. In embodiments, when R1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1C is substituted, it is substituted with at least one lower substituent group. [0261] In embodiments, a substituted R1D (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 R1D 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 R1D is substituted, it is substituted with at least one substituent group. In embodiments, when R1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1D is substituted, it is substituted with at least one lower substituent group. [0262] In embodiments, R1A is hydrogen. In embodiments, R1A is unsubstituted C1-C4 alkyl. In embodiments, R1A is unsubstituted methyl. In embodiments, R1A is unsubstituted ethyl. In embodiments, R1A is unsubstituted propyl. In embodiments, R1A is unsubstituted n- propyl. In embodiments, R1A is unsubstituted isopropyl. In embodiments, R1A is unsubstituted butyl. In embodiments, R1A is unsubstituted n-butyl. In embodiments, R1A is unsubstituted isobutyl. In embodiments, R1A is unsubstituted tert-butyl. [0263] In embodiments, R1B is hydrogen. In embodiments, R1B is unsubstituted C1-C4 alkyl. In embodiments, R1B is unsubstituted methyl. In embodiments, R1B is unsubstituted ethyl. In embodiments, R1B is unsubstituted propyl. In embodiments, R1B is unsubstituted n- propyl. In embodiments, R1B is unsubstituted isopropyl. In embodiments, R1B is unsubstituted butyl. In embodiments, R1B is unsubstituted n-butyl. In embodiments, R1B is unsubstituted isobutyl. In embodiments, R1B is unsubstituted tert-butyl. [0264] In embodiments, R1C is hydrogen. In embodiments, R1C is unsubstituted C1-C4 alkyl. In embodiments, R1C is unsubstituted methyl. In embodiments, R1C is unsubstituted ethyl. In embodiments, R1C is unsubstituted propyl. In embodiments, R1C is unsubstituted n- propyl. In embodiments, R1C is unsubstituted isopropyl. In embodiments, R1C is unsubstituted butyl. In embodiments, R1C is unsubstituted n-butyl. In embodiments, R1C is unsubstituted isobutyl. In embodiments, R1C is unsubstituted tert-butyl. [0265] In embodiments, R1D is hydrogen. In embodiments, R1D is unsubstituted C1-C4 alkyl. In embodiments, R1D is unsubstituted methyl. In embodiments, R1D is unsubstituted ethyl. In embodiments, R1D is unsubstituted propyl. In embodiments, R1D is unsubstituted n- propyl. In embodiments, R1D is unsubstituted isopropyl. In embodiments, R1D is unsubstituted butyl. In embodiments, R1D is unsubstituted n-butyl. In embodiments, R1D is unsubstituted isobutyl. In embodiments, R1D is unsubstituted tert-butyl. [0266] In embodiments, R1 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0267] In embodiments, R1 is hydrogen. In embodiments, R1 is halogen. In embodiments, R1 is –F. In embodiments, R1 is –Cl. In embodiments, R1 is –Br. In embodiments, R1 is –I. In embodiments, R1 is -CCl3. In embodiments, R1 is -CBr3. In embodiments, R1 is -CF3. In embodiments, R1 is -CI3. In embodiments, R1 is -CH2Cl. In embodiments, R1 is -CH2Br. In embodiments, R1 is -CH2F. In embodiments, R1 is -CH2I. In embodiments, R1 is -CHCl2. In embodiments, R1 is -CHBr2. In embodiments, R1 is -CHF2. In embodiments, R1 is -CHI2. In embodiments, R1 is –CN. In embodiments, R1 is –OH. In embodiments, R1 is -NH2. In embodiments, R1 is –COOH. In embodiments, R1 is -C(NR1C)NR1AR1B. In embodiments, R1 is -C(NH)NH2. In embodiments, R1 is -C(NH)NHOH. In embodiments, R1 is -C(O)NR1AR1B. In embodiments, R1 is -CONH2. In embodiments, R1 is -NO2. In embodiments, R1 is –SH. In embodiments, R1 is -SO3H. In embodiments, R1 is -OSO3H. In embodiments, R1 is -SO2NH2. In embodiments, R1 is ^NHNH2. In embodiments, R1 is ^ONH2. In embodiments, R1 is ^NHC(O)NH2. In embodiments, R1 is -NHSO2H. In embodiments, R1 is -NHC(O)H. In embodiments, R1 is -NHC(O)OH. In embodiments, R1 is –NHOH. In embodiments, R1 is -OCCl3. In embodiments, R1 is -OCBr3. In embodiments, R1 is -OCF3. In embodiments, R1 is -OCI3. In embodiments, R1 is -OCH2Cl. In embodiments, R1 is -OCH2Br. In embodiments, R1 is -OCH2F. In embodiments, R1 is -OCH2I. In embodiments, R1 is -OCHCl2. In embodiments, R1 is -OCHBr2. In embodiments, R1 is -OCHF2. In embodiments, R1 is -OCHI2. In embodiments, R1 is -SF5. In embodiments, R1 is -N3. In embodiments, R1 is unsubstituted C1-C4 alkyl. In embodiments, R1 is unsubstituted methyl. In embodiments, R1 is unsubstituted ethyl. In embodiments, R1 is unsubstituted propyl. In embodiments, R1 is unsubstituted n-propyl. In embodiments, R1 is unsubstituted isopropyl. In embodiments, R1 is unsubstituted butyl. In embodiments, R1 is unsubstituted n-butyl. In embodiments, R1 is unsubstituted isobutyl. In embodiments, R1 is unsubstituted tert-butyl. In embodiments, R1 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1 is unsubstituted methoxy. In embodiments, R1 is unsubstituted ethoxy. In embodiments, R1 is unsubstituted propoxy. In embodiments, R1 is unsubstituted n-propoxy. In embodiments, R1 is unsubstituted isopropoxy. In embodiments, R1 is unsubstituted butoxy. [0268] In embodiments, R1 is substituted or unsubstituted 2 to 8 membered heteroalkyl. In is In embodiments R1 is . In embodiments, R1 eger from 0 to 10. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. [0269] In embodiments, R1 is E. In embodiments, E is O R11 O R11 ,
-N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0271] X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0272] In embodiments, E is O R11
In embodiments In embodiments, E is . In In embodiments, E is is . In embodiments, E . In embodiments, E . In embodiments, E In X11 X11 embodiments, E . In embodiments, E . In embodiments, E . In embodiments, E . In embodiments, E . In In . O Cl [0274] In embodiments, R1 . In embodiments, R1 is . 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 R11 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 R11 is substituted, it is substituted with at least one substituent group. In embodiments, when R11 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11 is substituted, it is substituted with at least one lower substituent group. [0276] In embodiments, R11 is hydrogen. In embodiments, R11 is unsubstituted C1-C4 alkyl. In embodiments, R11 is unsubstituted methyl. In embodiments, R11 is unsubstituted ethyl. In embodiments, R11 is unsubstituted propyl. In embodiments, R11 is unsubstituted n- propyl. In embodiments, R11 is unsubstituted isopropyl. In embodiments, R11 is unsubstituted butyl. In embodiments, R11 is unsubstituted n-butyl. In embodiments, R11 is unsubstituted isobutyl. In embodiments, R11 is unsubstituted tert-butyl. [0277] In embodiments, a substituted R12 (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 R12 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 R12 is substituted, it is substituted with at least one substituent group. In embodiments, when R12 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R12 is substituted, it is substituted with at least one lower substituent group. [0278] In embodiments, R12 is hydrogen. In embodiments, R12 is unsubstituted C1-C4 alkyl. In embodiments, R12 is unsubstituted methyl. In embodiments, R12 is unsubstituted ethyl. In embodiments, R12 is unsubstituted propyl. In embodiments, R12 is unsubstituted n- propyl. In embodiments, R12 is unsubstituted isopropyl. In embodiments, R12 is unsubstituted butyl. In embodiments, R12 is unsubstituted n-butyl. In embodiments, R12 is unsubstituted isobutyl. In embodiments, R12 is unsubstituted tert-butyl. [0279] In embodiments, a substituted R13 (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 R13 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 R13 is substituted, it is substituted with at least one substituent group. In embodiments, when R13 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R13 is substituted, it is substituted with at least one lower substituent group. [0280] In embodiments, R13 is hydrogen. In embodiments, R13 is unsubstituted C1-C4 alkyl. In embodiments, R13 is unsubstituted methyl. In embodiments, R13 is unsubstituted ethyl. In embodiments, R13 is unsubstituted propyl. In embodiments, R13 is unsubstituted n- propyl. In embodiments, R13 is unsubstituted isopropyl. In embodiments, R13 is unsubstituted butyl. In embodiments, R13 is unsubstituted n-butyl. In embodiments, R13 is unsubstituted isobutyl. In embodiments, R13 is unsubstituted tert-butyl. [0281] In embodiments, a substituted R14 (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 R14 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 R14 is substituted, it is substituted with at least one substituent group. In embodiments, when R14 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14 is substituted, it is substituted with at least one lower substituent group. [0282] In embodiments, R14 is hydrogen. In embodiments, R14 is unsubstituted C1-C4 alkyl. In embodiments, R14 is unsubstituted methyl. In embodiments, R14 is unsubstituted ethyl. In embodiments, R14 is unsubstituted propyl. In embodiments, R14 is unsubstituted n- propyl. In embodiments, R14 is unsubstituted isopropyl. In embodiments, R14 is unsubstituted butyl. In embodiments, R14 is unsubstituted n-butyl. In embodiments, R14 is unsubstituted isobutyl. In embodiments, R14 is unsubstituted tert-butyl. [0283] In embodiments, R11, R12, R13, and R14 are hydrogen. O , embodiments, R1 . In embodiments, R1 . In embodiments, O . In embodiments, R1 is embodiments, R1 . In embodiments, R1 is embodiments, R1 . In embodiments, R1 is . [0285] In embodiments, a substituted R2 (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 R2 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 R2 is substituted, it is substituted with at least one substituent group. In embodiments, when R2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2 is substituted, it is substituted with at least one lower substituent group. [0286] In embodiments, a substituted ring formed when two R2 substituents are joined (e.g., 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 ring formed when two R2 substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R2 substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R2 substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R2 substituents are joined is substituted, it is substituted with at least one lower substituent group. [0287] In embodiments, a substituted R2A (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 R2A 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 R2A is substituted, it is substituted with at least one substituent group. In embodiments, when R2A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2A is substituted, it is substituted with at least one lower substituent group. [0288] In embodiments, a substituted R2B (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 R2B 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 R2B is substituted, it is substituted with at least one substituent group. In embodiments, when R2B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2B is substituted, it is substituted with at least one lower substituent group. [0289] In embodiments, a substituted ring formed when R2A and R2B substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R2A and R2B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2A and R2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2A and R2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2A and R2B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0290] In embodiments, a substituted R2C (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 R2C 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 R2C is substituted, it is substituted with at least one substituent group. In embodiments, when R2C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2C is substituted, it is substituted with at least one lower substituent group. [0291] In embodiments, a substituted R2D (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 R2D 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 R2D is substituted, it is substituted with at least one substituent group. In embodiments, when R2D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2D is substituted, it is substituted with at least one lower substituent group. [0292] In embodiments, R2A is independently hydrogen. In embodiments, R2A is independently unsubstituted C1-C4 alkyl. In embodiments, R2A is independently unsubstituted methyl. In embodiments, R2A is independently unsubstituted ethyl. In embodiments, R2A is independently unsubstituted propyl. In embodiments, R2A is independently unsubstituted n-propyl. In embodiments, R2A is independently unsubstituted isopropyl. In embodiments, R2A is independently unsubstituted butyl. In embodiments, R2A is independently unsubstituted n-butyl. In embodiments, R2A is independently unsubstituted isobutyl. In embodiments, R2A is independently unsubstituted tert-butyl. [0293] In embodiments, R2B is independently hydrogen. In embodiments, R2B is independently unsubstituted C1-C4 alkyl. In embodiments, R2B is independently unsubstituted methyl. In embodiments, R2B is independently unsubstituted ethyl. In embodiments, R2B is independently unsubstituted propyl. In embodiments, R2B is independently unsubstituted n-propyl. In embodiments, R2B is independently unsubstituted isopropyl. In embodiments, R2B is independently unsubstituted butyl. In embodiments, R2B is independently unsubstituted n-butyl. In embodiments, R2B is independently unsubstituted isobutyl. In embodiments, R2B is independently unsubstituted tert-butyl. [0294] In embodiments, R2C is independently hydrogen. In embodiments, R2C is independently unsubstituted C1-C4 alkyl. In embodiments, R2C is independently unsubstituted methyl. In embodiments, R2C is independently unsubstituted ethyl. In embodiments, R2C is independently unsubstituted propyl. In embodiments, R2C is independently unsubstituted n-propyl. In embodiments, R2C is independently unsubstituted isopropyl. In embodiments, R2C is independently unsubstituted butyl. In embodiments, R2C is independently unsubstituted n-butyl. In embodiments, R2C is independently unsubstituted isobutyl. In embodiments, R2C is independently unsubstituted tert-butyl. [0295] In embodiments, R2D is independently hydrogen. In embodiments, R2D is independently unsubstituted C1-C4 alkyl. In embodiments, R2D is independently unsubstituted methyl. In embodiments, R2D is independently unsubstituted ethyl. In embodiments, R2D is independently unsubstituted propyl. In embodiments, R2D is independently unsubstituted n-propyl. In embodiments, R2D is independently unsubstituted isopropyl. In embodiments, R2D is independently unsubstituted butyl. In embodiments, R2D is independently unsubstituted n-butyl. In embodiments, R2D is independently unsubstituted isobutyl. In embodiments, R2D is independently unsubstituted tert-butyl. [0296] In embodiments, R2 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0297] In embodiments, R2 is independently halogen. In embodiments, R2 is independently –F. In embodiments, R2 is independently –Cl. In embodiments, R2 is independently –Br. In embodiments, R2 is independently –I. In embodiments, R2 is independently -CCl3. In embodiments, R2 is independently -CBr3. In embodiments, R2 is independently -CF3. In embodiments, R2 is independently -CI3. In embodiments, R2 is independently -CH2Cl. In embodiments, R2 is independently -CH2Br. In embodiments, R2 is independently -CH2F. In embodiments, R2 is independently -CH2I. In embodiments, R2 is independently -CHCl2. In embodiments, R2 is independently -CHBr2. In embodiments, R2 is independently -CHF2. In embodiments, R2 is independently -CHI2. In embodiments, R2 is independently –CN. In embodiments, R2 is independently –OH. In embodiments, R2 is independently -NH2. In embodiments, R2 is independently -C(O)R2C, wherein R2C is as described herein, including in embodiments. In embodiments, R2 is independently -C(O)H. In embodiments, R2 is independently -C(O)OR2C, wherein R2C is as described herein, including in embodiments. In embodiments, R2 is independently –COOH. In embodiments, R2 is independently -C(O)CH3. In embodiments, R2 is independently -CONH2. In embodiments, R2 is independently -NO2. In embodiments, R2 is independently –SH. In embodiments, R2 is independently -SO3H. In embodiments, R2 is independently -OSO3H. In embodiments, R2 is independently -SO2NH2. In embodiments, R2 is independently ^NHNH2. In embodiments, R2 is independently ^ONH2. In embodiments, R2 is independently ^NHC(O)NH2. In embodiments, R2 is independently -NHSO2H. In embodiments, R2 is independently -NHC(O)H. In embodiments, R2 is independently -NHC(O)OH. In embodiments, R2 is independently –NHOH. In embodiments, R2 is independently -OCCl3. In embodiments, R2 is independently -OCBr3. In embodiments, R2 is independently -OCF3. In embodiments, R2 is independently -OCI3. In embodiments, R2 is independently -OCH2Cl. In embodiments, R2 is independently -OCH2Br. In embodiments, R2 is independently -OCH2F. In embodiments, R2 is independently -OCH2I. In embodiments, R2 is independently -OCHCl2. In embodiments, R2 is independently -OCHBr2. In embodiments, R2 is independently -OCHF2. In embodiments, R2 is independently -OCHI2. In embodiments, R2 is independently -SF5. In embodiments, R2 is independently -N3. In embodiments, R2 is independently unsubstituted C1-C4 alkyl. In embodiments, R2 is independently unsubstituted methyl. In embodiments, R2 is independently unsubstituted ethyl. In embodiments, R2 is independently unsubstituted propyl. In embodiments, R2 is independently unsubstituted n-propyl. In embodiments, R2 is independently unsubstituted isopropyl. In embodiments, R2 is independently unsubstituted butyl. In embodiments, R2 is independently unsubstituted n-butyl. In embodiments, R2 is independently unsubstituted isobutyl. In embodiments, R2 is independently unsubstituted tert-butyl. In embodiments, R2 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R2 is independently unsubstituted methoxy. In embodiments, R2 is independently unsubstituted ethoxy. In embodiments, R2 is independently unsubstituted propoxy. In embodiments, R2 is independently unsubstituted n-propoxy. In embodiments, R2 is independently unsubstituted isopropoxy. In embodiments, R2 is independently unsubstituted butoxy. [0298] In embodiments, R2 is independently halogen, -CX23, -C(O)R2C, -C(O)OR2C, -OR2D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R2 is independently –Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3. [0299] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. [0300] In embodiments, a substituted R3 (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 R3 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 R3 is substituted, it is substituted with at least one substituent group. In embodiments, when R3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3 is substituted, it is substituted with at least one lower substituent group. [0301] In embodiments, R3 is hydrogen. In embodiments, R3 is halogen. In embodiments, R3 is –F. In embodiments, R3 is –Cl. In embodiments, R3 is –Br. In embodiments, R3 is –I. In embodiments, R3 is -CCl3. In embodiments, R3 is -CBr3. In embodiments, R3 is -CF3. In embodiments, R3 is -CI3. In embodiments, R3 is -CH2Cl. In embodiments, R3 is -CH2Br. In embodiments, R3 is -CH2F. In embodiments, R3 is -CH2I. In embodiments, R3 is -CHCl2. In embodiments, R3 is -CHBr2. In embodiments, R3 is -CHF2. In embodiments, R3 is -CHI2. In embodiments, R3 is –CN. In embodiments, R3 is –OH. In embodiments, R3 is -NH2. In embodiments, R3 is –COOH. In embodiments, R3 is -CONH2. In embodiments, R3 is -NO2. In embodiments, R3 is –SH. In embodiments, R3 is -SO3H. In embodiments, R3 is -OSO3H. In embodiments, R3 is -SO2NH2. In embodiments, R3 is ^NHNH2. In embodiments, R3 is ^ONH2. In embodiments, R3 is ^NHC(O)NH2. In embodiments, R3 is -NHSO2H. In embodiments, R3 is -NHC(O)H. In embodiments, R3 is -NHC(O)OH. In embodiments, R3 is –NHOH. In embodiments, R3 is -OCCl3. In embodiments, R3 is -OCBr3. In embodiments, R3 is -OCF3. In embodiments, R3 is -OCI3. In embodiments, R3 is -OCH2Cl. In embodiments, R3 is -OCH2Br. In embodiments, R3 is -OCH2F. In embodiments, R3 is -OCH2I. In embodiments, R3 is -OCHCl2. In embodiments, R3 is -OCHBr2. In embodiments, R3 is -OCHF2. In embodiments, R3 is -OCHI2. In embodiments, R3 is -SF5. In embodiments, R3 is -N3. In embodiments, R3 is unsubstituted C1-C4 alkyl. In embodiments, R3 is unsubstituted methyl. In embodiments, R3 is unsubstituted ethyl. In embodiments, R3 is unsubstituted propyl. In embodiments, R3 is unsubstituted n-propyl. In embodiments, R3 is unsubstituted isopropyl. In embodiments, R3 is unsubstituted butyl. In embodiments, R3 is unsubstituted n-butyl. In embodiments, R3 is unsubstituted isobutyl. In embodiments, R3 is unsubstituted tert-butyl. In embodiments, R3 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3 is unsubstituted methoxy. In embodiments, R3 is unsubstituted ethoxy. In embodiments, R3 is unsubstituted propoxy. In embodiments, R3 is unsubstituted n-propoxy. In embodiments, R3 is unsubstituted isopropoxy. In embodiments, R3 is unsubstituted butoxy. In embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R3 is substituted or unsubstituted cyclopropyl. In embodiments, R3 is substituted or unsubstituted cyclobutyl. In embodiments, R3 is substituted or unsubstituted cyclopentyl. In embodiments, R3 is substituted or unsubstituted cyclohexyl. In embodiments, R3 is substituted or unsubstituted cycloheptyl. In embodiments, R3 is substituted or unsubstituted cyclooctyl. In embodiments, R3 is substituted or unsubstituted phenyl. [0302] In embodiments, a substituted R4 (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 R4 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 R4 is substituted, it is substituted with at least one substituent group. In embodiments, when R4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4 is substituted, it is substituted with at least one lower substituent group. [0303] In embodiments, R4 is hydrogen. In embodiments, R4 is halogen. In embodiments, R4 is –F. In embodiments, R4 is –Cl. In embodiments, R4 is –Br. In embodiments, R4 is –I. In embodiments, R4 is –CCl3. In embodiments, R4 is –CBr3. In embodiments, R4 is –CF3. In embodiments, R4 is –CI3. In embodiments, R4 is -CH2Cl. In embodiments, R4 is -CH2Br. In embodiments, R4 is -CH2F. In embodiments, R4 is -CH2I. In embodiments, R4 is -CHCl2. In embodiments, R4 is -CHBr2. In embodiments, R4 is -CHF2. In embodiments, R4 is -CHI2. In embodiments, R4 is –CN. In embodiments, R4 is –OH. In embodiments, R4 is -NH2. In embodiments, R4 is –COOH. In embodiments, R4 is -CONH2. In embodiments, R4 is -NO2. In embodiments, R4 is –SH. In embodiments, R4 is –SO3H. In embodiments, R4 is –OSO3H. In embodiments, R4 is -SO2NH2. In embodiments, R4 is ^NHNH2. In embodiments, R4 is ^ONH2. In embodiments, R4 is ^NHC(O)NH2. In embodiments, R4 is -NHSO2H. In embodiments, R4 is -NHC(O)H. In embodiments, R4 is -NHC(O)OH. In embodiments, R4 is –NHOH. In embodiments, R4 is –OCCl3. In embodiments, R4 is –OCBr3. In embodiments, R4 is –OCF3. In embodiments, R4 is –OCI3. In embodiments, R4 is -OCH2Cl. In embodiments, R4 is -OCH2Br. In embodiments, R4 is -OCH2F. In embodiments, R4 is -OCH2I. In embodiments, R4 is -OCHCl2. In embodiments, R4 is -OCHBr2. In embodiments, R4 is -OCHF2. In embodiments, R4 is -OCHI2. In embodiments, R4 is -SF5. In embodiments, R4 is –N3. In embodiments, R4 is unsubstituted C1-C4 alkyl. In embodiments, R4 is unsubstituted methyl. In embodiments, R4 is unsubstituted ethyl. In embodiments, R4 is unsubstituted propyl. In embodiments, R4 is unsubstituted n-propyl. In embodiments, R4 is unsubstituted isopropyl. In embodiments, R4 is unsubstituted butyl. In embodiments, R4 is unsubstituted n-butyl. In embodiments, R4 is unsubstituted isobutyl. In embodiments, R4 is unsubstituted tert-butyl. In embodiments, R4 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4 is unsubstituted methoxy. In embodiments, R4 is unsubstituted ethoxy. In embodiments, R4 is unsubstituted propoxy. In embodiments, R4 is unsubstituted n-propoxy. In embodiments, R4 is unsubstituted isopropoxy. In embodiments, R4 is unsubstituted butoxy. [0304] In embodiments, a substituted ring formed when R3 and R4 substituents are joined (e.g., substituted cycloalkyl and/or substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3 and R4 substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size- limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R3 and R4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3 and R4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3 and R4 substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0305] In embodiments, R3 and R4 combine to form a substituted or unsubstituted C3-C8 heterocycloalkyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cyclopropyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cyclobutyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cyclopentyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cyclohexyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cycloheptyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted cyclooctyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted tetrahydropyranyl. In embodiments, R3 and R4 combine to form a substituted or unsubstituted piperidinyl. In embodiments, R3 and R4 combine to In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . In embodiments, R3 and R4 combine to . [0306] In embodiments, a substituted R5 (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 R5 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 R5 is substituted, it is substituted with at least one substituent group. In embodiments, when R5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5 is substituted, it is substituted with at least one lower substituent group. [0307] In embodiments, R5 is halogen. In embodiments, R5 is –F. In embodiments, R5 is –Cl. In embodiments, R5 is –Br. In embodiments, R5 is –I. In embodiments, R5 is –CCl3. In embodiments, R5 is –CBr3. In embodiments, R5 is –CF3. In embodiments, R5 is –CI3. In embodiments, R5 is -CH2Cl. In embodiments, R5 is -CH2Br. In embodiments, R5 is -CH2F. In embodiments, R5 is -CH2I. In embodiments, R5 is -CHCl2. In embodiments, R5 is -CHBr2. In embodiments, R5 is -CHF2. In embodiments, R5 is -CHI2. In embodiments, R5 is –CN. In embodiments, R5 is –OH. In embodiments, R5 is -NH2. In embodiments, R5 is –COOH. In embodiments, R5 is -CONH2. In embodiments, R5 is -NO2. In embodiments, R5 is –SH. In embodiments, R5 is –SO3H. In embodiments, R5 is –OSO3H. In embodiments, R5 is -SO2NH2. In embodiments, R5 is ^NHNH2. In embodiments, R5 is ^ONH2. In embodiments, R5 is ^NHC(O)NH2. In embodiments, R5 is -NHSO2H. In embodiments, R5 is -NHC(O)H. In embodiments, R5 is -NHC(O)OH. In embodiments, R5 is –NHOH. In embodiments, R5 is –OCCl3. In embodiments, R5 is –OCBr3. In embodiments, R5 is –OCF3. In embodiments, R5 is –OCI3. In embodiments, R5 is -OCH2Cl. In embodiments, R5 is -OCH2Br. In embodiments, R5 is -OCH2F. In embodiments, R5 is -OCH2I. In embodiments, R5 is -OCHCl2. In embodiments, R5 is -OCHBr2. In embodiments, R5 is -OCHF2. In embodiments, R5 is -OCHI2. In embodiments, R5 is -SF5. In embodiments, R5 is –N3. In embodiments, R5 is unsubstituted C1-C4 alkyl. In embodiments, R5 is unsubstituted methyl. In embodiments, R5 is unsubstituted ethyl. In embodiments, R5 is unsubstituted propyl. In embodiments, R5 is unsubstituted n-propyl. In embodiments, R5 is unsubstituted isopropyl. In embodiments, R5 is unsubstituted butyl. In embodiments, R5 is unsubstituted n-butyl. In embodiments, R5 is unsubstituted isobutyl. In embodiments, R5 is unsubstituted tert-butyl. In embodiments, R5 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5 is unsubstituted methoxy. In embodiments, R5 is unsubstituted ethoxy. In embodiments, R5 is unsubstituted propoxy. In embodiments, R5 is unsubstituted n- propoxy. In embodiments, R5 is unsubstituted isopropoxy. In embodiments, R5 is unsubstituted butoxy. [0308] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. [0309] In embodiments, a substituted R6 (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 R6 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 R6 is substituted, it is substituted with at least one substituent group. In embodiments, when R6 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6 is substituted, it is substituted with at least one lower substituent group. [0310] In embodiments, R6 is halogen. In embodiments, R6 is –F. In embodiments, R6 is –Cl. In embodiments, R6 is –Br. In embodiments, R6 is –I. In embodiments, R6 is –CCl3. In embodiments, R6 is –CBr3. In embodiments, R6 is –CF3. In embodiments, R6 is –CI3. In embodiments, R6 is -CH2Cl. In embodiments, R6 is -CH2Br. In embodiments, R6 is -CH2F. In embodiments, R6 is -CH2I. In embodiments, R6 is -CHCl2. In embodiments, R6 is -CHBr2. In embodiments, R6 is -CHF2. In embodiments, R6 is -CHI2. In embodiments, R6 is –CN. In embodiments, R6 is –OH. In embodiments, R6 is -NH2. In embodiments, R6 is –COOH. In embodiments, R6 is -CONH2. In embodiments, R6 is -NO2. In embodiments, R6 is –SH. In embodiments, R6 is –SO3H. In embodiments, R6 is –OSO3H. In embodiments, R6 is -SO2NH2. In embodiments, R6 is ^NHNH2. In embodiments, R6 is ^ONH2. In embodiments, R6 is ^NHC(O)NH2. In embodiments, R6 is -NHSO2H. In embodiments, R6 is -NHC(O)H. In embodiments, R6 is -NHC(O)OH. In embodiments, R6 is –NHOH. In embodiments, R6 is –OCCl3. In embodiments, R6 is –OCBr3. In embodiments, R6 is –OCF3. In embodiments, R6 is –OCI3. In embodiments, R6 is -OCH2Cl. In embodiments, R6 is -OCH2Br. In embodiments, R6 is -OCH2F. In embodiments, R6 is -OCH2I. In embodiments, R6 is -OCHCl2. In embodiments, R6 is -OCHBr2. In embodiments, R6 is -OCHF2. In embodiments, R6 is -OCHI2. In embodiments, R6 is –SF5. In embodiments, R6 is –N3. In embodiments, R6 is unsubstituted C1-C4 alkyl. In embodiments, R6 is unsubstituted methyl. In embodiments, R6 is unsubstituted ethyl. In embodiments, R6 is unsubstituted propyl. In embodiments, R6 is unsubstituted n-propyl. In embodiments, R6 is unsubstituted isopropyl. In embodiments, R6 is unsubstituted butyl. In embodiments, R6 is unsubstituted n-butyl. In embodiments, R6 is unsubstituted isobutyl. In embodiments, R6 is unsubstituted tert-butyl. [0311] In embodiments, a substituted R7 (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 R7 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 R7 is substituted, it is substituted with at least one substituent group. In embodiments, when R7 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7 is substituted, it is substituted with at least one lower substituent group. [0312] In embodiments, R7 is halogen. In embodiments, R7 is –F. In embodiments, R7 is –Cl. In embodiments, R7 is –Br. In embodiments, R7 is –I. In embodiments, R7 is –CCl3. In embodiments, R7 is –CBr3. In embodiments, R7 is –CF3. In embodiments, R7 is –CI3. In embodiments, R7 is -CH2Cl. In embodiments, R7 is -CH2Br. In embodiments, R7 is -CH2F. In embodiments, R7 is -CH2I. In embodiments, R7 is -CHCl2. In embodiments, R7 is -CHBr2. In embodiments, R7 is -CHF2. In embodiments, R7 is -CHI2. In embodiments, R7 is –CN. In embodiments, R7 is –OH. In embodiments, R7 is -NH2. In embodiments, R7 is –COOH. In embodiments, R7 is -CONH2. In embodiments, R7 is -NO2. In embodiments, R7 is –SH. In embodiments, R7 is –SO3H. In embodiments, R7 is –OSO3H. In embodiments, R7 is -SO2NH2. In embodiments, R7 is ^NHNH2. In embodiments, R7 is ^ONH2. In embodiments, R7 is ^NHC(O)NH2. In embodiments, R7 is -NHSO2H. In embodiments, R7 is -NHC(O)H. In embodiments, R7 is -NHC(O)OH. In embodiments, R7 is –NHOH. In embodiments, R7 is –OCCl3. In embodiments, R7 is –OCBr3. In embodiments, R7 is –OCF3. In embodiments, R7 is –OCI3. In embodiments, R7 is -OCH2Cl. In embodiments, R7 is -OCH2Br. In embodiments, R7 is -OCH2F. In embodiments, R7 is -OCH2I. In embodiments, R7 is -OCHCl2. In embodiments, R7 is -OCHBr2. In embodiments, R7 is -OCHF2. In embodiments, R7 is -OCHI2. In embodiments, R7 is –SF5. In embodiments, R7 is –N3. In embodiments, R7 is unsubstituted C1-C4 alkyl. In embodiments, R7 is unsubstituted methyl. In embodiments, R7 is unsubstituted ethyl. In embodiments, R7 is unsubstituted propyl. In embodiments, R7 is unsubstituted n-propyl. In embodiments, R7 is unsubstituted isopropyl. In embodiments, R7 is unsubstituted butyl. In embodiments, R7 is unsubstituted n-butyl. In embodiments, R7 is unsubstituted isobutyl. In embodiments, R7 is unsubstituted tert-butyl. [0313] In embodiments, a substituted R8 (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 R8 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 R8 is substituted, it is substituted with at least one substituent group. In embodiments, when R8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8 is substituted, it is substituted with at least one lower substituent group. [0314] In embodiments, R8 is halogen. In embodiments, R8 is –F. In embodiments, R8 is –Cl. In embodiments, R8 is –Br. In embodiments, R8 is –I. In embodiments, R8 is –CCl3. In embodiments, R8 is –CBr3. In embodiments, R8 is –CF3. In embodiments, R8 is –CI3. In embodiments, R8 is -CH2Cl. In embodiments, R8 is -CH2Br. In embodiments, R8 is -CH2F. In embodiments, R8 is -CH2I. In embodiments, R8 is -CHCl2. In embodiments, R8 is -CHBr2. In embodiments, R8 is -CHF2. In embodiments, R8 is -CHI2. In embodiments, R8 is –CN. In embodiments, R8 is –OH. In embodiments, R8 is -NH2. In embodiments, R8 is –COOH. In embodiments, R8 is -CONH2. In embodiments, R8 is -NO2. In embodiments, R8 is –SH. In embodiments, R8 is –SO3H. In embodiments, R8 is –OSO3H. In embodiments, R8 is -SO2NH2. In embodiments, R8 is ^NHNH2. In embodiments, R8 is ^ONH2. In embodiments, R8 is ^NHC(O)NH2. In embodiments, R8 is -NHSO2H. In embodiments, R8 is -NHC(O)H. In embodiments, R8 is -NHC(O)OH. In embodiments, R8 is –NHOH. In embodiments, R8 is –OCCl3. In embodiments, R8 is –OCBr3. In embodiments, R8 is –OCF3. In embodiments, R8 is –OCI3. In embodiments, R8 is -OCH2Cl. In embodiments, R8 is -OCH2Br. In embodiments, R8 is -OCH2F. In embodiments, R8 is -OCH2I. In embodiments, R8 is -OCHCl2. In embodiments, R8 is -OCHBr2. In embodiments, R8 is -OCHF2. In embodiments, R8 is -OCHI2. In embodiments, R8 is –SF5. In embodiments, R8 is –N3. In embodiments, R8 is unsubstituted C1-C4 alkyl. In embodiments, R8 is unsubstituted methyl. In embodiments, R8 is unsubstituted ethyl. In embodiments, R8 is unsubstituted propyl. In embodiments, R8 is unsubstituted n-propyl. In embodiments, R8 is unsubstituted isopropyl. In embodiments, R8 is unsubstituted butyl. In embodiments, R8 is unsubstituted n-butyl. In embodiments, R8 is unsubstituted isobutyl. In embodiments, R8 is unsubstituted tert-butyl. [0315] In embodiments, when Ring A is substituted, Ring A is substituted with one or more first substituent groups denoted by RA.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RA.1 substituent group is substituted, the RA.1 substituent group is substituted with one or more second substituent groups denoted by RA.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RA.2 substituent group is substituted, the RA.2 substituent group is substituted with one or more third substituent groups denoted by RA.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, RA, RA.1, RA.2, and RA.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to RA, RA.1, RA.2, and RA.3, respectively. [0316] In embodiments, when Ring B is substituted, Ring B is substituted with one or more first substituent groups denoted by RB.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB.1 substituent group is substituted, the RB.1 substituent group is substituted with one or more second substituent groups denoted by RB.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB.2 substituent group is substituted, the RB.2 substituent group is substituted with one or more third substituent groups denoted by RB.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, RB, RB.1, RB.2, and RB.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to RB, RB.1, RB.2, and RB.3, respectively. [0317] In embodiments, when R1 is substituted, R1 is substituted with one or more first substituent groups denoted by R1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1 substituent group is substituted, the R1.1 substituent group is substituted with one or more second substituent groups denoted by R1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2 substituent group is substituted, the R1.2 substituent group is substituted with one or more third substituent groups denoted by R1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1, R1.1, R1.2, and R1.3, respectively. [0318] In embodiments, when R1A is substituted, R1A is substituted with one or more first substituent groups denoted by R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1A, R1A.1, R1A.2, and R1A.3, respectively. [0319] In embodiments, when R1B is substituted, R1B is substituted with one or more first substituent groups denoted by R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted, the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1B, R1B.1, R1B.2, and R1B.3, respectively. [0320] In embodiments, when R1A and R1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R1A.1, R1A.2, and R1A.3, respectively. [0321] In embodiments, when R1A and R1B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted, the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R1B.1, R1B.2, and R1B.3, respectively. [0322] In embodiments, when R1C is substituted, R1C is substituted with one or more first substituent groups denoted by R1C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.1 substituent group is substituted, the R1C.1 substituent group is substituted with one or more second substituent groups denoted by R1C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.2 substituent group is substituted, the R1C.2 substituent group is substituted with one or more third substituent groups denoted by R1C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1C, R1C.1, R1C.2, and R1C.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1C, R1C.1, R1C.2, and R1C.3, respectively. [0323] In embodiments, when R1D is substituted, R1D is substituted with one or more first substituent groups denoted by R1D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.1 substituent group is substituted, the R1D.1 substituent group is substituted with one or more second substituent groups denoted by R1D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.2 substituent group is substituted, the R1D.2 substituent group is substituted with one or more third substituent groups denoted by R1D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D.1, R1D.2, and R1D.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1D, R1D.1, R1D.2, and R1D.3, respectively. [0324] In embodiments, when R2 is substituted, R2 is substituted with one or more first substituent groups denoted by R2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1 substituent group is substituted, the R2.1 substituent group is substituted with one or more second substituent groups denoted by R2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2 substituent group is substituted, the R2.2 substituent group is substituted with one or more third substituent groups denoted by R2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2, R2.1, R2.2, and R2.3, respectively. [0325] In embodiments, when two R2 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 R2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1 substituent group is substituted, the R2.1 substituent group is substituted with one or more second substituent groups denoted by R2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2 substituent group is substituted, the R2.2 substituent group is substituted with one or more third substituent groups denoted by R2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2, R2.1, R2.2, and R2.3, respectively. [0326] In embodiments, when R2A is substituted, R2A is substituted with one or more first substituent groups denoted by R2A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1 substituent group is substituted, the R2A.1 substituent group is substituted with one or more second substituent groups denoted by R2A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2 substituent group is substituted, the R2A.2 substituent group is substituted with one or more third substituent groups denoted by R2A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A, R2A.1, R2A.2, and R2A.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2A, R2A.1, R2A.2, and R2A.3, respectively. [0327] In embodiments, when R2B is substituted, R2B is substituted with one or more first substituent groups denoted by R2B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1 substituent group is substituted, the R2B.1 substituent group is substituted with one or more second substituent groups denoted by R2B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2 substituent group is substituted, the R2B.2 substituent group is substituted with one or more third substituent groups denoted by R2B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B, R2B.1, R2B.2, and R2B.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2B, R2B.1, R2B.2, and R2B.3, respectively. [0328] In embodiments, when R2A and R2B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1 substituent group is substituted, the R2A.1 substituent group is substituted with one or more second substituent groups denoted by R2A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2 substituent group is substituted, the R2A.2 substituent group is substituted with one or more third substituent groups denoted by R2A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A.1, R2A.2, and R2A.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R2A.1, R2A.2, and R2A.3, respectively. [0329] In embodiments, when R2A and R2B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1 substituent group is substituted, the R2B.1 substituent group is substituted with one or more second substituent groups denoted by R2B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2 substituent group is substituted, the R2B.2 substituent group is substituted with one or more third substituent groups denoted by R2B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B.1, R2B.2, and R2B.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R2B.1, R2B.2, and R2B.3, respectively. [0330] In embodiments, when R2C is substituted, R2C is substituted with one or more first substituent groups denoted by R2C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.1 substituent group is substituted, the R2C.1 substituent group is substituted with one or more second substituent groups denoted by R2C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.2 substituent group is substituted, the R2C.2 substituent group is substituted with one or more third substituent groups denoted by R2C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2C, R2C.1, R2C.2, and R2C.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2C, R2C.1, R2C.2, and R2C.3, respectively. [0331] In embodiments, when R2D is substituted, R2D is substituted with one or more first substituent groups denoted by R2D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.1 substituent group is substituted, the R2D.1 substituent group is substituted with one or more second substituent groups denoted by R2D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.2 substituent group is substituted, the R2D.2 substituent group is substituted with one or more third substituent groups denoted by R2D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2D, R2D.1, R2D.2, and R2D.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2D, R2D.1, R2D.2, and R2D.3, respectively. [0332] In embodiments, when R3 is substituted, R3 is substituted with one or more first substituent groups denoted by R3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1 substituent group is substituted, the R3.1 substituent group is substituted with one or more second substituent groups denoted by R3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2 substituent group is substituted, the R3.2 substituent group is substituted with one or more third substituent groups denoted by R3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R3, R3.1, R3.2, and R3.3, respectively. [0333] In embodiments, when R4 is substituted, R4 is substituted with one or more first substituent groups denoted by R4.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1 substituent group is substituted, the R4.1 substituent group is substituted with one or more second substituent groups denoted by R4.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2 substituent group is substituted, the R4.2 substituent group is substituted with one or more third substituent groups denoted by R4.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R4, R4.1, R4.2, and R4.3, respectively. [0334] In embodiments, when R3 and R4 substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1 substituent group is substituted, the R3.1 substituent group is substituted with one or more second substituent groups denoted by R3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2 substituent group is substituted, the R3.2 substituent group is substituted with one or more third substituent groups denoted by R3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3.1, R3.2, and R3.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R3.1, R3.2, and R3.3, respectively. [0335] In embodiments, when R3 and R4 substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl or substituted heterocycloalkyl), the moiety is substituted with one or more first substituent groups denoted by R4.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1 substituent group is substituted, the R4.1 substituent group is substituted with one or more second substituent groups denoted by R4.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2 substituent group is substituted, the R4.2 substituent group is substituted with one or more third substituent groups denoted by R4.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4.1, R4.2, and R4.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R4.1, R4.2, and R4.3, respectively. [0336] In embodiments, when R5 is substituted, R5 is substituted with one or more first substituent groups denoted by R5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1 substituent group is substituted, the R5.1 substituent group is substituted with one or more second substituent groups denoted by R5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2 substituent group is substituted, the R5.2 substituent group is substituted with one or more third substituent groups denoted by R5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R5, R5.1, R5.2, and R5.3, respectively. [0337] In embodiments, when R6 is substituted, R6 is substituted with one or more first substituent groups denoted by R6.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.1 substituent group is substituted, the R6.1 substituent group is substituted with one or more second substituent groups denoted by R6.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.2 substituent group is substituted, the R6.2 substituent group is substituted with one or more third substituent groups denoted by R6.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6, R6.1, R6.2, and R6.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R6, R6.1, R6.2, and R6.3, respectively. [0338] In embodiments, when R7 is substituted, R7 is substituted with one or more first substituent groups denoted by R7.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1 substituent group is substituted, the R7.1 substituent group is substituted with one or more second substituent groups denoted by R7.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2 substituent group is substituted, the R7.2 substituent group is substituted with one or more third substituent groups denoted by R7.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7, R7.1, R7.2, and R7.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R7, R7.1, R7.2, and R7.3, respectively. [0339] In embodiments, when R8 is substituted, R8 is substituted with one or more first substituent groups denoted by R8.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.1 substituent group is substituted, the R8.1 substituent group is substituted with one or more second substituent groups denoted by R8.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.2 substituent group is substituted, the R8.2 substituent group is substituted with one or more third substituent groups denoted by R8.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8, R8.1, R8.2, and R8.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R8, R8.1, R8.2, and R8.3, respectively. [0340] In embodiments, when R10 is substituted, R10 is substituted with one or more first substituent groups denoted by R10.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1 substituent group is substituted, the R10.1 substituent group is substituted with one or more second substituent groups denoted by R10.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2 substituent group is substituted, the R10.2 substituent group is substituted with one or more third substituent groups denoted by R10.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R10, R10.1, R10.2, and R10.3, respectively. [0341] In embodiments, when R11 is substituted, R11 is substituted with one or more first substituent groups denoted by R11.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.1 substituent group is substituted, the R11.1 substituent group is substituted with one or more second substituent groups denoted by R11.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.2 substituent group is substituted, the R11.2 substituent group is substituted with one or more third substituent groups denoted by R11.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11, R11.1, R11.2, and R11.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R11, R11.1, R11.2, and R11.3, respectively. [0342] In embodiments, when R12 is substituted, R12 is substituted with one or more first substituent groups denoted by R12.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.1 substituent group is substituted, the R12.1 substituent group is substituted with one or more second substituent groups denoted by R12.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.2 substituent group is substituted, the R12.2 substituent group is substituted with one or more third substituent groups denoted by R12.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12, R12.1, R12.2, and R12.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R12, R12.1, R12.2, and R12.3, respectively. [0343] In embodiments, when R13 is substituted, R13 is substituted with one or more first substituent groups denoted by R13.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.1 substituent group is substituted, the R13.1 substituent group is substituted with one or more second substituent groups denoted by R13.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.2 substituent group is substituted, the R13.2 substituent group is substituted with one or more third substituent groups denoted by R13.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13, R13.1, R13.2, and R13.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R13, R13.1, R13.2, and R13.3, respectively. [0344] In embodiments, when R14 is substituted, R14 is substituted with one or more first substituent groups denoted by R14.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R14.1 substituent group is substituted, the R14.1 substituent group is substituted with one or more second substituent groups denoted by R14.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R14.2 substituent group is substituted, the R14.2 substituent group is substituted with one or more third substituent groups denoted by R14.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R14, R14.1, R14.2, and R14.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R14, R14.1, R14.2, and R14.3, respectively. [0345] In embodiments, when R20 is substituted, R20 is substituted with one or more first substituent groups denoted by R20.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1 substituent group is substituted, the R20.1 substituent group is substituted with one or more second substituent groups denoted by R20.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2 substituent group is substituted, the R20.2 substituent group is substituted with one or more third substituent groups denoted by R20.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R20, R20.1, R20.2, and R20.3, respectively. [0346] In embodiments, when R30 is substituted, R30 is substituted with one or more first substituent groups denoted by R30.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R30.1 substituent group is substituted, the R30.1 substituent group is substituted with one or more second substituent groups denoted by R30.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R30.2 substituent group is substituted, the R30.2 substituent group is substituted with one or more third substituent groups denoted by R30.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R30, R30.1, R30.2, and R30.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R30, R30.1, R30.2, and R30.3, respectively. [0347] In embodiments, when R40 is substituted, R40 is substituted with one or more first substituent groups denoted by R40.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R40.1 substituent group is substituted, the R40.1 substituent group is substituted with one or more second substituent groups denoted by R40.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R40.2 substituent group is substituted, the R40.2 substituent group is substituted with one or more third substituent groups denoted by R40.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R40, R40.1, R40.2, and R40.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R40, R40.1, R40.2, and R40.3, respectively. [0348] In embodiments, when R50 is substituted, R50 is substituted with one or more first substituent groups denoted by R50.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R50.1 substituent group is substituted, the R50.1 substituent group is substituted with one or more second substituent groups denoted by R50.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R50.2 substituent group is substituted, the R50.2 substituent group is substituted with one or more third substituent groups denoted by R50.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R50, R50.1, R50.2, and R50.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R50, R50.1, R50.2, and R50.3, respectively. [0349] In embodiments, when R60 is substituted, R60 is substituted with one or more first substituent groups denoted by R60.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R60.1 substituent group is substituted, the R60.1 substituent group is substituted with one or more second substituent groups denoted by R60.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R60.2 substituent group is substituted, the R60.2 substituent group is substituted with one or more third substituent groups denoted by R60.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R60, R60.1, R60.2, and R60.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R60, R60.1, R60.2, and R60.3, respectively. [0350] In embodiments, when R70 is substituted, R70 is substituted with one or more first substituent groups denoted by R70.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R70.1 substituent group is substituted, the R70.1 substituent group is substituted with one or more second substituent groups denoted by R70.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R70.2 substituent group is substituted, the R70.2 substituent group is substituted with one or more third substituent groups denoted by R70.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R70, R70.1, R70.2, and R70.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R70, R70.1, R70.2, and R70.3, respectively. [0351] In embodiments, when R80 is substituted, R80 is substituted with one or more first substituent groups denoted by R80.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R80.1 substituent group is substituted, the R80.1 substituent group is substituted with one or more second substituent groups denoted by R80.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R80.2 substituent group is substituted, the R80.2 substituent group is substituted with one or more third substituent groups denoted by R80.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R80, R80.1, R80.2, and R80.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R80, R80.1, R80.2, and R80.3, respectively. [0352] In embodiments, when R90 is substituted, R90 is substituted with one or more first substituent groups denoted by R90.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R90.1 substituent group is substituted, the R90.1 substituent group is substituted with one or more second substituent groups denoted by R90.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R90.2 substituent group is substituted, the R90.2 substituent group is substituted with one or more third substituent groups denoted by R90.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R90, R90.1, R90.2, and R90.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R90, R90.1, R90.2, and R90.3, respectively. [0353] In embodiments, when L1 is substituted, L1 is substituted with one or more first substituent groups denoted by RL1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.1 substituent group is substituted, the RL1.1 substituent group is substituted with one or more second substituent groups denoted by RL1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.2 substituent group is substituted, the RL1.2 substituent group is substituted with one or more third substituent groups denoted by RL1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L1, RL1.1, RL1.2, and RL1.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L1, RL1.1, RL1.2, and RL1.3, respectively. [0354] In embodiments, when L2 is substituted, L2 is substituted with one or more first substituent groups denoted by RL2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL2.1 substituent group is substituted, the RL2.1 substituent group is substituted with one or more second substituent groups denoted by RL2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL2.2 substituent group is substituted, the RL2.2 substituent group is substituted with one or more third substituent groups denoted by RL2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L2, RL2.1, RL2.2, and RL2.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L2, RL2.1, RL2.2, and RL2.3, respectively. [0355] In embodiments, when L3 is substituted, L3 is substituted with one or more first substituent groups denoted by RL3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL3.1 substituent group is substituted, the RL3.1 substituent group is substituted with one or more second substituent groups denoted by RL3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL3.2 substituent group is substituted, the RL3.2 substituent group is substituted with one or more third substituent groups denoted by RL3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L3, RL3.1, RL3.2, and RL3.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L3, RL3.1, RL3.2, and RL3.3, respectively. [0356] In embodiments, when L5 is substituted, L5 is substituted with one or more first substituent groups denoted by RL5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL5.1 substituent group is substituted, the RL5.1 substituent group is substituted with one or more second substituent groups denoted by RL5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL5.2 substituent group is substituted, the RL5.2 substituent group is substituted with one or more third substituent groups denoted by RL5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L5, RL5.1, RL5.2, and RL5.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L5, RL5.1, RL5.2, and RL5.3, respectively. [0357] In embodiments, when L6 is substituted, L6 is substituted with one or more first substituent groups denoted by RL6.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL6.1 substituent group is substituted, the RL6.1 substituent group is substituted with one or more second substituent groups denoted by RL6.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL6.2 substituent group is substituted, the RL6.2 substituent group is substituted with one or more third substituent groups denoted by RL6.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L6, RL6.1, RL6.2, and RL6.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L6, RL6.1, RL6.2, and RL6.3, respectively. [0358] In embodiments, the compound has the formula: O
O Cl N O Cl formula: . In embodiments, the compound has O
has the formula: . In embodiments, the compound has the . [0359] In embodiments, the . In embodiments, the compound In embodiments, the compound has the . [0360] In embodiments, has the . In embodiments, the compound has the In embodiments, the compound has the . In embodiments, the compound has the . In embodiments, the compound has the the pound has the . In embodiments, the compound has the In embodiments, the O the compound has the In embodiments, the nd embodiments, the compound has the . In embodiments, the compound has the . In embodiments, the compound has the
nts, 5 the
the . , p p p . embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables). [0362] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III. Pharmaceutical compositions [0363] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0364] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. [0365] In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), or (Vb), including all embodiments thereof. In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VII), (VIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including all embodiments thereof. IV. Methods of use [0366] In an aspect is provided a method of treating a 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, or a pharmaceutically acceptable salt thereof. [0367] In embodiments, the cancer is an estrogen receptor positive cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is endometrial cancer. In embodiments, the cancer is uterine cancer. [0368] In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), or (Vb), including all embodiments thereof. In embodiments, the compound is a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VII), (VIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including all embodiments thereof. [0369] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–ERα protein complex in a subject, the method including administering to the subject a compound, or a pharmaceutically acceptable salt thereof, having the formula:
z2, [0370] W is O or NH. [0371] R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0372] In embodiments, the method includes administering to the subject a compound, or a pharmaceutically acceptable salt thereof, having the formula: [0373] In embodiments, W is O. In embodiments, W is NH. [0374] In embodiments, a substituted R50 (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 R50 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 R50 is substituted, it is substituted with at least one substituent group. In embodiments, when R50 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R50 is substituted, it is substituted with at least one lower substituent group. [0375] In embodiments, R50 is hydrogen. In embodiments, R50 is halogen. In embodiments, R50 is –F. In embodiments, R50 is –Cl. In embodiments, R50 is –Br. In embodiments, R50 is –I. In embodiments, R50 is –CCl3. In embodiments, R50 is –CBr3. In embodiments, R50 is –CF3. In embodiments, R50 is –CI3. In embodiments, R50 is -CH2Cl. In embodiments, R50 is -CH2Br. In embodiments, R50 is -CH2F. In embodiments, R50 is -CH2I. In embodiments, R50 is -CHCl2. In embodiments, R50 is -CHBr2. In embodiments, R50 is -CHF2. In embodiments, R50 is -CHI2. In embodiments, R50 is –CN. In embodiments, R50 is –OH. In embodiments, R50 is -NH2. In embodiments, R50 is –COOH. In embodiments, R50 is -CONH2. In embodiments, R50 is -NO2. In embodiments, R50 is –SH. In embodiments, R50 is –SO3H. In embodiments, R50 is –OSO3H. In embodiments, R50 is -SO2NH2. In embodiments, R50 is ^NHNH2. In embodiments, R50 is ^ONH2. In embodiments, R50 is ^NHC(O)NH2. In embodiments, R50 is -NHSO2H. In embodiments, R50 is -NHC(O)H. In embodiments, R50 is -NHC(O)OH. In embodiments, R50 is –NHOH. In embodiments, R50 is –OCCl3. In embodiments, R50 is –OCBr3. In embodiments, R50 is –OCF3. In embodiments, R50 is –OCI3. In embodiments, R50 is -OCH2Cl. In embodiments, R50 is -OCH2Br. In embodiments, R50 is -OCH2F. In embodiments, R50 is -OCH2I. In embodiments, R50 is -OCHCl2. In embodiments, R50 is -OCHBr2. In embodiments, R50 is -OCHF2. In embodiments, R50 is -OCHI2. In embodiments, R50 is -SF50. In embodiments, R50 is –N3. In embodiments, R50 is unsubstituted C1-C4 alkyl. In embodiments, R50 is unsubstituted methyl. In embodiments, R50 is unsubstituted ethyl. In embodiments, R50 is unsubstituted propyl. In embodiments, R50 is unsubstituted n-propyl. In embodiments, R50 is unsubstituted isopropyl. In embodiments, R50 is unsubstituted butyl. In embodiments, R50 is unsubstituted n-butyl. In embodiments, R50 is unsubstituted isobutyl. In embodiments, R50 is unsubstituted tert-butyl. [0376] In embodiments, a substituted R60 (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 R60 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 R60 is substituted, it is substituted with at least one substituent group. In embodiments, when R60 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R60 is substituted, it is substituted with at least one lower substituent group. [0377] In embodiments, R60 is hydrogen. In embodiments, R60 is halogen. In embodiments, R60 is –F. In embodiments, R60 is –Cl. In embodiments, R60 is –Br. In embodiments, R60 is –I. In embodiments, R60 is –CCl3. In embodiments, R60 is –CBr3. In embodiments, R60 is –CF3. In embodiments, R60 is –CI3. In embodiments, R60 is -CH2Cl. In embodiments, R60 is -CH2Br. In embodiments, R60 is -CH2F. In embodiments, R60 is -CH2I. In embodiments, R60 is -CHCl2. In embodiments, R60 is -CHBr2. In embodiments, R60 is -CHF2. In embodiments, R60 is -CHI2. In embodiments, R60 is –CN. In embodiments, R60 is –OH. In embodiments, R60 is -NH2. In embodiments, R60 is –COOH. In embodiments, R60 is -CONH2. In embodiments, R60 is -NO2. In embodiments, R60 is –SH. In embodiments, R60 is –SO3H. In embodiments, R60 is –OSO3H. In embodiments, R60 is -SO2NH2. In embodiments, R60 is ^NHNH2. In embodiments, R60 is ^ONH2. In embodiments, R60 is ^NHC(O)NH2. In embodiments, R60 is -NHSO2H. In embodiments, R60 is -NHC(O)H. In embodiments, R60 is -NHC(O)OH. In embodiments, R60 is –NHOH. In embodiments, R60 is –OCCl3. In embodiments, R60 is –OCBr3. In embodiments, R60 is –OCF3. In embodiments, R60 is –OCI3. In embodiments, R60 is -OCH2Cl. In embodiments, R60 is -OCH2Br. In embodiments, R60 is -OCH2F. In embodiments, R60 is -OCH2I. In embodiments, R60 is -OCHCl2. In embodiments, R60 is -OCHBr2. In embodiments, R60 is -OCHF2. In embodiments, R60 is -OCHI2. In embodiments, R60 is –SF5. In embodiments, R60 is –N3. In embodiments, R60 is unsubstituted C1-C4 alkyl. In embodiments, R60 is unsubstituted methyl. In embodiments, R60 is unsubstituted ethyl. In embodiments, R60 is unsubstituted propyl. In embodiments, R60 is unsubstituted n-propyl. In embodiments, R60 is unsubstituted isopropyl. In embodiments, R60 is unsubstituted butyl. In embodiments, R60 is unsubstituted n-butyl. In embodiments, R60 is unsubstituted isobutyl. In embodiments, R60 is unsubstituted tert-butyl. [0378] In embodiments, a substituted R70 (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 R70 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 R70 is substituted, it is substituted with at least one substituent group. In embodiments, when R70 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R70 is substituted, it is substituted with at least one lower substituent group. [0379] In embodiments, R70 is hydrogen. In embodiments, R70 is halogen. In embodiments, R70 is –F. In embodiments, R70 is –Cl. In embodiments, R70 is –Br. In embodiments, R70 is –I. In embodiments, R70 is –CCl3. In embodiments, R70 is –CBr3. In embodiments, R70 is –CF3. In embodiments, R70 is –CI3. In embodiments, R70 is -CH2Cl. In embodiments, R70 is -CH2Br. In embodiments, R70 is -CH2F. In embodiments, R70 is -CH2I. In embodiments, R70 is -CHCl2. In embodiments, R70 is -CHBr2. In embodiments, R70 is -CHF2. In embodiments, R70 is -CHI2. In embodiments, R70 is –CN. In embodiments, R70 is –OH. In embodiments, R70 is -NH2. In embodiments, R70 is –COOH. In embodiments, R70 is -CONH2. In embodiments, R70 is -NO2. In embodiments, R70 is –SH. In embodiments, R70 is –SO3H. In embodiments, R70 is –OSO3H. In embodiments, R70 is -SO2NH2. In embodiments, R70 is ^NHNH2. In embodiments, R70 is ^ONH2. In embodiments, R70 is ^NHC(O)NH2. In embodiments, R70 is -NHSO2H. In embodiments, R70 is -NHC(O)H. In embodiments, R70 is -NHC(O)OH. In embodiments, R70 is –NHOH. In embodiments, R70 is –OCCl3. In embodiments, R70 is –OCBr3. In embodiments, R70 is –OCF3. In embodiments, R70 is –OCI3. In embodiments, R70 is -OCH2Cl. In embodiments, R70 is -OCH2Br. In embodiments, R70 is -OCH2F. In embodiments, R70 is -OCH2I. In embodiments, R70 is -OCHCl2. In embodiments, R70 is -OCHBr2. In embodiments, R70 is -OCHF2. In embodiments, R70 is -OCHI2. In embodiments, R70 is –SF5. In embodiments, R70 is –N3. In embodiments, R70 is unsubstituted C1-C4 alkyl. In embodiments, R70 is unsubstituted methyl. In embodiments, R70 is unsubstituted ethyl. In embodiments, R70 is unsubstituted propyl. In embodiments, R70 is unsubstituted n-propyl. In embodiments, R70 is unsubstituted isopropyl. In embodiments, R70 is unsubstituted butyl. In embodiments, R70 is unsubstituted n-butyl. In embodiments, R70 is unsubstituted isobutyl. In embodiments, R70 is unsubstituted tert-butyl. [0380] In embodiments, a substituted R80 (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 R80 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 R80 is substituted, it is substituted with at least one substituent group. In embodiments, when R80 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R80 is substituted, it is substituted with at least one lower substituent group. [0381] In embodiments, R80 is hydrogen. In embodiments, R80 is halogen. In embodiments, R80 is –F. In embodiments, R80 is –Cl. In embodiments, R80 is –Br. In embodiments, R80 is –I. In embodiments, R80 is –CCl3. In embodiments, R80 is –CBr3. In embodiments, R80 is –CF3. In embodiments, R80 is –CI3. In embodiments, R80 is -CH2Cl. In embodiments, R80 is -CH2Br. In embodiments, R80 is -CH2F. In embodiments, R80 is -CH2I. In embodiments, R80 is -CHCl2. In embodiments, R80 is -CHBr2. In embodiments, R80 is -CHF2. In embodiments, R80 is -CHI2. In embodiments, R80 is –CN. In embodiments, R80 is –OH. In embodiments, R80 is -NH2. In embodiments, R80 is –COOH. In embodiments, R80 is -CONH2. In embodiments, R80 is -NO2. In embodiments, R80 is –SH. In embodiments, R80 is –SO3H. In embodiments, R80 is –OSO3H. In embodiments, R80 is -SO2NH2. In embodiments, R80 is ^NHNH2. In embodiments, R80 is ^ONH2. In embodiments, R80 is ^NHC(O)NH2. In embodiments, R80 is -NHSO2H. In embodiments, R80 is -NHC(O)H. In embodiments, R80 is -NHC(O)OH. In embodiments, R80 is –NHOH. In embodiments, R80 is –OCCl3. In embodiments, R80 is –OCBr3. In embodiments, R80 is –OCF3. In embodiments, R80 is –OCI3. In embodiments, R80 is -OCH2Cl. In embodiments, R80 is -OCH2Br. In embodiments, R80 is -OCH2F. In embodiments, R80 is -OCH2I. In embodiments, R80 is -OCHCl2. In embodiments, R80 is -OCHBr2. In embodiments, R80 is -OCHF2. In embodiments, R80 is -OCHI2. In embodiments, R80 is –SF5. In embodiments, R80 is –N3. In embodiments, R80 is unsubstituted C1-C4 alkyl. In embodiments, R80 is unsubstituted methyl. In embodiments, R80 is unsubstituted ethyl. In embodiments, R80 is unsubstituted propyl. In embodiments, R80 is unsubstituted n-propyl. In embodiments, R80 is unsubstituted isopropyl. In embodiments, R80 is unsubstituted butyl. In embodiments, R80 is unsubstituted n-butyl. In embodiments, R80 is unsubstituted isobutyl. In embodiments, R80 is unsubstituted tert-butyl. [0382] In embodiments, R50, R60, R70, and R80 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R50, R60, R70, and R80 are independently hydrogen or unsubstituted methyl. [0383] In embodiments, the compound is a compound described herein. [0384] In embodiments, the compound has the formula: O O Cl N O O the has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the . In embodiments, the compound has the In embodiments, the compound has the . In embodiments, the compound has the has the . In embodiments, the compound the odiments, the compound has the . [0385] In embodiments, the in a subject is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50- , 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a subject is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a subject is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein– ERα protein complex in a subject is increased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by about 1000-fold relative to a control (e.g., absence of the compound). [0386] In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a subject is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a subject is increased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein– ERα protein complex in a subject is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a subject is increased by at least 1000-fold relative to a control (e.g., absence of the compound). [0387] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–ERα protein complex in a cell, the method including contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, having the formula: R2, embodiments. [0388] In embodiments, the method includes contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, having the formula:
herein, including in embodiments. [0389] In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a cell is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a cell is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by about 1000-fold relative to a control (e.g., absence of the compound). [0390] In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a cell is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3- 3 protein–ERα protein complex in a cell is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of a 14-3-3 protein–ERα protein complex in a cell is increased by at least 1000-fold relative to a control (e.g., absence of the compound). [0391] In an aspect is provided a method of forming a 14-3-3 protein–ERα protein– compound complex, the method including combining a 14-3-3 protein, an ERα protein, and a compound, or a pharmaceutically acceptable salt thereof, in a reaction vessel, cell, or organism, thereby forming the 14-3-3 protein–ERα protein–compound complex bound together noncovalently; wherein the compound has the formula:
R2, embodiments. [0392] In embodiments, the compound has the formula: [0393] In an aspect is provided a method of stabilizing a 14-3-3 protein–ERα protein complex, the method including contacting the 14-3-3 protein–ERα protein complex with a compound, or a pharmaceutically acceptable salt thereof, thereby stabilizing the 14-3-3 protein–ERα protein complex; wherein the compound has the formula: R2, embodiments. [0394] In embodiments, the compound has the formula:
herein, including in embodiments. [0395] In embodiments, the stabilizing occurs in a cell. In embodiments, the stabilizing occurs in an organism. In embodiments, the stabilizing occurs in a cell in an organism. [0396] In embodiments, the compound binds to C38 of the 14-3-3 ^ (e.g., human 14-3-3 ^) protein. In embodiments, the compound binds covalently to C38 of the 14-3-3 ^ (e.g., human 14-3-3 ^) protein. V. Embodiments [0397] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CH2I, -CN, -OH, -NH2, - - - - - - - -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0398] Embodiment P2. The compound of embodiment P1, having the formula: . of embodiment P1, having the formula: R1 L2 2 L1 R A R3 R4 H . P1, having the formula: . of embodiments P1 to P4, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0402] Embodiment P6. The compound of one of embodiments P1 to P5, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0403] Embodiment P7. The compound of one of embodiments P1 to P6, wherein , R2 is halogen. [0405] Embodiment P9. The compound of one of embodiments P1 to P7, wherein R2 is -Cl. [0406] Embodiment P10. The compound of one of embodiments P1 to P9, wherein R3 and R4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0407] Embodiment P11. The compound of one of embodiments P1 to P9, wherein R3 and R4 combine to form a substituted or unsubstituted tetrahydropyranyl. [0408] Embodiment P12. The compound of one of embodiments P1 to P9, wherein R3 and R4 combine to . [0409] Embodiment of embodiments P1 to P1 1 2, wherein L is a bond or unsubstituted C1-C4 alkylene. [0410] Embodiment P14. The compound of one of embodiments P1 to P12, wherein L1 is a bond or unsubstituted methylene. [0411] Embodiment P15. The compound of one of embodiments P1 to P14, wherein L2 is a bond. [0412] Embodiment P16. The compound of one of embodiments P1 to P15, wherein R1 is E. [0413] Embodiment P17. The compound of embodiment P16, wherein E is O R11
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0414] Embodiment P18. The compound of embodiment P17, wherein R11, R12, R13, and R14 are hydrogen. [0415] Embodiment P19. The compound of one of embodiments P1 to P16, wherein R1 is O Cl . The compound of embodiment P1, having the formula: O O Cl Cl
or o e . co pou , o a parmaceutically acceptable salt thereof, having the formula:
or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R5, R6, R7, and R8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0418] Embodiment P22. The compound of embodiment P21, having the formula: (IIb). [0420] Embodiment P24. The compound of embodiment P21, having the formula: . of embodiment P21, having the formula: . is halogen. [0423] Embodiment P27. The compound of one of embodiments P21 to P25, wherein R2 is -Cl. [0424] Embodiment P28. The compound of one of embodiments P21 to P27, wherein L1 is a bond or unsubstituted C1-C4 alkylene. [0425] Embodiment P29. The compound of one of embodiments P21 to P27, wherein L1 is a bond or unsubstituted methylene. [0426] Embodiment P30. The compound of one of embodiments P21 to P29, wherein L2 is a bond. [0427] Embodiment P31. The compound of one of embodiments P21 to P30, wherein R1 is E. [0428] Embodiment P32. The compound of embodiment P31, wherein E is
O R11 N R12 -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0429] Embodiment P33. The compound of embodiment P32, wherein R11, R12, R13, and R14 are hydrogen. [0430] Embodiment P34. The compound of one of embodiments P21 to P30, wherein R1 . P35. The compound of embodiment P21, having the formula: , [0 3 ] mbod ment 36. p armaceut ca compos t on compr s ng t e compound of one of embodiments P1 to P35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0433] Embodiment P37. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of embodiments P1 to P35, or a pharmaceutically acceptable salt thereof. [0434] Embodiment P38. The method of embodiment P37, wherein the cancer is an estrogen receptor positive cancer. [0435] Embodiment P39. The method of embodiment P37, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. [0436] Embodiment P40. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a subject, said method comprising administering to said subject a compound, or a pharmaceutically acceptable salt thereof, having the formula: Ring A and Ring B are independently a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; W is O or NH; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0437] Embodiment P41. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a cell, said method comprising contacting the cell with a compound, or a salt thereof, having the formula: Ring A and Ring B are independently a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0438] Embodiment P42. The method of one of embodiments P40 to P41, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0439] Embodiment P43. The method of one of embodiments P40 to P42, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0440] Embodiment P44. The method of one of embodiments P40 to P43, wherein , R3 and R4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0442] Embodiment P46. The method of one of embodiments P40 to P44, wherein R3 and R4 combine to form a substituted or unsubstituted tetrahydropyranyl. [0443] Embodiment P47. The method of one of embodiments P40 to P44, wherein R3 and . one of embodiments P40 to P41, wherein W is O. [0445] Embodiment P49. The method of one of embodiments P40 to P41, wherein W is NH. [0446] Embodiment P50. The method of one of embodiments P40 to P41 and P48 to P49, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted C1-C4 alkyl. [0447] Embodiment P51. The method of one of embodiments P40 to P41 and P48 to P49, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted methyl. [0448] Embodiment P52. The method of one of embodiments P40 to P51, wherein R2 is independently halogen. [0449] Embodiment P53. The method of one of embodiments P40 to P51, wherein R2 is independently -Cl. [0450] Embodiment P54. The method of one of embodiments P40 to P53, wherein z2 is 1. [0451] Embodiment P55. The method of one of embodiments P40 to P54, wherein L1 is a bond or unsubstituted C1-C4 alkylene. [0452] Embodiment P56. The method of one of embodiments P40 to P54, wherein L1 is a bond or unsubstituted methylene. [0453] Embodiment P57. The method of one of embodiments P40 to P56, wherein L2 is a bond. [0454] Embodiment P58. The method of one of embodiments P40 to P57, wherein R1 is E. Embodiment P59. The method of embodiment P58, wherein E is O R11
R11, R12, R13, and R14 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0456] Embodiment P60. The method of embodiment P59, wherein R11, R12, R13, and R14 are hydrogen. [0457] Embodiment P61. The method of one of embodiments P40 to P58, wherein R1 is O . The method of one of embodiments P40 to P41, wherein the compound has the formula: O O
N O H Cl , , , . [0459] Embodiment 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; wherein or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0460] Embodiment 2. The compound of embodiment 1, having the formula: . of embodiment 1, having the formula: R1 2 1 L R2 L . 1, having the formula: c). e of embodiments 1 to 4, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0464] Embodiment 6. The compound of one of embodiments 1 to 5, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0465] Embodiment 7. The compound of one of embodiments 1 to 6, wherein , R2 is halogen. [0467] Embodiment 9. The compound of one of embodiments 1 to 7, wherein R2 is -Cl. [0468] Embodiment 10. The compound of one of embodiments 1 to 9, wherein R3 and R4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0469] Embodiment 11. The compound of one of embodiments 1 to 9, wherein R3 and R4 combine to form a substituted or unsubstituted tetrahydropyranyl. [0470] Embodiment 12. The compound of one of embodiments 1 to 9, wherein R3 and . [0471] Embodiment 13. The compound of one of embodiments 1 to 12, wherein L1 is a bond or unsubstituted C1-C4 alkylene. [0472] Embodiment 14. The compound of one of embodiments 1 to 12, wherein L1 is a bond or unsubstituted methylene. [0473] Embodiment 15. The compound of one of embodiments 1 to 14, wherein L2 is a bond. [0474] Embodiment 16. The compound of one of embodiments 1 to 15, wherein R1 is E. [0475] Embodiment 17. The compound of embodiment 16, wherein E is O R11 -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0476] Embodiment 18. The compound of embodiment 17, wherein R11, R12, R13, and R14 are hydrogen. [0477] Embodiment 19. The compound of one of embodiments 1 to 16, wherein R1 is O Cl . The compound of embodiment 1, having the formula: O O Cl O Cl N O
or , armaceutically acceptable salt thereof, having the formula: - -, - , - -, - , - , - , - , - -, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R5, R6, R7, and R8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0480] Embodiment 22. The compound of embodiment 21, having the formula: (IIb). (IIIa). [0482] Embodiment 24. The compound of embodiment 21, having the formula: ). d of embodiment 21, having the formula: . is halogen. [0485] Embodiment 27. The compound of one of embodiments 21 to 25, wherein R2 is -Cl. [0486] Embodiment 28. The compound of one of embodiments 21 to 27, wherein L1 is a bond or unsubstituted C1-C4 alkylene. [0487] Embodiment 29. The compound of one of embodiments 21 to 27, wherein L1 is a bond or unsubstituted methylene. [0488] Embodiment 30. The compound of one of embodiments 21 to 29, wherein L2 is a bond. [0489] Embodiment 31. The compound of one of embodiments 21 to 30, wherein R1 is E. [0490] Embodiment 32. The compound of embodiment 31, wherein E is O R11
O X11 N , -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0491] Embodiment 33. The compound of embodiment 32, wherein R11, R12, R13, and R14 are hydrogen. [0492] Embodiment 34. The compound of one of embodiments 21 to 30, wherein R1 is . 35. The compound of embodiment 21, having the formula: , or a pharmaceutically acceptable salt thereof, having the formula: or ; (O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 4; z6 is an integer from 0 to 2; each R10, R20, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0495] Embodiment 37. The compound of embodiment 36, having the formula: (VIIa). bodiment 36, having the formula: (VIIIa). embodiment 36, having the formula: (VIIIb). embodiment 36, having the formula: . 36, having the formula: O . 36, having the formula: (VIIIe). embodiment 36, having the formula: R3 R4 (R2) L5 z2 . 36 to 43, wherein L4 is -O-. [0503] Embodiment 45. The compound of one of embodiments 36 to 43, wherein L4 is -NH-. [0504] Embodiment 46. The compound of one of embodiments 36 and 38 to 45, wherein L5 is –NH- or substituted or unsubstituted 2 to 8 membered heteroalkylene. [0505] Embodiment 47. The compound of one of embodiments 36 and 38 to 45, . [0506] of embodiments 36 to 47, wherein R2 is independently halogen, -CX23, -C(O)R2C, -C(O)OR2C, -OR2D, substituted or unsubstituted C1- C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0507] Embodiment 49. The compound of one of embodiments 36 to 47, wherein R2 is independently –Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3. [0508] Embodiment 50. The compound of one of embodiments 36 to 47, wherein z2 is 0. [0509] Embodiment 51. The compound of one of embodiments 36 to 49, wherein z2 is 1. Embodiment 52. The compound of one of embodiments 36 to 49, wherein z2 is 2. [0511] Embodiment 53. The compound of one of embodiments 36 to 52, wherein R3 and R4 are independently unsubstituted C1-C4 alkyl. [0512] Embodiment 54. The compound of one of embodiments 36 to 52, wherein R3 and R4 are unsubstituted methyl. [0513] Embodiment 55. The compound of one of embodiments 36 to 52, wherein R3 and R4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0514] Embodiment 56. The compound of one of embodiments 36 to 52, wherein R3 and R4 combine to form a substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl. [0515] Embodiment 57. The compound of one of embodiments 36 to 52, wherein R3 and R4 combine to form: NH2 . 57, wherein L1 is a bond. [0517] Embodiment 59. The compound of one of embodiments 36 to 58, wherein L2 is a bond. [0518] Embodiment 60. The compound of one of embodiments 36 to 59, wherein R1 is -C(NR1C)NR1AR1B or -C(O)NR1AR1B. [0519] Embodiment 61. The compound of one of embodiments 36 to 59, wherein R1 is -C(NH)NH2, -C(NH)NHOH, or –C(O)NH2. [0520] Embodiment 62. The compound of one of embodiments 36 to 59, wherein R1 is -C(NH)NH2. [0521] Embodiment 63. A pharmaceutical composition comprising the compound of one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0522] Embodiment 64. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof. [0523] Embodiment 65. The method of embodiment 64, wherein the cancer is an estrogen receptor positive cancer. [0524] Embodiment 66. The method of embodiment 64, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. [0525] Embodiment 67. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a subject, said method comprising administering to said subject a compound, or a pharmaceutically acceptable salt thereof, having the formula:
r in d cycloalkylene or substituted or unsubstituted heterocycloalkylene; W is O or NH; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; z6 is an integer from 0 to 2; each R10, R20, R30, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, - -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0526] Embodiment 68. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a cell, said method comprising contacting the cell with a compound, or a salt thereof, having the formula: substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; z6 is an integer from 0 to 2; each R10, R20, R30, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. [0527] Embodiment 69. The method of one of embodiments 67 to 68, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0528] Embodiment 70. The method of one of embodiments 67 to 69, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0529] Embodiment 71. The method of one of embodiments 67 to 70, wherein , one R3 and R4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0531] Embodiment 73. The method of one of embodiments 67 to 71, wherein R3 and R4 combine to form a substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl. [0532] Embodiment 74. The method of one of embodiments 67 to 71, wherein R3 and NH2 , W is O. [0534] Embodiment 76. The method of one of embodiments 67 to 68, wherein W is NH. [0535] Embodiment 77. The method of one of embodiments 67 to 68 and 75 to 76, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted C1-C4 alkyl. [0536] Embodiment 78. The method of one of embodiments 67 to 68 and 75 to 76, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted methyl. [0537] Embodiment 79. The method of one of embodiments 67 to 78, wherein R2 is independently halogen, -CX23, -C(O)R2C, -C(O)OR2C, -OR2D, substituted or unsubstituted C1- C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0538] Embodiment 80. The method of one of embodiments 67 to 78, wherein R2 is independently -Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3. [0539] Embodiment 81. The method of one of embodiments 67 to 78, wherein z2 is 0. [0540] Embodiment 82. The method of one of embodiments 67 to 80, wherein z2 is 1. [0541] Embodiment 83. The method of one of embodiments 67 to 80, wherein z2 is 2. [0542] Embodiment 84. The method of one of embodiments 67 to 82, wherein L1 is a bond or unsubstituted C1-C4 alkylene. [0543] Embodiment 85. The method of one of embodiments 67 to 82, wherein L1 is a bond or unsubstituted methylene. [0544] Embodiment 86. The method of one of embodiments 67 to 85, wherein L2 is a bond. [0545] Embodiment 87. The method of one of embodiments 67 to 86, wherein R1 is E. [0546] Embodiment 88. The method of embodiment 87, wherein E is O R11 -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. [0547] Embodiment 89. The method of embodiment 88, wherein R11, R12, R13, and R14 are hydrogen. [0548] Embodiment 90. The method of one of embodiments 67 to 87, wherein R1 is O Cl . The method of one of embodiments 67 to 8 1 6, wherein R is -C(NR1C)NR1AR1B or -C(O)NR1AR1B. [0550] Embodiment 92. The method of one of embodiments 67 to 86, wherein R1 is -C(NH)NH2, -C(NH)NHOH, or –C(O)NH2. [0551] Embodiment 93. The method of one of embodiments 67 to 86, wherein R1 is -C(NH)NH2. [0552] Embodiment 94. The method of one of embodiments 67 to 68, wherein the compound has the formula: O O Cl Cl
, 5 , ,
. mbodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES Example 1: Structure-based optimization of covalent, small molecule stabilizers of the 14-3-3σ/ERα protein-protein interaction from nonselective fragments [0554] Protein-protein interactions (PPIs) play a central role in biological networks and are often dysregulated in pathological conditions (1-3). PPIs are considered particularly difficult targets for small molecules, due to the large, usually hydrophobic, surfaces, the lack of suitable deep pockets and the difficulty in identifying new chemical matter to target them (4). Despite such challenges, the modulation of PPIs has emerged as an attractive strategy both in chemical biology and drug discovery (5-7). In chemical biology, the inhibition or stabilization of specific PPIs allows the study of complex networks and the dissection of certain functions. In drug discovery, induced proximity of PPI, as with molecular glue and PROTAC degraders, have successfully provided an alternative approach for targeting “undruggable” protein targets (8-10). [0555] Particularly interesting challenges within PPI modulator discovery are the “hub” proteins that have the ability to interact with numerous protein clients, typically via intrinsically disordered regions and post-translational modifications (11-13). The extensive interactome of hub proteins provides tremendous potential for drug discovery, but at the same time raises the question of selective targeting, since the underlying biology might be intertwined and the molecular recognition principles within a hub protein’s PPI network are potentially based on similar chemical motifs. Herein, we focus, inter alia, on the hub protein 14-3-3, a highly abundant adaptor and scaffolding protein. We show that despite the vast number of 14-3-3 clients (estimated to be approximately 3000) (14), selective small molecule stabilizers or molecular glues (15,16) can be systematically developed by targeting the chemically unique composite binding pocket formed by a given 14-3-3/client PPI interface. [0556] 14-3-3 is a dimeric hub protein that binds to its clients via their phospho-serine or phospho-threonine sites and upon binding creates order in these disordered client regions (17,18).14-3-3 is involved in the regulation of transcription factors, cell signaling, cell cycle progression, signal-transduction pathways, and protein stability (19-24). In humans, 14-3-3 is present via seven highly conserved isoforms with seemingly overlapping functions (23,26). Among them, the sigma (σ) isoform is often associated with the role of tumor suppressor (27- 29), and there is evidence of downregulation or degradation in certain types of cancer (30- 32). Structurally, only the sigma isoform has a native cysteine residue in the central binding channel that accommodates the phosphorylated client protein (position Cys38). We hypothesize that this cysteine can be used as a handle for selective targeting of 14-3-3σ. [0557] Here, we demonstrate the selective stabilization of 14-3-3σ interactions with estrogen-receptor alpha (ERα) via small molecules that act as orthosteric PPI stabilizers or molecular glues. In breast cancer treatments, blocking the function of ERα is a well- established strategy and includes small molecules that bind to the ligand-binding pocket of ERα. However, inhibition of ERα in this manner often leads to the development of resistance (33,34). An alternative approach for modulating ERα function could be the stabilization of the interaction between 14-3-3 and ERα, since 14-3-3 is a known negative regulator of ERα (25).14-3-3 binds at the extreme C-terminus of the receptor via the recognition of the penultimate threonine (ERα-T594). As a result, at a cellular level, cell growth and receptor/DNA interactions are modulated (25). To address the issue of selectivity among 14- 3-3 clients, we selected the 14-3-3/C-RAF interaction (35) as a counter-target, and similarly relevant onco-target. [0558] In the urgent quest to explore new chemical matter, fragment-based approaches have recently been explored. A crystallography-based fragment screen identified amidine fragments, that although weak stabilizers, selectively bound to 14-3-3/p53-peptide or 14-3- 3/TAZ-peptide complexes (36). A second crystallography screen identified aldehyde- containing fragments that targeted a conserved lysine residue on 14-3-3 in close proximity to the client protein binding-site and stabilized the 14-3-3/p65 complex (37). Disulfide tethering (38,39) has been applied both to engineered cysteine residues and the native cysteine of the 14-3-3 σ isoform to identify fragment stabilizers of 14-3-3/ERα (40). We have recently shown that disulfide tethering can be used to target 14-3-3/client interactions with diverse shapes and binding modes. The native cysteine (Cys38) at the periphery of the peptide- binding groove on 14-3-3σ (FIG.1A) was targeted with a library consisting of ~1600 disulfide fragments and both client-selective and general stabilizing fragments were identified. A non-selective disulfide fragment (917949) was able to stabilize both 14-3-3/ΕRα and 14-3-3/C-RAF peptide complexes. Although the disulfide fragment showed preferential stabilization for C-RAF (38-fold stabilization for C-RAF and 4-fold stabilization for ERα at 100 μΜ compound), the crystal structures showed a similar binding mode with both clients. Here, we report the structure-guided chemical optimization of this non-selective disulfide hit toward small molecule covalent stabilizers that preferentially stabilize the 14-3-3σ/ERα complex over 14-3-3σ/C-RAF. Chemical modifications were strategically evaluated with a focus on increasing the cooperativity with 14-3-3σ/ERα and reducing stabilization of 14-3- 3σ/C-RAF via increased steric hindrance (FIG.1B). [0559] The chemical modifications on the original disulfide fragment can be divided into five groups (FIGS.1B-1C). Modifications (1) and (2), at the periphery of the binding groove, included the replacement of the reversible disulfide tether with irreversible electrophiles (1) with varying linker lengths (2). Modifications (3) and (4), at the protein – peptide interface focused on optimizing the substituents in close proximity to the client peptides (protein/peptide interface), aiming to increase cooperativity and selectivity via specific interactions with the client of 14-3-3. The last modification (5) was the rigidification of the linkers, aiming to “lock” the compounds’ conformations, resulting in the best stabilizer of the series, compound 1083744. Representative examples of the compound evolution and their cocrystal structures with 14-3-3σ/ERα are shown in FIG.1C. [0560] Two orthogonal assays were developed for screening. For the primary assay, mass spectrometry was used to monitor the formation of the covalent bond between the compound and the native cysteine (Cys38 on 14-3-3σ) (FIG.1D). The assay was first performed in the absence of peptide to determine binding only to 14-3-3σ (apo screening, D1) and then in the presence of both 14-3-3σ and peptide as an indication of how much the peptide stabilized compound binding (D2). To normalize the amount of 14-3-3/client complex, peptides were included at 2-times their dissociation constant (2xKD), e.g., 1 µM for ERa phosphopeptide. Compounds that bound better in the presence of peptide than the absence were classified as stabilizers, whereas compounds for which % bound did not change significantly were classified as neutral binders. As a confirmatory assay, a fluorescence anisotropy assay was used. In this case, compounds were titrated in the presence of 14-3-3σ and FAM-labeled peptides. For stabilizers, a dose-dependent increase in anisotropy was observed, whereas for neutral binders no significant increase occurred (FIG.1E). [0561] The first step of our strategy to develop selective, covalent stabilizers was the replacement of the disulfide tether with electrophiles. We introduced four electrophilic warheads (acrylamides, oxiranes, vinylsulfonamides and chloroacetamides) with varying linker lengths (FIG.2A). We measured a dose-response every 8 hours, after a one-hour incubation of the compounds with 100 nM 14-3-3 without peptides (apo screen) or in the presence of peptides at 2xKD (FIG.2B). The four time-course graphs in each case were analyzed and compared to the apo screen. The full quantification, however, of those graphs proved to be complicated since compounds did not always reach 100% bound and kinetics differed significantly. We hypothesized that cooperative compounds (increased % bound in the presence of the peptide) at low compound concentrations will correlate with improved stabilization, especially for relatively fast binding. To visualize and easily compare the graphs, the original dose-response curves were represented as bar graphs, focusing at the 1:1 [compound]:[protein] % bound measurement at four time points (FIG.2B). The measurement in the presence of peptides is shown with different colors, whereas binding to protein only as black bars. Following the primary mass spectrometry assay, fluorescence anisotropy (FA) experiments were performed as a confirmatory assay (FIG.2C). Compounds were incubated with FAM-labeled peptides (10 nM) and 1 μΜ of protein for ERα or 5 µM of protein for C- RAF. Two measurements were performed (at 0 h and 24 h). EC50 values were calculated from the overnight measurement and plotted as bar graphs (FIG.2C). [0562] Regarding the screening of the four electrophilic warheads with varying linker lengths (0-3 carbon linkers, FIG.2A), both assays showed that not all warheads were tolerated. Oxiranes and acrylamides were classified as inactive, since neither labeling was observed in the mass spectrometry nor an increase in fluorescence in the FA assay. Most of the vinylsulfonamides were inactive, with the exception of the 1C-linker, which showed a weak stabilization effect (FA EC50 = 33 ± 1 μΜ for ΕRα). Chloroacetamide analogs were the most promising and revealed that the linker length also has a significant effect. The analog with the shortest linker (n=0) (1074360) was the weakest stabilizer (FA EC50 > 150 μΜ), whereas the longer linkers significantly improved the potency. In particular, in the mass spectrometry assay with ERα, the 1C-linker (1074202) led to increased labeling in the overnight measurement, whereas with C-RAF the 2C-linker (1074210) was slightly better (FIG.2B). Interestingly, in the FA assay for ERα 1C- and 2C-linkers showed similar stabilization (FA EC50 = 19 ± 1 μΜ and 24 ± 16 μΜ for ΕRα respectively), whereas the 3C- linker (1074359) was better (FA EC50 = 9 ± 0.4 μΜ) (FIG.2C). For C-RAF, 1C-linker was more tolerated (1074202, FA EC50 = 16 ± 4 μΜ for C-RAF). Encouragingly, the four chloroacetamide analogs showed low binding to 14-3-3 in the absence of peptide in the mass spectrometry assay, indicating that the compounds act as cooperative molecular glues and stabilize a binary complex of 14-3-3 and each of the peptides. Crystal structures were solved for three analogs (linkers n=1,2,3) in complex with 14-3-3/ΕRα and compared with the binding mode of the original tethering hit 917949. Although the tethering hit was crystallized using the soaking method, a co-crystallization method was more successful for the electrophilic analogs in obtaining high resolution structures confirming the covalent binding mode. Compound 1074202 (1C-linker) bound in a similar mode as the tethering hit with the gem-dimethyl substituent positioned at 4.4 Å from the methyl group of Val595 of ERα (FIG. 2D). Differences were observed, as expected, in the orientation of the amide bond close to the warhead, since the amide bonds in the two analogs are reversed and differently positioned. Analogs 1074210 (2C-linker) and 1074359 (3C-linker) showed similarities with each other regarding the orientation of the linker, but changes were observed in the positioning of the gem-dimethyl group (for 1074210 the distance from Val595 was 5.5 Å and for 10743594.0 Å). An additional difference for compound 1074359 is the orientation of the ether group, which is located in the front of the binding groove, facing away from 14-3-3 (FIG.2D). For further SAR optimization, the 1C-chloroacetamide warhead was selected, since it showed most consistency in the mass spectrometry and FA assays (FIG.2E). [0563] After selecting the linker length, we focused on the potential effect of the warhead reactivity in stabilization. The more reactive α-chloroketone analog (1074203) was synthesized and tested. In the mass spectrometry assay, the compound showed remarkably faster kinetics, however this correlated with increased binding with 14-3-3 in the absence of peptides, thus significantly lacking cooperativity for the PPI. The compound was considered a “neutral binder” in the mass spectrometry assay. The reduced cooperativity translated in the FA assay, as a higher EC50 value for the α-chloroketone (1074203) compared to the chloroacetamide analog 1074202 (EC50 = 44 ± 2 μΜ for ΕRα, and 19 ± 1 μΜ respectively). As a result, the 1C-chloroacetamide with moderate reactivity and a clear cooperative effect for PPI stabilization was selected for further SAR development. [0564] After selecting the warhead, our main focus was to increase the cooperativity for the PPI complex and tune the selectivity toward the stabilization of 14-3-3/ERα. The main structural difference between the ERα and C-RAF peptide is the +1 residue, which is a valine for ΕRα and a threonine for C-RAF. Based on the crystal structure of 1074202 with 14-3- 3/ERα, we aimed to increase the hydrophobic interactions between the compound and ERα Val595. The original gem-dimethyl substituent was replaced with various bigger hydrophobic substituents (from 2-methyl-cyclopropyl to benzyl). For those analogs, no crystal structures were solved, and the observed SAR was inconsistent. Larger substituents that could potentially interact with Val595 did not correlate with improved stabilization. [0565] The inconclusive SAR of the first analogs led us to revise our hypothesis for addressing only the +1 position of the peptides. Instead, we explored more interactions with 14-3-3, hypothesizing that favorable interactions in the protein/peptide interface would increase cooperativity. The residues on 14-3-3 in close proximity to the compound/peptide interface are hydrophobic (Leu218, Ile219). Moreover, the selected scaffold 1074202 fills a small pocket, where Lys122 is located. Lys122, a polar amino acid, deeply buried in the middle of the binding groove, is able to form a hydrogen bond with the terminal carboxylic acid of Val595 of ΕRα and a halogen bond with the compound. Therefore, our next SAR modifications aimed to target those particular amino acids, in addition to the +1 amino acid (Val595) on the peptide. Two modifications were performed: the replacement of the gem- dimethyl group with cyclic aliphatic rings and the introduction of anilines instead of ethers (FIG.3A). Compound 1074202 (gem-dimethyl, ether) was non-selective and stabilized both ERα and C-RAF peptides (FA EC50 = 19 ± 1 μΜ for ERα, 16 ± 4 μΜ for C-RAF) (FIGS.3B- 3C). Interestingly, compound 1080291 (gem-dimethyl, aniline), although weaker, showed selectivity for ERα (FA EC50 = 55 ± 2 μΜ), and no affinity for C-RAF (FA EC50 >150 μΜ for C-RAF). Crystallography showed that the aniline group in 1080291 was oriented in the “front” of the binding groove, whereas the ether in 1074202 was oriented in the back. In both cases, the gem-dimethyl group participated in van der Waals interactions with Val595 and the p-Cl group was forming a halogen bond with Lys122. The orientation of the halogen bond varied and in the case of ether 1074202 the interaction was between the p-Cl and the terminal amine, whereas for the aniline 1080291 the interaction was with the adjacent methylene at 3.5Å. The analog lacking the p-Cl group (compound 1080268) was unable to stabilize either peptide, highlighting the importance of the interaction with Lys122. [0566] The next modification was replacing the gem-dimethyl group with alicyclic rings with increasing size (cyclopropyl to cyclohexyl), aiming to improve the hydrophobic interactions both with ERα Val595 and the hydrophobic residues of 14-3-3 (Leu218, Ile219) (MS data: FIG.3B, FIGS.17-19, FA data: FIG.3C, FIGS.20-21). Cyclization with the small cyclopropyl groups didn’t correlate with improved cooperativity and the analogs appeared less selective than the gem-dimethyl analogs. Increasing the size of the ring to cyclopentyl resulted in improved potency (FIG.3B). However, 1075297 (cyclopentyl, ether) showed improved cooperativity with both peptides (FA EC50 =15 ± 2 μΜ for ΕRα, 32 ± 8 μΜ for C- RAF), whereas 1075306 (cyclopentyl, aniline) showed selectivity for ERα (FA EC50 = 5 ± 0.4 μΜ, EC50 >150 μΜ for C-RAF) (FIGS.3B-3C). The two cyclopentyl-featuring compounds showed different binding modes with ERα. The crystal structure of 1075297/14- 3-3/ΕRα showed that the cyclopentyl ring was participating in van der Waals interactions with Leu218, which correlated with improved cooperativity. The ether group was orientated toward the back (FIG.3D). On the contrary, in the crystal structure of 1075306/14-3-3/ΕRα, the aniline was oriented in the front, forcing the cyclopentyl group to adopt a different conformation, while maintaining the hydrophobic interactions with Leu218, Ile219 and Val595. The orientation of the aniline allowed the formation of a water-mediated hydrogen bond with the terminal carboxyl group of Val595. The second oxygen of the acid was forming a hydrogen bond with Lys122 of 14-3-3. Water-mediated hydrogen bonds were also formed between the carbonyl of 1075306 and Asp215 of 14-3-3 (FIG.3D). The observed interactions account for improved cooperativity for ERα. Surprisingly, a similar binding mode was observed for the cyclopentyl ether analog, lacking the p-Cl substituent (1075300). The compound was non-selective for the two peptides, with a small preference for C-RAF both in the mass spec and FA assays (FA EC50 =24 ± 2 μΜ for ΕRα, 18 ± 0.3 μΜ for C- RAF). A plausible explanation for the stabilization of ERα lies in the binding mode: the ether was oriented in the front of the pocket and formed a water-mediated hydrogen bond with Asn42 and Ser45, but lacked interactions with ERα. With the exception of this analog, the difference in compound orientation between an ether and an aniline analog, was consistent in the crystal structures for the gem-dimethyl-, the cyclopropyl-, the cyclopentyl- and the cyclohexyl groups. Additional to this effect, increasing the ring sizes eventually led to more favorable interactions with both with ERα and 14-3-3. [0567] Crystal structures of compounds bearing the cyclopentyl group (1075297 and 1075306) were also solved with 14-3-3/C-RAF (FIG.3E). For compound 1075297, the ether was again orientated in the back and hydrophobic interactions were observed with Ile219. The C-RAF peptide was in close proximity to the compound, however no specific interactions were formed. For compound 1075306, the aniline was oriented in the front and the peptide adopted a different conformation, moving away from the compound, indicating a potential steric clash. The differences in the binding mode with C-RAF translated in the biophysical assays: the ether was stabilizing C-RAF, in contrast to the aniline (FIGS.3B-3C). [0568] The replacement of the cyclopentyl ring with a cyclohexyl led to weaker analogs for both peptides. Interestingly, the introduction of heteroatoms (F, O, N) on the cyclohexyl ring significantly improved the cooperativity for the 14-3-3/ERα complex. More specifically, the gem-fluoro analogs were more selective for ΕRα, with the aniline analog (1075311) being slightly more potent than the ether (1075299) (FA EC50 =12 ± 2 μM and 18 ± 0.4 μM, respectively; for C-RAF EC50 > 150 μM). The tetrahydropyran analog (1075305) as an ether was more selective for ERα (FA EC50= 9 ± 2 μM for ΕRα, EC50 > 150 μM for C-RAF), whereas replacing the ether with an aniline (1075310) significantly improved the cooperativity and tuned the selectivity for ΕRα (FA EC50 =2 ± 0.3 μM, EC50 > 150 μM for C- RAF). The crystal structures of those analogs with 14-3-3/ΕRα showed that for the first time, both the ether and aniline groups were oriented in the front, thus participating in the water- mediated hydrogen bond with Val595 (FIG.3F). [0569] A more detailed analysis of the binding mode of 1075305 and 1075310, revealed that the tetrahydropyrane moiety, in addition to the hydrophobic interactions, was interacting via water molecules with the terminal carboxy group of Val595. Taken as a whole, the two compounds adopted conformations that allowed them to participate in a water network, which facilitated polar interactions both with 14-3-3 and ERα. [0570] Replacing the tetrahydropyrane with a piperidine or an amino-cyclohexyl group significantly improved the binding in the presence of ERα in the mass spectrometry experiment and faster binding was observed at the 1 h time point (FIG.3B). In the FA assay, the aniline analogs 1075481 and 1076394 showed low EC50 values (FA EC50 =2 ± 0.3 μM and 8 ± 1 μM, respectively) and the two compounds were selective for ERα in both the mass spec and FA assays; no stabilization was observed for C-RAF (FIGS.3B-3C). An explanation for the lack of stabilization for C-RAF for those compounds is steric hindrance, as the size of the substituents in close proximity to the peptide increased. Additionally, close analogs of 1075481 and 1076394 either as anilines without the p-Cl substituent or as ethers were significantly less potent in both assays, in agreement with previous observations. Boc- protected precursors of those compounds were also screened, but led to inconsistent SAR and appeared less cooperative and weaker than the deprotected analogs. [0571] Based on structure-activity relationships and crystal structures, for C-RAF, small groups in X position (close to the peptide) were well-tolerated and ethers were preferably orientated in the back of the pocket. On the contrary for ERα, larger rings with hydrogen bond acceptors or donors close to the peptide were more favorable. An aniline substituent oriented in the front and interacting with the water network was preferable for ERα (FIG. 3G). It is noteworthy that chemical modifications up to this point are correlated with cooperative binding, since the compounds showed low binding with 14-3-3 only in the mass spectrometry assay. [0572] We then focused our attention on further improving the cooperativity for the 14-3- 3/ΕRα complex. The most promising and selective derivatives 1075310 and 1075481 showed an identical binding mode in the crystal structures, despite having a hydrogen bond acceptor (1075310) versus a hydrogen bond donor (1075481) (FIG.4A). Interestingly, although the protein/peptide interface is primarily hydrophobic (Val595 of ERα, Leu218 and Ile219 of 14- 3-3), a significant number of polar interactions were observed through the water network. Polar interactions were formed both with Asp215 of 14-3-3 and with the backbone carboxylic acid of Val595 of ERα. The crystal structures support the hypothesis that favorable interactions both with the protein and the peptide were necessary for increasing the cooperativity, even indirectly via the water network (FIG.4B). For these two analogs FA protein titrations were performed at 100 μΜ compound.14-3-3 σ was titrated into FAM- labeled ERα peptide in the presence of DMSO or saturating concentration of the compounds. The apparent dissociation constant of 14-3-3/ERα (appKd) was 1493 nΜ, and decreased to 77 nM in the presence of compound 1075310 and to 49 nM in the presence of 1075481. Thus, compounds 1075310 and 1075481 stabilized the 14-3-3/ERα complex by 19- and 30-fold, respectively, compared to DMSO. [0573] To identify the optimal substituent to address both Val595 and the hydrophobic 14- 3-3 surface, methylated analogs of the tetrahydropyran-analog 1075310 were synthesized (FIG.4C). Introducing two methyl groups (compound 1080299) led to faster binding in the mass spectrometry experiment, especially at the 1 h and 8 h time-points in the presence of ERα (FIG.4D). However, this observation did not translate to improved stabilization in the FA assay (FA EC50 = 12 ± 1 μM, appKd 94 nM, 15-fold stabilization) (FIG.4E). The bulky analog with four methyl groups (1080300) appeared weaker in both assays (FA EC50 = 23 ± 2 μM), indicative of steric hindrance, as shown in the crystal structure (FIG.4F). Crystallography showed that 1080299 induced a movement of 14-3-3 Leu218 and in addition to previously observed hydrophobic interactions, in this case a shallow hydrophobic pocket was formed by the movement of Leu218 and Leu222, which was filled by one of the methyl groups (FIG.4G). [0574] We then shifted our attention from the 14-3-3/ERα interface and refocused on the warheads and, in particular, on the effect of the linker length. Four chloroacetamide analogs with longer linkers (2C or 3C) were synthesized and compared to analogs 1075310 and 1075481 (FIG.4H). Different trends were observed for the tetrahydropyran and the piperidine analogs. For tetrahydropyrans, 1C- and 3C-linkers were well-tolerated and resulted in comparable stabilization (FA EC50 = 2 ± 0.3 μM for 1075310, 4 ± 0.4 μM for 1075478 respectively) (FIGS.4I-4J). In protein titrations, compound 1075478 (3C-linker) showed an appKd of 27 nM and 55-fold stabilization. Strikingly, the 2C-linker was significantly weaker (FA EC50 = 92 ± 8 μM). For the piperidine analogs, in both assays, only the 1C-linker showed comparable stabilization with the tetrahydropyran analogs, whereas 2C- and 3C- linkers were tolerated, but were weaker (FA EC50 = 16 ± 2 μM for 1080293 and 16 ± 1 μM for 1076392, respectively). Comparison of the crystal structures of the tetrahydropyran analogs (1075310, 1080267, 1075478) showed a similar binding mode of the tetrahydropyran moiety. The main difference for the 2C- and 3C-linker analog was the orientation of the linkers. The longer, flexible 3C-linker of 1075478 adopted a more favorable conformation (FIG.4K). An additional hydrogen bond was formed between the carbonyl group of the warhead and Arg41. Two more warheads were synthesized for the tetrahydropyran analogs (the vinylsulfonamide 1075479 and the α-chloro-ketone 1075351). Consistent with our previous observations, the vinylsulfonamide was inactive (FA EC50 >150 μM). The ketone, although appearing active in the FA assay, lacked selectivity in the mass spectrometry assay in the presence of ERα and C-RAF peptides and showed significantly increased apo binding. [0575] The last modification on the scaffold was the rigidification of the warhead linker by introducing spirocycles, and thus restricting the conformations at the rim of the interface (FIG.5A). These modifications, although far from the protein/peptide interface, had a significant effect on the stabilization potential of the compounds. Crystallography indicated that the conformation of the spiro-rings, as well as their size, has an effect on how the warhead is oriented and whether it can form hydrogen bonds with the adjacent polar amino acids Arg41 and Asn42. Different sizes of spiro rings were included. The first two compounds (1080265 and 1080266) had the smallest spiro rings of the series, and varied in the attachment of the same spiro building block. For those compounds, in both the mass spectrometry and FA assays, less stabilization was observed, compared to the linear analog 1075310 (FA EC50 = 2 ± 0.3 μM, 16 ± 1 μM for 1080265 and 22 ± 1 μM for 1080266 respectively) (FIGS.5B-5C, FIGS.31-32). Crystallography showed similar binding modes for both 1080265 and 1080266 (FIG.5D). An alignment with the analog 1075478 (3C-linker) indicated that the overall binding mode close to the protein/peptide interface was identical for compounds 1075478, 1080265, and 1080266. However, the spiro analogs might need a slightly longer linker to interact more favorably with Cys38. Taking this crystallography- based information into account, one extra bond was added to the spiro warheads and compounds 1080294 and 1080295 were synthesized. In the mass spec assay, both compounds appeared highly potent and showed faster binding kin netics than 1075310. In the FA compound titrations, both compounds showed low EC50 values (FA EC50 = 4 ± 1 μM for 1080294 and 6 ± 0.3 μM for 1080295) (FIGS.5B-5C). However, in the case of 1080294, apo binding also increased over time, although the compound remained cooperative. One hypothesis for the increased apo binding was the formation of a direct hydrogen bond with Arg41 (2.8Å between the carbonyl of the warhead and the Arg41) (FIG.5E). In contrast, the orientation of the warhead differed in 1080295. The hydrogen bond was not formed and apo binding was less. The introduction of two fused piperidine rings (compound 1080296) was well tolerated in the mass spectrometry assay, with relatively low apo binding, but also a low EC50 in the FA assay (8 ± 1 μΜ) (FIGS.5B-5C). All three analogs with similar length of spiro rings (1080294, 1080295, 1080296) showed faster kinetics in the mass spectrometry assay and potent stabilization effect in the FA assay, comparable to the linear analog 1075310 (FIGS.5B-5C). In protein titrations, compounds 1080294, 1080295, and 1080296 showed appKd of 77 nM (18-fold stabilization), 160 nM (13-fold stabilization), and 119 nM (12-fold stabilization), respectively. To determine the optimum size for the spiro warheads, two larger analogs were synthesized, which included an additional methylene group (compounds 1080297, 1080298). Both analogs appeared to be weaker (FA EC50 = 15 ± 2 μM, and 97 ± 9 μM, respectively) than the structurally similar but smaller analogs 1080294 and 1080295 (FIGS.5B-5C). Significantly different orientations were observed in the crystal structures of 1080297 and 1080298, especially for the latter analog; an indication that the bigger spiro warhead was less tolerated due to potential steric hindrance (FIG.5F). The formation of a hydrogen bond with Arg41 did not have a favorable effect in those cases. [0576] The structural modifications provided valuable insight both on the interactions in the interface and on the conformations in close proximity to the warhead. Two more analogs were synthesized to explore potential synergistic effects of those changes (FIG.6A), combining the addition of the two methyl groups with medium size spiro warheads. In the mass spectrometry assay, especially for compound 1083744, 100% bound was reached at low compound concentrations in the 1 h time-point (FIG.6B). This translated to faster stabilization in the FA assay (at 0 h: FA EC50 =34 ± 3 μM) (FIG.6C). The analog with the smaller spiro-rings (1083743) was weaker than 1083744 in the FA assay (FA EC50 = 10 ± 2 μM, and 1 ± 0.8 μM respectively in the overnight measurement), but more cooperative than 1080299 (FA EC50 = 12 ± 1μM). In protein titrations, compounds 1083743 and 1083744 showed an appKd of 192 nM (7-fold stabilization) and 18 nM (116-fold stabilization), respectively. Crystal structures showed that one of the methyl groups was adopting a similar binding mode as in the case of 1080299, interacting with Leu222 and inducing the formation of the shallow hydrophobic pocket (FIG.6E, right panel). The orientation of the tetrahydropyran moiety was identical in 1083743 and 1083744 (FIG.6D, FIG.6E left panel). The orientation of the common piperidine ring was similar in both analogs. An alignment of 1080299 and 1083744 showed that the first piperidine ring was orientated in an identical position, whereas the second piperidine was perfectly aligned with the linear linker and at the same time filled the available space towards 14-3-3. Overall, compounds 1083743 and 1083744 had a common binding mode and similar interactions, and are able to participate in the water network, thus forming indirect polar interactions both with 14-3-3 and ERα. [0577] Despite the similarities in the binding mode of compounds 1083743 and 1083744, remarkable differences were observed both in the mass spectrometry and FA assays, indicating that in addition to maintaining key interactions both 14-3-3 and ERα, an optimal compound conformation is fundamental for stabilization of the 14-3-3/ERα complex. Taking into account that the interaction of 14-3-3 to its clients has a dynamic nature and upon binding to its clients, 14-3-3 brings order into disordered regions, restricting the possible conformations that a stabilizer can adopt is crucial for improved cooperativity. Compound 1083744 is achieving the ideal conformation to stabilize the complex with the presence of bigger spiro rings compared to 1083743. In the crystal structure, this is shown as conformational locking in the rim of the interface and overall shape complementarity. In the activity assays, it translates as remarkable cooperativity. By adopting the optimal conformation, the compound can avoid paying the energetic penalty associated with the loss of entropy due to organization upon binding. [0578] As a hub protein, 14-3-3 interacts with numerous clients in a wide range of affinities. We hypothesize that selective stabilization with small molecules can be achieved by aiming for unique interactions at the 14-3-3/client interface and by conformationally locking of the whole complex. To confirm this, selectivity studies were performed for eight 14-3-3 clients. Protein titrations were performed at 100 μΜ 1083744 with ERα (pT594, +1 Val), CRAF (pS259, +1 Thr), SOS1 (pS1161, +1 Ala), ChREBP (interacts with 14-3-3 in a phosphorylation-independent manner), p65 (pS45, +1 Ile), BRAF (pS365, +1 Ala), USP8 (pS718, +1 Ser) and Pin1 (pS72, +1 Trp). In addition to the differences in the +1 residues, the peptides vary in their shape, binding mode and occupancy of the amphipathic groove. In those experiments, compound 1083744 showed remarkable selectivity for 14-3-3/ERα (115- fold stabilization at 100 μM compound) compared to the other clients (fold-stabilization varied from 0 to 15-fold). An overlay with the other peptides indicates the lack of favorable interactions and shape complementarity (FIG.8). [0579] For compound 1083744, a more detailed comparison was made between the covalent stabilizer 1083744 and the natural product Fusicoccin-A (FC-A) (FIG.7A, FIG. 7D). Structurally, 1083744 is forming polar interactions both with 14-3-3 and ERα via the water network, whereas FC-A forms hydrogen bonds with Asp215 and Lys122 directly (FIG. 7B, FIG.7E). Although the natural product is non-covalent, in contrast to 1083744, a comparison was made using biophysical assays. FA protein titrations were performed, by titrating 14-3-3 σ into FAM-labeled ERα peptide in the presence of DMSO or 100 μΜ of the compounds. The apparent dissociation constant of 14-3-3/ERα (appKd) resulted to 13 nM in the presence of FC-A and to 18 nM in the presence of compound 1083744. Thus, FC-A and 1083744 stabilized the 14-3-3/ERα complex by 163- and 116-fold, respectively, compared to DMSO. Encouraged by the observed stabilization effects, FA 2D titrations were performed; 14-3-3σ was titrated to FAM-labeled ERα-peptide in the presence of varied but constant concentrations of either 1083744 (FIG.7C) or FC-A (FIG.7F), starting from 250 µM. A thermodynamic equilibrium model was used to determine the cooperativity factors (α) for FC-A and 1083744, which were calculated to be 240 for FC-A and 181 for 1083744. Although α is comparable for the two compounds, the observed difference could be attributed to the higher affinity of 1083744 for 14-3-3 alone (KD = 37 µM), which highlights the need for maintaining the apo binding of the compounds as low as possible to achieve a more cooperative effect and reduce the possibility of off-target effects on other 14-3-3 clients. [0580] Lastly, ITC experiments were performed to study and compare the thermodynamics of the interaction between the ERα-peptide and 14-3-3σ in the presence of either 1083744 of FC-A (FIGS.7G-7H). As a reference experiment, a full S-curve was obtained by titrating ERα peptide (300 µM) to 14-3-3σ (30 µM) with a determined KD value of 1.2 ± 0.1 µM, which is in close correlation with the KD value of ~2 µM determined by FA. The measured negative enthalpy (ΔH = -z3.9 ± 0.4 kcal.mol-1) indicates favorable (polar) binding interactions, driving the complex formation, supported by an increased entropy (ΔS = 14.1 ± 1.8 cal/mol.K), most probably from structured water molecules, which compensate the loss in entropy of the ERα sequence binding to the rigid 14-3-3. Addition of the covalent stabilizer 1083744 and non-covalent FC-A (500 µM) to the system, lowered the KD of the 14-3-3 / ERα interaction (30 ± 10 nM and 25 ± 11 nM, respectively). Deconvolution of the similar ΔG of 1083744 and FC-A, showed a difference in enthalpic and entropic contributions, with an increased enthalpically driven process for 1083744 binding, while FC-A binding was mainly entropically driven (FIG.7H). The decrease of entropy of 1083744, compared to the DMSO reference, could be associated with the presence of water molecules, which were stabilized by the covalent compound and therefore not displaced from the binding site (FIG.7B), while for FC-A, more water molecules are displaced from the binding pocket resulting in an increased disorder of the system (FIG.7E). [0581] In summary, we show the structure-guided optimization of a non-selective disulfide fragment toward first-in-class small molecule, potent and selective stabilizers for the 14-3- 3/ERα complex.14-3-3, as a hub protein is involved in complex PPI networks and regulates pathways often dysregulated in pathological conditions. The extensive interactome of 14-3-3, in addition to the lack of suitable starting points for chemical optimization, represents a considerable challenge in targeting this hub protein. 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K.; Davies, J. L.; Merron, C.; Ogden, P.; Sijbesma, E.; Ottmann, C.; Renslo, A. R.; Wilson, C.; Arkin, M. R. SLAS Discov.2018, 23 (2), 183–192. doi.org/10.1177/2472555217732072. 39. Hallenbeck, K.; Turner, D.; Renslo, A.; Arkin, M. Curr. Top. Med. Chem.2016, 17 (1), 4–15. doi.org/10.2174/1568026616666160719163839. 40. Sijbesma, E.; Hallenbeck, K. K.; Leysen, S.; de Vink, P. J.; Skóra, L.; Jahnke, W.; Brunsveld, L.; Arkin, M. R.; Ottmann, C. J. Am. Chem. Soc.2019, 141 (8), 3524–3531. doi.org/10.1021/jacs.8b11658. Example 2: Experimental procedures for Example 1 [0583] Protein expression and purification [0584] The 14-3-3 σ isoform (full-length for mass spectrometry and fluorescence anisotropy assays, ΔC for crystallography) with an N-terminal His6 tag was expressed in RosettaTM 2(DE3)pLysS competent E. coli (Novagen) from a pPROEX HTb expression vector. After transformation following manufacturer’s instructions, single colonies were picked to inoculate 30 mL precultures (LB), which were added to 1.5 L terrific broth (TB) medium after overnight growth at 37 °C, 250 rpm. Expression was induced upon reaching OD6001.9−2.1 by adding 400 μM IPTG. After overnight expression at 30 °C, 150 rpm, cells were harvested by centrifugation at 6,500 rpm, resuspended in lysis buffer (50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 10% glycerol, 1 mM TCEP), and lysed by sonication. The His6-tagged protein was purified by Ni-affinity chromatography (Ni-NTA Agarose, Invitrogen) (Wash buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 1 mM TCEP; Elution buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 500 mM imidazole, 1 mM TCEP) and analyzed for purity by SDS-PAGE and Q-Tof LC/MS. The protein was buffer exchanged (Storage buffer 25 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP) and concentrated to ~16 mg/mL and aliquotsflash-frozen for storage at −80 °C. The ΔC variant was truncated at the C-terminus after T231 to enhance crystallization and after the first Ni- affinity chromatography column, the construct was treated with TEV protease to cleave of the His6 tag during dialysis (25 mM HEPES, pH 7.5, 200 mM NaCl, 5% glycerol, 10 mM MgCl2, 250 µM TCEP) overnight at 4 °C. The flow-through of a second Ni-affinity column was subjected to a final purification step by size exclusion chromatography (Superdex 75 pg 16/60 size exclusion column (GE Life Science) (SEC buffer: 25 mM HEPES pH 7.5, 100 mM NaCl, 10 mM MgCl2, 250 µM TCEP). The protein was concentrated to ~60 mg/mL, analyzed for purity by SDS-PAGE and Q-Tof LC/MS and aliquots flash-frozen for storage at -80 °C. [0585] Peptide sequences [0586] Peptides for mass spectrometry dose responses were purchased from Elim Biopharmaceuticals, Inc. (Hayward,CA). Sequences were as follows: Ac- KYYITGEAEGFPA{pT}V-COOH (SEQ ID NO: 1) (ERα-pp), Ac-RQRST{pS}TPNVH- CONH2 (CRAF pS259-pp). Peptides for X-ray crystallography and fluorescein-labeled peptides were purchased from GenScript Biotech Corp. Sequences were: Ac- or 5-FAM- AEGFPA{pT}V-COOH (SEQ ID NO: 2) (8mer ERα-pp) and QRST{pS}TPNVH-CONH2 (SEQ ID NO: 3) (CRAF pS259-pp). Kd values of the fluorescently labeled peptides for 14-3- 3σ are 2 µM for ERα and 10 µM for C-RAF. [0587] LC-MS dose response assays [0588] Mass spectrometry dose response assays were performed on a Waters Acquity UPLC/ Xevo G2-XS Q-Tof mass spectrometer. A Waters UPLC Protein BEH-C4 Column (300 Å, 1.7 μm, 2.1 mm x 50 mm) was used to desalt the samples prior to application on the mass spectrometer. For 19-point LC-MS dose responses, 50 mM compound stocks in DMSO were serially diluted in 3-fold increment in a master plate, then 1000 nl of the compounds were transferred in the assay plates. Master mixes containing 100 nM full-length wild type 14-3-3σ in the absence or presence of either 2 μΜ ERα or 18 μM C-RAF were then dispensed into 384 well plates (Greiner Bio-One, catalog number 784201). Assay buffer was TRIS (10 mM, pH 8.0) and final volume per well was 50 μl, with final top concentration of compounds dose response series at 1 mM. The reaction mixtures were incubated for 1 h at rt before subjected to LC/MS. Four measurements (1 h, 8 h, 16 h, 24 h) were performed for time- course experiments. Data collection and automated processing followed a custom workflow, as previously described. Plots were created using GraphPad Prism with the log(agonist) vs. response (variable slope, four parameters) fitting model. [0589] Fluorescence anisotropy measurements [0590] Fluorescein-labeled peptides (5-FAM), 14-3-3σ FL protein, the compounds (50 mM stock solution in DMSO) were diluted in buffer (10 mM HEPES, pH 7.5, 150 mM NaCl, 0.1% Tween20, 1 mg/mL Bovine Serum Albumin (BSA; Sigma-Aldrich). Final DMSO in the assay was always 1%. Dilution series of 14-3-3 proteins or compounds were made in black, round-bottom 384-microwell plates (Corning) in a final sample volume of 10 µL in triplicates. [0591] Compound titrations were made by titrating the compound in a 2-fold dilution series (starting at 500 or 1000 µM) to a mix of fluorescein-labeled peptide (10 nM) and 14-3- 3σ (concentration at EC20 value of the protein-peptide complex; 1 µM for ERα and 5 µM for C-RAF). Fluorescence anisotropy measurements were performed directly and after overnight incubation at room temperature. [0592] Protein titrations were made by titrating 14-3-3σ in a 2-fold dilution series (starting at 300 µM) to a mix of fluorescein-labeled peptide (10 nM) and DMSO or compound (100 µM). Fluorescence anisotropy measurements were performed after overnight incubation at room temperature. [0593] Protein 2D titrations were made by titrating 14-3-3σ in a 2-fold dilution series (starting at 300 µM) to a mix of fluorescein-labeled peptide (10 nM) against varying fixed concentrations of compound (2-fold dilution, starting at 250 µM), or DMSO. Fluorescence anisotropy measurements were performed after overnight incubation at room temperature. [0594] Fluorescence anisotropy values were measured using a Tecan Infinite F500 plate reader (filter set lex: 485 ± 20 nm, lem: 535 ± 25 nm; mirror: Dichroic 510; flashes: 20; integration time: 50 ms; settle time: 0 ms; gain: 55; and Z-position: calculated from well). Wells containing only FAM-peptide were used to set as G-factor at 35 mP. Data reported are at endpoint. EC50 and apparent Kd values were obtained from fitting the data with a four- parameter logistic model (4PL) in GraphPad Prism 7 for Windows. Data was obtained and averaged based on either three (compound titrations) or two (protein titrations) independent experiments. [0595] Isothermal titration calorimetry [0596] The 14-3-3σ FL protein, ac-ERα peptide and compounds (50 mM stock solution in DMSO) were dissolved in ITC buffer (25 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 0.5 M tris-(2-carboxyethyl)phosphine (TCEP)) to a concentration of 30 µM of 14-3- 3σ for the cell, and 300 µM of ERα-peptide for the syringe. DMSO or compound concentrations were matched in the cell and syringe till 500 µM of compound and 1% DMSO. Samples were degassed at 450 mmHg, 10 minutes prior to measurement. Measurements were performed on an Affinity ITC LV (TA instruments), with injection size set to 2 µL, stirring speed of 150 rpm and temperature at 25 °C. The data was processed and analyzed with NanoAnalyze v3.11. The baseline was manually inspected and corrected, after which a blank constant model was fitted to correct for the heat of injection. Subsequently, an independent model was fitted, which the NanoAnalyze software uses to report the thermodynamic binding properties reported in this paper. [0597] Cooperativity analysis [0598] To determine the cooperativity parameters from the 2D-titration of 14-3-3/ERα- peptide with 1083744 and FC-A we used the general framework for straightforward model construction of multi-component thermodynamic equilibrium systems as described by Geertjens et al. (2). This general platform generates a model to describe multi-component equilibrium systems when given a system description. In our case we gave the following system description: R + P = RP ; KDI RP + S = RPS; KDII / α peptide and S = stabilizer. The KDII and α are determined based on the equilibrium equations. The data from 2D-titrations was provided to the model including the KDI at 2.0 µM, P_tot = 10 nM and the variable concentrations of 14-3-3 and stabilizer at each data point. Fit parameters were given the following initial guess values: KD II: 66 µM, α:1000. [0599] X-Ray crystallography data collection and refinement [0600] The 14-3-3σΔC protein, Ac-ERα or Ac-C-RAF peptide and compounds (50 mM stock solution in DMSO) were dissolved in complexation buffer (25 mM HEPES pH 7.5, 2 mM MgCl2 and 2 mM βME) and mixed in a 1:2:2 molar stoichiometry (protein : peptide : compound) at a final protein concentration of 12 mg/mL. The complex was set up for sitting- drop crystallization after overnight incubation at 4 °C, in a custom crystallization liquor (0.095 M HEPES (pH 7.1, 7.3, 7.5, 7.7), 0.19 M CaCl2, 24-29 % PEG 400 and 5% (v/v) glycerol). Crystals grew within 10 – 14 days at 4 °C. Crystals were fished and flash-cooled in liquid nitrogen. X-ray diffraction (XRD) data were collected at either an in-house system Rigaku Micromax-003 (Rigaku, Europe, Kemsing Sevenoaks, UK) equipped with an Dectris Pilatus 200K detector, the Deutsche Elektronen-Synchrotron (DESY) Petra III beamline P11, Hamburg, Germany, the European Synchrotron Radiation Facility (ESRF Grenoble, France, beamline ID23-2, ID30A-1/MASSIF-1 or beamline ID30B/MAD) or at Diamond Light Source (DLS) (Oxfordshire, United Kingdom, beamline I03). Initial data processing was performed at DESY using XDS or at ESRF and Diamond using DIALS (3) after which pre- processed data was taken towards further scaling steps, molecular replacement and refinement. [0601] Data was processed using the CCP4i2 suite (version 8.0.003) (4). After indexing and integrating the data, scaling was done using AIMLESS (5,6). The data was phased with MolRep (7), using 4JC3 and 3IQU as a template for ERα and C-RAF containing crystals, respectively. Presence of co-crystallized ligands was verified by visual inspection of the Fo- Fc and 2Fo-Fc electron density maps in COOT (version 0.9.6) (8). If electron density corresponding to the co-crystallized ligand was present, its structure and restrains were generated using either AceDRG (9) or eLBOW (10). For compounds 1080268 (PDB ID 8AI0) and 1076403 (PDB ID 8ALV), eLBOW was used to generate the structures and restraints, followed by model rebuilding and refinement using phenix.refine (11,12) from the Phenix software suite (version 1.19.2-4158) and Coot. For all the remaining compounds AceDRG was used to generate the structures and restraints, followed by model rebuilding and refinement using REFMAC5 (13). The PDB REDO server (pdb-redu.edu) (14) was used to complete the model building and refinement. The images were created using the PyMOL Molecular Graphics System (Schrödinger LLC, version 2.2.3). [0602] The structures were deposited in the protein data bank (PDB) with IDs: 8AV7 (1074202 non-covalent), 8AWG (1074202 covalent), 8AXE (1074210), 8ANF (1074359), 8ARO (1080291), 8AI0 (1080268), 8ARX (1074378), 8ARZ (1076406), 8AT9 (1080269), 8AXU (1075297 - ERα), 8ATR (1075297 – C-RAF), 8AZE (1075306 – ERα), 8ATS (1075306 – C-RAF), 8AV8 (1075300), 8ALR (1080272), 8ARY (1080273), 8ALV (1076403), 8AV3 (1075299), 8ALT (1075311), 8AV4 (1075305), 8ALW (1075310), 8AM7 (1076397), 8AS1 (1076398), 8ATP (1075481), 8ARG (1076405), 8ARW (1076402), 8ARR (1076394), 8ARX (1080299), 8AR4 (1080300), 8AQZ (1080267), 8AOY (1075478), 8AU2 (1080293), 8AR5 (1080265), 8ARQ (1080266), 8AQC (1080294), 8AQE (1080295), 8AUS (1080297), 8AUY (1080298), 8AQ1 (1083743), 8APS (1083744). [0603] Docking [0604] Computational design for SAR optimization and docking was performed with SeeSAR version 11.2.0; BioSolveIT GmbH, Sankt Augustin, Germany, 2022, biosolveit.de/SeeSAR Example 3: Synthetic procedures for Example 1 [0605] All solvents and reagents were commercially available and used without purification, unless otherwise stated. Deuterated solvents were obtained from Cambridge Isotope Laboratories. Reaction progress was monitored by analytical thin-layer chromatography (TLC, pre-coated silica gel 60 F254 plates, Merck) using ultraviolet (UV) light (254 and 365 nm). Analytical liquid chromatography coupled with mass spectrometry (LC-MS) was performed on a C4 Jupiter SuC4300A 150 x 2.0 mm column (using a 15 min. gradient of 5% to 100% acetonitrile in H2O (0.1% formic acid)), connected to a ThermoFischer LCQ Fleet Ion Trap Mass Spectrometer. Preparative high-pressure column chromatography was performed on a Waters 150 system using SRC C18 cartridges. NMR data were recorded on a Bruker Advance-III 400 MHz equipped with a BBFO probe from Bruker (400 MHz for 1H-NMR and 100 MHz for 13C-NMR). Chemical shifts were reported in parts per million (ppm) referenced to an internal standard (d-chloroform; 7.26 ppm for 1H- NMR and 77 ppm for 13C-NMR), relative to tetramethylsilane (TMS). The majority of building blocks mentioned in scheme 8 were synthesized by ChemPartner. [0606] Scheme 1. Synthetic route for gem-dimethyl derivatives with irreversible covalent warheads a h; (c) acrolyl chloride (10), Et3N, DCM, 0 oC to rt, 2 h; (d) 2-chloroethanesulfonyl chloride (15), Et3N, DCM, 0 oC to rt, 2 h; (e) 2-(chloromethyl)oxirane (20), K2CO3, DMF, 60 oC, overnight; (f) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0607] General procedures [0608] Procedure A. At 0 oC 2-(4-chlorophenoxy)isobutyric acid 5 (1 equiv) and HATU (1.2 equiv) were dissolved in dry DMF (2 ml for 1 mmol reaction scale). The appropriate amine (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). The product was confirmed with LCMS and used directly in the next step. [0609] Procedure B. The boc-protected amine was dissolved in 3 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained HCl salt was used directly in the next step. [0610] Procedure C. The HCl salt (1 equiv) was suspended in 2 ml dry DCM. At 0 oC, Et3N (4 equiv) was added. After 10 min, acrolyl chloride 10 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0611] N-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)acrylamide (11) 1047427 [0612] Obtained using oil, 25 mg, 35% yield.1H NMR (400 MHz, CDCl3) δ: 7.14 – 7.11 (m, 2H), 6.73 – 6.69 (m, 2H), 6.23 – 6.19 (m, 1H), 6.08 – 6.01 (m, 1H), 5.59 (dd, J = 10.2, 1.5 Hz, 1H), 4.63 – 4.60 (m, 2H), 3.15 – 3.10 (m, 1H), 3.04 – 2.99 (m, 1H), 2.87 – 2.81 (m, 1H), 2.53 – 2.47 (m, 1H), 1.73 – 1.66 (m, 2H), 1.56 (s, 6H), 1.05 – 0.96 (m, 1H), 0.75 – 0.67 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.1, 165.7, 154.0, 130.6, 129.1, 126.5, 126.1, 118.2, 81.0, 45.4, 44.4, 43.1, 36.2, 30.0, 29.5, 26.0, 25.8. LCMS (ESI): m/z calcd for C18H23ClN2O3; found [M+H]+ 351.80. [0613] N-((1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)methyl)acrylamide (12) 1074200 [0614] Obtained using 1 oil, 20 mg, 27% yield. H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 6.29 – 6.17 (m, 1H), 6.09 – 5.96 (m, 1H), 5.92 – 5.76 (m, 1H), 5.68 – 5.51 (m, 1H), 4.78 –4.52 (m, 2H), 3.25 – 2.76 (m, 3H), 2.64 – 2.41 (m, 1H), 1.72 – 1.70 (m, 3H), 1.56 (s, 6H), 1.05 – 0.96 (m, 1H), 0.75 – 0.67 (m, 1H). LCMS (ESI): m/z calcd for C19H25ClN2O3; found [M+H]+ 365.18. [0615] N-(2-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)ethyl)acrylamide (13) 1074201 [0616] Obtained using oil, 19 mg, 25% yield.1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.32 – 6.17 (m, 1H), 6.10 – 5.93 (m, 1H), 5.70 – 5.50 (m, 2H), 4.75 – 4.44 (m, 2H), 3.42 – 3.11 (m, 2H), 2.82 – 2.80 (m, 1H), 2.64 – 2.42 (m, 1H), 1.64 – 1.62 (m, 3H), 1.61 (s, 6H), 1.41 – 1.30 (m, 2H), 1.05 – 0.96 (m, 1H), 0.75 – 0.67 (m, 1H). LCMS (ESI): m/z calcd for C20H27ClN2O3; found [M+Na]+ 399.00. [0617] N-(3-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)propyl)acrylamide (14) 1074357 [0618] Obtained using on oil, 20 mg, 25% yield.1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.30 – 6.20 (m, 1H), 6.10 – 5.96 (m, 1H), 5.71 – 5.50 (m, 2H), 4.76 – 4.44 (m, 2H), 3.33 – 3.18 (m, 2H), 2.91 – 2.73 (m, 1H), 2.62 – 2.34 (m, 1H), 1.62 (s, 6H), 1.54 – 1.35 (m, 5H), 1.22 – 1.07 (m, 2H), 1.03 – 0.89 (m, 1H), 0.76 – 0.56 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.0, 165.5, 154.2, 130.8, 129.3, 126.3, 118.2, 117.0, 81.1, 45.8, 43.6, 39.6, 35.6, 33.3, 31.8, 26.5, 25.9. LCMS (ESI): m/z calcd for C21H29ClN2O3; found [M+H]+ 393.24. [0619] Procedure D. The HCl salt (1 equiv) was suspended in 2 ml dry DCM. At 0oC, Et3N (4 equiv) was added. After 10 min, 2-chloroethanesulfonyl chloride 15 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0620] N-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)ethenesulfonamide (16) 1047426 [0621] Obtained using oil, 21 mg, 54% yield.1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 6.43 (dd, J = 16.5, 9.9 Hz, 1H), 6.18 (d, J = 16.5 Hz, 1H), 5.89 (d, J = 9.9 Hz, 1H), 4.87 – 4.84 (m, 1H), 4.63 (d, J = 13.3 Hz, 2H), 2.86 – 2.82 (m, 1H), 2.73 (t, J = 6.3 Hz, 2H), 2.52 – 2.50 (m, 1H), 1.75 – 1.72 (m, 1H), 1.66 – 1.63 (m, 1H), 1.58 (s, 6H), 1.00 – 0.95 (m, 1H), 0.72 – 0.64 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.2, 154.0, 135.7, 129.2, 126.6, 126.2, 118.2, 81.0, 48.0, 45.2, 42.3, 36.4, 29.9, 29.3, 25.9. LCMS (ESI): m/z calcd for C17H23ClN2O4S; found [M+Na]+ 409.81. [0622] N-((1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4- yl)methyl)ethenesulfonamide (17) 1074199 O Cl [0623] Obtained using the procedure D on 0.2 mmol scale, white solid, 15.2 mg, 20% yield. HPLC retention time 12.5 min.1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 8.9 Hz, 2H), 6.45 (dd, J = 16.5, 9.9 Hz, 1H), 6.20 (d, J = 16.5 Hz, 1H), 5.92 (d, J = 9.9 Hz, 1H), 4.67 (d, J = 13.3 Hz, 2H), 4.52 (t, J = 6.3 Hz, 1H), 2.87 (t, J = 12.6 Hz, 1H), 2.76 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 12.3 Hz, 1H), 1.77 – 1.75 (m, 2H), 1.68 – 1.66 (m, 1H), 1.61 (s, 6H), 1.04 – 0.96 (m, 1H), 0.72 – 0.64 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 171.2, 154.1, 135.7, 129.2, 126.8, 126.3, 118.2, 81.0, 48.1, 45.3, 43.0, 36.5, 29.9, 29.4, 26.0. LCMS (ESI): m/z calcd for C18H25ClN2O4S; found [M+H] + 401.25, [M+Na]+ 423.15. [0624] N-(2-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4- yl)ethyl)ethenesulfonamide (18) 1074209 [0625] Obtained using oil, 21.0 mg, 25% yield.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 6.45 (dd, J = 16.5, 9.9 Hz, 1H), 6.20 (d, J = 16.5 Hz, 1H), 5.92 (d, J = 9.9 Hz, 1H), 4.77 – 4.51 (m, 2H), 4.29 – 4.17 (m, 1H), 3.07 – 2.93 (m, 2H), 3.01 – 2.79 (m, 3H), 2.65 – 2.44 (m, 2H), 1.62 (s, 6H), 1.42 – 1.35 (m, 2H), 1.09 – 0.94 (m, 1H), 0.75 – 0.59 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.0, 154.1, 129.2, 126.2, 118.2, 81.0, 45.6, 43.4, 42.6, 37.2, 35.7, 33.6, 32.2, 31.7, 25.9. LCMS (ESI): m/z calcd for C19H27ClN2O4S; found [M+Na]+ 437.80. [0626] N-(3-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4- yl)propyl)ethenesulfonamide (19) 1074356 [0627] Obtained using on oil, 22.0 mg, 25% yield.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 6.45 (dd, J = 16.5, 9.9 Hz, 1H), 6.20 (d, J = 16.5 Hz, 1H), 5.92 (d, J = 9.9 Hz, 1H), 4.87 – 4.343 (m, 2H), 4.36 – 3.96 (m, 1H), 3.05 – 2.75 (m, 3H), 2.58 – 2.40 (m, 1H), 1.64 – 1.63 (m, 1H), 1.62 (s, 6H), 1.54 – 1.31 (m, 4H), 1.24 -1.13 (m, 2H), 1.07 – 0.91 (m, 1H), 0.76 – 0.50 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.4, 154.5, 129.5, 127.0, 126.5, 118.6, 81.4, 46.1, 43.8, 43.4, 35.9, 33.3, 32.7, 32.1, 27.3, 26.4, 26.3. LCMS (ESI): m/z calcd for C20H29ClN2O4S; found [M+H]+ 429.06. [0628] Procedure E. The HCl salt (1 equiv) was dissolved in 2 ml dry DMF. At 0oC, K2CO3 (3 equiv) was added. After 10 min, 2-(chloromethyl)oxirane 20, was added slowly (1.2 equiv). Stirring at 0oC for 30min and then heating at 60oC overnight. The reaction mixture was quenched with sat. NaHCO3 (10 ml), diluted with EtOAc (10ml) and extracted (x3). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0629] 2-(4-chlorophenoxy)-2-methyl-1-(4-((oxiran-2-ylmethyl)amino)piperidin-1- yl)propan-1-one (21) 1074353 [0630] Obtained using oil, 8.0 mg, 10% yield. 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 4.53 (t, J = 11.7 Hz, 2H), 3.00 (t, J = 12.2 Hz, 1H), 2.82 (ddd, J = 14.1, 10.0, 3.9 Hz, 1H), 2.72 (t, J = 12.2 Hz, 1H), 1.83 – 1.80 (m, 1H), 1.70 – 1.68 (m, 7H), 1.61 (s, 6H), 1.18 – 1.14 (m, 1H), 0.92 – 0.86 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.2, 154.1, 129.3, 126.3, 118.2, 81.0, 53.4, 48.5, 44.1, 42.1, 35.5, 35.1, 26.0. LCMS (ESI): m/z calcd for C18H25ClN2O3; found [M+H]+ 353.16. [0631] 2-(4-chlorophenoxy)-2-methyl-1-(4-(((oxiran-2-ylmethyl)amino)methyl)piperidin- 1-yl)propan-1-one (22) 1074310 [0632] Obtained using on oil, 48.0 mg, 32% yield.1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 4.71 – 4.43 (m, 3H), 3.94 – 3.72 (m, 1H), 3.67 – 3.33 (m, 2H), 3.29 – 3.03 (m, 2H), 3.00 – 2.71 (m, 2H), 2.62 – 2.27 (m, 1H), 1.82 – 1.66 (m, 1H), 1.60 (s, 6H), 1.51 – 1.26 (m, 3H), 1.09 – 0.88 (m, 1H), 0.78 – 0.56 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.0, 154.1, 129.2, 126.1, 118.2, 81.0, 62.8, 45.7, 45.3, 43.4, 41.4, 33.4, 33.2, 32.1, 31.7. LCMS (ESI): m/z calcd for C19H27ClN2O3; found [M+H]+ 367.20. [0633] 2-(4-chlorophenoxy)-2-methyl-1-(4-(2-((oxiran-2-ylmethyl)amino)ethyl)piperidin- 1-yl)propan-1-one (23) 1074311 [0634] Obtained using oil, 45.0 mg, 30% yield.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 4.71 – 4.43 (m, 3H), 4.29 – 4.17 (m, 2H), 3.67 – 3.33 (m, 2H), 3.29 – 3.03 (m, 2H), 3.00 – 2.71 (m, 2H), 2.62 – 2.27 (m, 2H), 1.82 – 1.66 (m, 1H), 1.60 (s, 6H), 1.51 – 1.26 (m, 3H), 1.09 – 0.88 (m, 1H), 0.78 – 0.56 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.0, 154.1, 129.2, 126.2, 118.2, 81.0, 45.6, 43.4, 42.6, 37.2, 35.7, 33.6, 32.2, 31.7, 25.9. LCMS (ESI): m/z calcd for C20H29ClN2O3; found [M+H]+ 380.04. [0635] 2-(4-chlorophenoxy)-2-methyl-1-(4-(3-((oxiran-2-ylmethyl)amino)propyl)piperidin- 1-yl)propan-1-one (24) 1074309 [0636] Obtained oil, 8.0 mg, 10% yield. 1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 4.73 – 4.55 (m, 3H), 4.30 – 4.21 (m, 2H), 3.67 – 3.33 (m, 2H), 3.29 – 3.03 (m, 2H), 3.04 – 2.74 (m, 2H), 2.61 – 2.42 (m, 2H), 1.64 – 1.62 (m, 1H), 1.61 (s, 6H), 1.54 – 1.28 (m, 3H), 1.24 – 1.08 (m, 2H), 1.06 – 0.89 (m, 1H), 0.76 – 0.52 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.4, 154.5, 129.5, 127.0, 126.5, 118.6, 81.4, 46.1, 43.8, 43.4, 35.9, 33.3, 32.7, 32.1, 27.3, 26.4, 26.3. LCMS (ESI): m/z calcd for C21H31ClN2O3; found [M+H]+ 395.80. [0637] Procedure F. The HCl salt (1 equiv) was suspended in 2 ml dry DCM. At 0 oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0638] 2-chloro-N-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)acetamide (26) 1074360 [0639] Obtained using oil, 28.0 mg, 25% yield.1H NMR (400 MHz, CDCl3) δ 7.20 – 7.16 (m, 2H), 6.77 – 6.73 (m, 2H), 6.32 (d, J = 7.6 Hz, 1H), 4.59 – 4.57 (m, 2H), 3.98 (s, 2H), 3.93 – 3.85 (m, 1H), 3.06 (t, J = 12.3 Hz, 1H), 2.75 (t, J = 12.2 Hz, 1H), 1.93 (d, J = 11.9 Hz, 1H), 1.78 (d, J = 12.1 Hz, 1H), 1.61 (s, 6H), 1.30 -1.26 (m, 1H), 0.97 – 0.87 (m, 1H).13C NMR (100 MHz, CDCl3) δ 171.3, 165.2, 154.0, 129.3, 126.4, 118.2, 81.0, 47.0, 44.2, 42.4, 42.1, 32.0, 31.5, 26.1, 25.8. LCMS (ESI): m/z calcd for C17H22Cl2N2O3; found [M+H]+ 374.30. [0640] 2-chloro-N-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)acetamide (27) 1074202 [0641] Obtained using semi-solid, 30.0 mg, yield 78%.1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.58 (s, 1H), 4.68 (d, J = 13.3 Hz, 2H), 4.03 (s, 2H), 3.10 (td, J = 6.3, 2.6 Hz, 2H), 2.88 (t, J = 13.0 Hz, 1H), 2.55 (t, J = 12.3 Hz, 1H), 1.71 (dd, J = 15.9, 7.3 Hz, 2H), 1.62 (s, 6H), 1.54 – 1.53 (m, 1H), 1.06 (dd, J = 22.3, 10.1 Hz, 1H), 0.75 (dd, J = 22.1, 9.5 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 171.2, 166.0, 154.1, 129.2, 126.2, 118.2, 81.0, 45.3, 44.7, 43.0, 42.6, 36.1, 30.0, 29.4, 26.0, 25.9. LCMS (ESI): m/z calcd for C18H24Cl2N2O3; found [M+H]+ 378.09. [0642] 2-chloro-N-(2-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4- yl)ethyl)acetamide (28) 1074210 [0643] Obtained using oil, 38.9 mg, 65% yield. HPLC retention time 12.5 min.1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 6.53 (b, 1H), 4.62 (d, J = 13.2 Hz, 2H), 4.00 (s, 2H), 3.26 (dd, J = 13.6, 6.8 Hz, 2H), 2.84 (t, J = 12.4 Hz, 1H), 2.51 (t, J = 12.2 Hz, 1H), 1.91 (b, 1H), 1.71 (d, J = 12.6 Hz, 2H), 1.60 (s, 6H), 1.44 – 1.33 (m, 2H), 1.05 – 1.00 (m, 1H), 0.74 – 0.68 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 171.1, 165.8, 154.2, 129.2, 126.2, 118.3, 81.1, 45.7, 43.4, 42.6, 37.2, 35.8, 33.6, 32.3, 31.8, 26.0, 25.7. LCMS (ESI): m/z calcd for C19H26Cl2N2O3; found [M+H]+ 401.40, [M+Na]+ 423.10. [0644] 2-chloro-N-(3-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4- yl)propyl)acetamide (29) 1074359 [0645] Obtained using oil, 34.0 mg, 55% yield. HPLC retention time 13.0 min. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 6.57 (s, 1H), 4.64 – 4.61 (m, 2H), 4.02 (s, 2H), 3.24 (dd, J = 13.5, 6.9 Hz, 2H), 2.83 (t, J = 12.5 Hz, 1H), 2.50 (t, J = 12.3 Hz, 1H), 2.04 – 2.03 (m, 1H), 1.69 – 1.67 (m, 1H), 1.61 (s, 6H), 1.52 – 1.38 (m, 3H), 1.17 – 1.12 (m, 2H), 1.00 – 0.96 (m, 1H), 0.68 – 0.64 (m, 1H).13C NMR (100 MHz, CDCl3) δ 171.0, 165.8, 154.2, 129.2, 126.1, 118.2, 81.0, 45.8, 43.6, 42.6, 39.9, 35.6, 33.2, 32.3, 31.8, 26.3, 26.0. LCMS (ESI): m/z calcd for C20H28Cl2N2O3; found [M+H]+ 415.20, [M+Na]+ 437.16. [0646] Scheme 2. Synthetic route for gem-dimethyl α-chloro-ketone derivative 37 (1074203) a KHMDS, THF, -78 oC, 1 h; (c) m-CPBA, DCM, 0 oC to rt, 2 h; (d) LiCl, AcOH, THF, rt, overnight; (e) DMP, NaHCO3, DCM, 0 oC to rt, 1 h; (f) TFA, DCM, 0 oC to rt, 2 h; (g) HATU, DIPEA, DMF, rt, 2 h. [0647] Procedure A. To a stirred solution of 30 (2 g, 8.2 mmol, 1 equiv) in DCM (20 ml) at 0 oC, NaHCO3 (1.4 g, 16.4 mmol, 2 equiv) and Dess-Martin periodinane (4.2 g, 9.8 mmol, 1.2 equiv) were added sequentially. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. Na2S2O3 (20 mL) and sat. aq. NaHCO3 (20 mL) and then extracted with DCM (3 x 20 ml). The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0648] Procedure B. To a stirred solution of PPh3CH3Br (5.4 g, 15 mmol, 2 equiv) in THF (25 ml) at -78 oC, KHMDS (1M in THF, 15 ml) was added dropwise. After stirring for 15 min, the mixture was warmed up to room temperature and stirred for 1 h, at which point the resulted yellow solution was re-cooled to -78 oC followed by the addition of 31 (1.8 g, 7.5 mmol, 1 equiv). After stirring at -78 oC for 1 h, the mixture was warmed up to room temperature and the progress of the reaction was monitored by using TLC. The reaction was diluted with sat. NH4Cl (50 ml) and EtOAc (30 ml) when the TLC analysis indicated full conversion. The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 30 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-20% EtOAc in hexane). [0649] Procedure C. To a stirred solution of 32 (1 g, 4.2 mmol, 1equiv) in DCM (10 ml) at 0 oC, m-CPBA (77%, 1.1 g, 5 mmol, 1.2 equiv) was added carefully. After addition, the reaction mixture was allowed to reach room temperature and stirred for 2 h before TLC analysis indicated full conversion. The reaction was diluted with sat. Na2SO3 (20 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0650] Procedure D. To a solution of 33 (580 mg, 2.3 mmol, 1equiv) and acetic acid (0.4 ml, 6.9 mmol, 3 equiv) in dry THF (6 ml) was added anhydrous LiCl (193 mg, 4.6 mmol, 2 equiv). The mixture was stirred at room temperature overnight. The reaction was diluted with sat. NH4Cl (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0651] Procedure E. To a stirred solution of 34 (300 mg, 1.03 mmol, 1 equiv) in DCM (5 ml) at 0 oC, NaHCO3 (173 mg, 2.06 mmol, 2 mmol) and Dess-Martin periodinane (524 mg, 1.24 mmol, 1.2 equiv) were added sequentially. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. Na2S2O3 (10 ml) and sat. aq. NaHCO3 (20 ml) and then extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and the solvents were removed under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0652] Procedure F. Intermediate 35 (120 mg, 0.42 mmol, 1 equiv) was dissolved in DCM (3 ml) and cooled to 0 oC. TFA (640 ul, 8.3 mmol, 20 equiv) was added dropwise. After addition, the reaction mixture was allowed to reach to room temperature and stirred for 2 h. Solvents were removed under reduced pressure to afford the corresponding TFA salt (36), which was used directly in the next step. [0653] Procedure G. The carboxylic acid 5 (32 mg, 0.15 mmol, 1 equiv) and HATU (68mg, 0.18 mmol, 1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The TFA amine salt 36 (0.18 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (80μl, 0.45 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with ethyl acetate (10 ml) and sat. NH4Cl was added. The organic phase was washed with NH4Cl (2x10ml) and Brine (1x10ml), and then dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0654] tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (31) [0655] Obtained using procedure slight yellow oil, 1.9 g, 95% yield. 1H NMR (400 MHz, CDCl3) δ 9.80 (t, J = 1.7 Hz, 1H), 4.30 – 3.98 (m, 2H), 2.68 (t, J = 12.2 Hz, 2H), 2.49 (td, J = 7.6, 1.7 Hz, 2H), 1.74 – 1.53 (m, 4H), 1.47 (s, 9H), 1.44 – 1.22 (m, 1H), 1.11 (ddd, J = 24.5, 12.5, 4.4 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 202.3, 154.8, 79.3, 41.1, 35.5, 31.9, 28.5, 28.4. [0656] tert-butyl 4-(but-3-en-1-yl)piperidine-1-carboxylate (32) [0657] Obtained using procedure colorless oil, 1.5 g, 83% yield. 1H NMR (400 MHz, CDCl3) δ 5.82 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.08 – 4.86 (m, (s, 2H), 2.69 (t, J = 12.2 Hz, 2H), 2.19 – 1.99 (m, 2H), 1.72 – 1.60 (m, 2H), 1.47 (s, 9H), 1.45 – 1.28 (m, 3H), 1.10 (ddd, J = 24.1, 12.7, 4.4 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 154.9, 138.8, 114.4, 79.2, 35.6, 35.4, 32.1, 30.8, 28.5. [0658] tert-butyl 4-(2-(oxiran-2-yl)ethyl)piperidine-1-carboxylate (33) [0659] Obtained using procedure on yellow oil, 600 mg, 60% yield.1H NMR (400 MHz, CDCl3) δ 4.09 (s, 2H), 2.97 – 2.87 (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.69 (t, J = 12.3 Hz, 2H), 2.48 (dd, J = 5.0, 2.7 Hz, 1H), 1.66 (t, J = 10.4 Hz, 2H), 1.62 – 1.50 (m, 2H), 1.47 (s, 9H), 1.45 – 1.25 (m, 3H), 1.10 (qd, J = 16.6, 4.0 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 154.9, 79.2, 52.4, 47.1, 35.8, 32.6, 32.1, 29.6, 28.5. [0660] tert-butyl 4-(4-chloro-3-hydroxybutyl)piperidine-1-carboxylate (34) [0661] Obtained using colorless oil, 520 mg, 78% yield. 1H NMR (400 MHz, CDCl3) δ 4.09 (s, 2H), 3.80 (s, 1H), 3.65 (dd, J = 11.1, 3.4 Hz, 1H), 3.50 (dd, J = 11.1, 7.0 Hz, 1H), 2.68 (t, J = 12.2 Hz, 2H), 2.26 (s, 1H), 1.67 (d, J = 11.4 Hz, 2H), 1.62 – 1.51 (m, 2H), 1.47 (s, 9H), 1.45 – 1.25 (m, 3H), 1.18 – 1.03 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 154.9, 79.3, 71.6, 50.4, 36.0, 32.3, 32.1, 31.3, 28.5. [0662] tert-butyl 4-(4-chloro-3-oxobutyl)piperidine-1-carboxylate (35) [0663] Obtained using colorless oil, 255 mg, 86% yield. 1H NMR (400 MHz, CDCl3) δ 4.30 – 3.94 (m, 4H), 2.66 (dd, J = 18.8, 11.3 Hz, 4H), 1.72 – 1.54 (m, 4H), 1.47 (s, 9H), 1.45 – 1.25 (m, 1H), 1.11 (ddd, J = 24.5, 12.5, 4.4 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 202.7, 154.8, 79.3, 48.1, 36.8, 35.4, 31.9, 29.9, 28.5. [0664] 1-chloro-4-(1-(2-(4-chlorophenoxy)-2-methylpropanoyl)piperidin-4-yl)butan-2-one (37) 1074203 [0665] Obtained using oil, 17.7 mg, 31% yield. HPLC retention time 14.5 min.1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 4.64 (d, J = 13.0 Hz, 2H), 4.03 (s, 2H), 2.84 (t, J = 12.5 Hz, 1H), 2.54 – 2.50 (m, 3H), 1.69 – 1.66 (m, 1H), 1.61 (s, 6H), 1.52 – 1.37 (m, 4H), 1.03 – 0.95 (m, 1H), 0.72 – 0.64 (m, 1H).13C NMR (100 MHz, CDCl3) δ 202.5, 171.2, 154.2, 129.2, 126.2, 118.2, 81.1, 48.0, 45.7, 43.4, 36.4, 35.2, 32.2, 31.5, 29.4, 26.0, 25.9. LCMS (ESI): m/z calcd for C19H25Cl2NO3; found [M+H]+ 386.14. [0666] Scheme 3. Synthetic route for cyclopropyl analog 46 (1074378) a
80 oC, 40 h; (c) TsCl, Et3N, DCM, 0 oC to rt, overnight; (d) LiHMDS, THF, -78 oC, 2 h; (e) LiOH, THF/H2O, rt, overnight; (f) 4-(boc-aminomethyl)piperidine (2), HATU, DIPEA, DMF, 0 oC to rt, overnight; (g) 4 N HCl/dioxane, rt, 1 h; (h) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0667] Procedure A. To a solution of 4-chlorophenol 39 (7.0 g, 54.4 mmol, 1 equiv) in DMF (60 ml) at 0oC was slowly added sodium hydride (4.36 g, 109 mmol, 2 equiv) in portions. The reaction mixture was stirred for 4 h and then 3-bromooxolan-2-one 38 (9.8 g, 59.9 mmol, 1.1 equiv) in 10 ml DMF was slowly added. Stirring rt overnight. The reaction mixture was quenched with sat. NaHC03 (100 ml) and then extracted with DCM (3x100ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0668] Procedure B.3-(4-chlorophenoxy)dihydrofuran-2(3H)-one 40 (1 gr, 4.71 mmol, 1 equiv) was dissolved in 12.0 ml MeOH. Iodine (20 mg, 0.16 mmol, 0.03 equiv) was added and the reaction mixture was heated at 80 oC for 40 h. The reaction was quenched with sat. Na2S2O3 (15 ml) and extracted with EtOAc (3x20 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0- 100% EtOAc in hexane). [0669] Procedure C. To a solution of methyl 2-(4-chlorophenoxy)-4-hydroxybutanoate 41 (670 mg, 2.74 mmol, 1 equiv) in 10 ml dry DCM at 0oC was added Et3N (460 μl, 3.3 mmol, 1.2 equiv). Under argon, 4-methylbenzene-1-sulfonyl chloride (570 mg, 3.0 mmol, 1.1 equiv) was added. The reaction mixture was stirred at 0oC for 1h and then rt overnight. The reaction was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0- 100% EtOAc in hexane). [0670] Procedure D. To a solution of methyl 2-(4-chlorophenoxy)-4-(tosyloxy)butanoate 42 (556 mg, 1.4 mmol, 1 equiv) in 10 ml dry THF at -78 oC under argon was added LiHMDS (544 μl, 2.8 mmol, 2 equiv). Stirring for 2 h. The reaction mixture was quenched with sat. NH4Cl (10 ml) and extracted with EtOAc (3 x 10ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. [0671] Procedure E. The methyl ester 43 (272 mg, 1.2 mmol, 1equiv) was suspended in a mixture of THF – H2O (2:1, 10ml) and LiOH (144 mg, 6.0 mmol, 5 equiv) was added. The reaction mixture was stirred rt overnight. Solvents were removed under reduced pressure. The residue was dissolved in 10 ml H2O and extracted with EtOAc (1 x 10 ml). The aqua phase was separated, cooled at 0 oC and acidified with 2 N HCl until pH = 1. Extraction with EtOAc (3x 20 ml), drying over MgSO4, filtration and evaporation under reduced pressure. [0672] Procedure F. At 0 oC 1-(4-chlorophenoxy)cyclopropane-1-carboxylic acid 43 (242 mg, 1.14 mmol, 1 equiv) and HATU (520mg, 1.36 mmol, 1.2 equiv) were dissolved in 3ml dry DMF.4-(Boc-aminomethyl)piperidine 2 (291 mg, 1.36 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (607 μl, 3.4 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). The product was confirmed with LCMS and used directly in the next step. [0673] Procedure G. The boc-protected intermediate 45 was dissolved in 3 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained HCl salt was used directly in the next step. [0674] Procedure H. The HCl salt (1 equiv) was suspended in 2 ml dry DCM. At 0 oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0675] 3-(4-chlorophenoxy)dihydrofuran-2(3H)-one (40) [0676] Obtained using procedure A scale, yellow oil, 5.7 g, 49% yield.1H NMR (400 MHz, CDCl3) δ: 7.25 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 5.01 – 4.83 (m, 1H), 4.61 – 4.46 (m, 1H), 4.43 – 4.29 (m, 1H), 2.83 – 2.62 (m, 1H), 2.57 – 2.34 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 173.3, 155.9, 129.6, 127.4, 117.3, 72.8, 65.4, 31.0, 29.7. [0677] methyl 2-(4-chlorophenoxy)-4-hydroxybutanoate (41) [0678] Obtained using procedure B scale, yellow oil, 770 mg, 67% yield. 1H NMR (400 MHz, CDCl3) δ: 7.25 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.93 – 4.65 (m, 1H), 3.95 – 3.83 (m, 2H), 3.77 (s, 3H), 2.32 – 2.25 (m, 2H), 1.88 – 1.71 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 172.3, 156.6, 129.8, 127.1, 116.8, 74.5, 58.7, 52.7, 35.6. [0679] methyl 2-(4-chlorophenoxy)-4-(tosyloxy)butanoate (42) [0680] Obtained using procedure C on 2.74 mmol scale, yellow oil, 556 mg, 51% yield.1H NMR (400 MHz, CDCl3) δ: 7.67 – 7.65 (m, 2H), 7.20 – 7.12 (m, 4H), 6.72 – 6.45 (m, 2H), 4.67 – 4.55 (m, 1H), 4.26 – 4.12 (m, 2H), 3.67 (s, 3H), 2.33 (s, 3H), 2.30 – 2.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 170.6, 155.7, 144.8, 132.1, 129.6, 129.1, 127.5, 126.5, 116.1, 72.1, 65.4, 52.3, 31.8, 21.3. [0681] methyl 1-(4-chlorophenoxy)cyclopropane-1-carboxylate (43) [0682] Obtained using procedure yellow oil, 272 mg, 86% yield.1H NMR (400 MHz, CDCl3) δ: 7.23 (d, J = 9.0 Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H), 3.73 (s, 3H), 1.65 – 1.56 (m, 2H), 1.35 – 1.28 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.4, 155.9, 129.2, 126.5, 116.5, 71.0, 53.7, 17.3. [0683] 1-(4-chlorophenoxy)cyclopropane-1-carboxylic acid (44) Cl [0684] Obtained using procedure white semi-solid, 242 mg, 95% yield.1H NMR (400 MHz, CDCl3) δ: 11.5 (b, 1H), 7.23 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 1.70 – 1.56 (m, 2H), 1.25 – 1.29 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 179.2, 155.9, 129.5, 127.0, 116.9, 71.0, 18.4. [0685] 2-chloro-N-((1-(1-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4- yl)methyl)acetamide (46) 1074378 [0686] Obtained using mg, yield (over 3 steps).1H NMR (400 MHz, CDCl3) δ: 7.20 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.62 (b, 1H), 4.60 – 4.41 (m, 2H), 4.03 (s, 2H), 3.15 – 2.98 (m, 3H), 2.60 – 2.58 (m, 1H), 1.79 – 1.70 (m, 3H), 1.47 – 1.37 (m, 2H), 1.16 – 1.00 (m, 4H).13C NMR (100 MHz, CDCl3) δ: 168.0, 166.1, 156.0, 129.4, 126.5, 116.6, 79.0, 60.6, 44.8, 42.6, 36.2, 30.2. LCMS (ESI): m/z calcd for C18H22Cl2N2O3; found [M+Na]+ 408.12. [0687] Scheme 4. Synthetic route for analog 53 (1075294) a chlorophenol (39), Cs2CO3, DMF, 80 oC, 2 h; (c) (CH3)3IO, NaH, DMSO, 15 oC to rt 3 h; (d) LiOH, THF/H2O, rt, overnight; (e) 4-(boc-aminomethyl)piperidine (2), HATU, DIPEA, DMF, 0 oC to rt, overnight; (f) TFA, DCM, 0 oC to rt, 2 h; (g) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0688] Procedure A. To a stirred a solution of 47 (1 g, 10 mmol, 1 equiv) in MeOH (10 ml), PyHBr3 (3.8 g, 12 mmol, 1.2 equiv) was added in one portion. The resulting red mixture was heated to 55 oC for 3 h before TLC analysis indicated full conversion. K2CO3 (2.8 g, 20 mmol, 2 equiv) was added and the suspension was heated for another 3 h before TLC analysis showed full conversion. The precipitate was filtered off and the filtrate was concentrated. The residue was partitioned between EtOAc (30 ml) and saturated aqueous NaHSO3 (30 ml). The organic phase was sequentially washed with 1 M HCl (30 ml) and brine (30 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0- 10% EtOAc in hexane). [0689] Procedure B. Methyl (Z)-2-bromobut-2-enoate 48 (1 g, 5.5 mmol, 1 equiv) and 4- chlorophenol 39 (718 mg, 5.5 mmol, 1 equiv) were dissolved in DMF (10 ml). Cs2CO3 (3.6 g, 11 mmol, 1 equiv) was added in one portion and the resulting mixture was heated to 80 oC for 2 h. The reaction mixture was diluted with sat. NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (1 x 50ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-20% EtOAc in hexane). [0690] Procedure C. To a suspension of trimethylsulfoxonium iodide (730 mg, 3.3 mmol, 1.1 equiv) in DMSO (10 ml), NaH (132 mg, 60% oil dispersion, 3.3 mmol, 1.1 equiv) was added in portions over 5 minutes. The suspension was stirred for 1 h, and then a solution of methyl (Z)-2-(4-chlorophenoxy)but-2-enoate 49 (500 mg, 2.2 mmol, 1 equiv) in DMSO (5 ml) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 3 h. The reaction mixture was diluted with sat. NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (1 x 50ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0 - 20% EtOAc in hexane). [0691] Procedure D. (±)-Methyl (1S,2R)-1-(4-chlorophenoxy)-2-methylcyclopropane-1- carboxylate 50 (120 mg, 0.5 mmol, 1 equiv) was suspended in a mixture of THF – H2O (2:1, 4 ml) and LiOH (60 mg, 2.5 mmol, 5 equiv) was added. The reaction mixture was stirred rt overnight. Solvents were removed under reduced pressure. The residue was dissolved in 10 ml H2O and extracted with EtOAc (1 x 10ml). The aqua phase was separated, cooled at 0 oC and acidified with 2 N HCl until pH = 1. Extraction with EtOAc (3x 20ml), drying over MgSO4, filtration and evaporation under reduced pressure. The crude was used directly in the next step. [0692] Procedure E. At 0 oC carboxylic acid 51 (110 mg, 0.5 mmol, 1 equiv) and HATU (228 mg, 0.6 mmol, 1.2 equiv) were dissolved in 3 ml dry DMF.4-(Boc- aminomethyl)piperidine 2 (128 mg, 0.6 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (267 μl, 1.5 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0693] Procedure F. The boc-protected intermediate 52 (100 mg, 0.24 mmol, 1 equiv) was dissolved in DCM (3 ml) and cooled at 0 oC. TFA (370 μl, 4.8 mmol, 20 equiv) was added dropwise. Stirring at 0 oC for 30 min, then rt for 2 h. Solvents were removed under reduced pressure and the obtained TFA salt was used directly in the next step. [0694] Procedure G. The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0695] Methyl (Z)-2-bromobut-2-enoate (48) [0696] Obtained using procedure A slight yellow oil, 1.7 g, 95% yield. 1H NMR (400 MHz, CDCl3) δ: 6.78 (q, J = 7.6 Hz, 1H), 3.82 (s, 3H), 2.05 (d, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ: 163.0, 141.7, 117.1, 53.2, 17.9. LCMS (ESI): m/z calcd for C5H7BrO2; found [M+H]+ 180.82. [0697] Methyl (Z)-2-(4-chlorophenoxy)but-2-enoate (49) [0698] Obtained using procedure slight yellow oil, 1.1 g, 90% yield. 1H NMR (400 MHz, CDCl3) δ: 7.24 – 7.20 (m, 2H), 6.88 – 6.81 (m, 2H), 6.72 (q, J = 7.2 Hz, 1H), 3.71 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ: 163.3, 155.82, 141.6, 129.5, 127.9, 127.1, 116.3, 52.2, 11.5. LCMS (ESI): m/z calcd for C11H11ClO3; found [M+H]+ 227.10. [0699] (±)-Methyl (1S,2R)-1-(4-chlorophenoxy)-2-methylcyclopropane-1-carboxylate (50) [0700] Obtained using procedure C on l scale, colorless oil, 158 mg, 30% yield.1H NMR (400 MHz, CDCl3) δ: 7.27 – 7.20 (m, 2H), 6.95 – 6.84 (m, 2H), 3.72 (s, 3H), 1.90 (m, 1H), 1.39 (dd, J = 10.3, 5.5 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 0.88 (dd, J = 7.8, 5.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 172.8, 156.4, 129.3, 126.4, 116.5, 61.1, 52.5, 23.9, 22.9, 12.3. LCMS (ESI): m/z calcd for C12H13ClO3; found [M+Na]+ 264.09. [0701] (±)-Tert-butyl ((1-((1S,2R)-1-(4-chlorophenoxy)-2-methylcyclopropane-1- carbonyl)piperidin-4-yl)methyl) carbamate (52) [0702] Obtained using oil, 127 mg, 60% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.19 (m, 2H), 7.02 (m, 2H), 4.56 (s, 1H), 4.41 (s, 2H), 3.14 – 2.73 (m, 3H), 2.70 – 2.18 (m, 1H), 1.76 – 1.56 (m, 5H), 1.43 (s, 9H), 1.17 (s, 2H), 1.10 – 0.88 (m, 3H), 0.62 (s, 1H).13C NMR (100 MHz, CDCl3) δ: 168.7, 156.4, 156.0, 129.4, 126.4, 116.6, 79.4, 63.4, 45.8, 42.9, 36.9, 30.1, 29.5, 28.4, 19.0, 18.4, 12.1. [0703] (±)-2-Chloro-N-((1-((1S,2R)-1-(4-chlorophenoxy)-2-methylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)acetamide (53) 1075294 [0704] Obtained using on oil, 42 mg, 45% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.25 – 7.17 (m, 2H), 7.05 – 6.94 (m, 2H), 6.64 (b, 1H), 4.45 – 4.43 (m, 2H), 4.02 (s, 2H), 3.32 – 3.06 (m, 2H), 3.04 – 2.88 (m, 1H), 2.73 – 2.49 (m, 1H), 1.90 – 1.52 (m, 5H), 1.20 (s, 3H), 1.08 – 0.93 (m, 2H), 0.64 (d, J = 22.5 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 168.8, 166.0, 156.4, 129.4, 126.4, 116.7, 63.3, 45.6, 44.9, 42.7, 36.3, 30.2, 29.6, 18.2, 12.1. LCMS (ESI): m/z calcd for C19H24Cl2N2O3; found [M+Na]+ 401.04. [0705] Scheme 5. Synthetic route for analog 60 (1075308) a chlorophenol (39), Cs2CO3, DMF, 80 oC, 2 h; (c) (CH3)3IO, NaH, DMSO, 15 oC to rt 3 h; (d) LiOH, THF/H2O, rt, overnight; (e) 4-(boc-aminomethyl)piperidine (2), HATU, DIPEA, DMF, 0 oC to rt, overnight; (f) TFA, DCM, 0 oC to rt, 2 h; (g) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0706] Procedure A. To a stirred a solution of 54 (2 g, 17.5 mmol, 1 equiv) in MeOH (20 ml), PyHBr3 (6.7 g, 21.5 mmol, 1.2 equiv) was added in one portion. The resulting red mixture was heated to 55 oC for 3 h before TLC analysis indicated full conversion. K2CO3 (4.8 g, 35 mmol, 2equiv) was added and the reaction mixture was heated for another 3 h before TLC analysis showed full conversion. The reaction mixture was quenched with saturated aqueous Na2S2O3 (50 ml) and extracted with EtOAc (3x50 ml). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0 -20% EtOAc in hexane). [0707] Procedure B. Methyl (Z)-2-bromopent-2-enoate 55 (1.1 g, 5.5 mmol, 1 equiv) and 4-chlorophenol 39 (718 mg, 5.5 mmol, 1 equiv) were dissolved in DMF (10 ml). Cs2CO3 (3.6 g, 11 mmol, 1 equiv) was added in one portion and the resulting mixture was heated to 80 oC for 2 h. The reaction mixture was diluted with sat. NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (1 x 50ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0 - 20% EtOAc in hexane). [0708] Procedure C. To a suspension of trimethylsulfoxonium iodide (730 mg, 3.3 mmol, 1.1 equiv) in DMSO (10 ml), NaH (132 mg, 60% oil dispersion, 3.3 mmol, 1.1 equiv) was added in portions over 5 minutes. The suspension was stirred for 1 h, and then a solution of methyl (Z)-2-(4-chlorophenoxy)pent-2-enoate 56 (528 mg, 2.2 mmol, 1 equiv) in DMSO (5 ml) was added dropwise over 10 minutes. The reaction mixture was allowed to reach room temperature and was stirred for 3 h. The reaction mixture was diluted with sat. NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (1 x 50 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0 - 20% EtOAc in hexane). [0709] Procedure D. (±)-Methyl (1S,2R)-1-(4-chlorophenoxy)-2-ethylcyclopropane-1- carboxylate 57 (127 mg, 0.5 mmol, 1equiv) was suspended in a mixture of THF – H2O (2:1, 4 ml) and LiOH (60 mg, 2.5 mmol, 5 equiv) was added. The reaction mixture was stirred rt overnight. Solvents were removed under reduced pressure. The residue was dissolved in 10 ml H2O and extracted with EtOAc (1 x 10ml). The aqua phase was separated, cooled at 0 oC and acidified with 2 N HCl until pH = 1. Extraction with EtOAc (3x 20ml), drying over MgSO4, filtration and evaporation under reduced pressure. The crude was used directly in the next step. [0710] Procedure E. At 0oC carboxylic acid 58 (100 mg, 0.5 mmol, 1 equiv) and HATU (228 mg, 0.6 mmol, 1.2 equiv) were dissolved in 3 ml dry DMF.4-(Boc- aminomethyl)piperidine 2 (128 mg, 0.6 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (267 μl, 1.5 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0711] Procedure F. The boc-protected intermediate 59 (105 mg, 0.24 mmol, 1 equiv) was dissolved in DCM (3ml) and cooled at 0 oC. TFA (370 μl, 4.8 mmol, 20 equiv) was added dropwise. Stirring at 0 oC for 30 min, then rt for 2 h. Solvents were removed under reduced pressure and the obtained TFA salt was used directly in the next step. [0712] Procedure G. The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0713] Methyl (Z)-2-bromopent-2-enoate (55) [0714] Obtained using procedure A scale, slight yellow oil, 3.2 g, 95% yield. 1H NMR (400 MHz, CDCl3) δ: 6.70 (t, J = 7.8 Hz, 1H), 3.84 (s, 3H), 2.54 (p, J = 7.6 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H).13C NMR (100 MHz, CDCl3) δ: 163.2, 150.7, 110.2, 53.0, 25.3, 12.6. LCMS (ESI): m/z calcd for C6H9BrO2; found [M+H] + 194.91. [0715] Methyl (Z)-2-(4-chlorophenoxy)pent-2-enoate (56) [0716] Obtained using procedure slight yellow oil, 1.1 g, 86% yield. 1H NMR (400 MHz, CDCl3) δ: 7.28 – 7.23 (m, 2H), 6.92 – 6.83 (m, 2H), 6.67 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 2.23 (p, J = 7.6 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ: 163.4, 156.0, 140.2, 134.3, 129.5, 127.1, 116.8, 52.2, 19.3, 12.8. LCMS (ESI): m/z calcd for C12H13ClO3; found [M+H]+ 241.05. [0717] (±)-Methyl (1S,2R)-1-(4-chlorophenoxy)-2-ethylcyclopropane-1-carboxylate (57) [0718] Obtained using procedure C cale, colorless, 250 mg, 30% yield.1H NMR (400 MHz, CDCl3) δ: 7.26 – 7.21 (m, 2H), 6.92 – 6.79 (m, 2H), 3.73 (s, 3H), 1.85 – 1.74 (m, 2H), 1.67 – 1.60 (m, 1H), 1.50 – 1.37 (m, 1H), 1.13 – 0.97 (m, 3H), 0.91 – 0.83 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 172.1, 156.2, 129.3, 126.4, 116.5, 61.3, 52.6, 31.9, 22.0, 21.1, 13.4. LCMS (ESI): m/z calcd for C13H15ClO3; found [M+H]+ 255.29. [0719] (±)-Tert-butyl ((1-((1S,2R)-1-(4-chlorophenoxy)-2-ethylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)carbamate (59) [0720] Obtained using oil, 127 mg, 60% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.26 – 7.14 (m, 2H), 7.08 – 6.93 (m, 2H), 4.75 – 4.32 (m, 3H), 3.23 – 2.77 (m, 3H), 2.59 (dt, J = 20.7, 10.3 Hz, 1H), 1.86 – 1.59 (m, 5H), 1.44 (s, 9H), 1.19 – 0.85 (m, 6H), 0.62 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 168.7, 166.9, 156.2, 129.5, 126.4, 116.8, 64.6, 45.7, 43.0, 36.8, 29.7, 28.4, 21.4, 20.7 (2C), 17.1, 14.2, 13.6, 13.2. [0721] (±)-2-chloro-N-((1-((1S,2R)-1-(4-chlorophenoxy)-2-ethylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)acetamide (60) 1075308 [0722] Obtained using on oil, 42 mg, 45% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.25 – 7.18 (m, 2H), 7.03 – 6.91 (m, 2H), 6.63 (s, 1H), 4.69 – 4.31 (m, 2H), 4.05 (s, 2H), 3.33 – 2.82 (m, 3H), 2.66 – 2.48 (m, 1H), 1.87 – 1.60 (m, 5H), 1.50 – 1.38 (m, 2H), 1.04 (dt, J = 26.0, 7.3 Hz, 5H), 0.61 (s, 1H).13C NMR (100 MHz, CDCl3) δ: 168.7, 166.0, 156.4, 129.4, 126.4, 116.6, 63.8, 44.9, 42.7, 36.3, 30.1, 20.6, 13.6. LCMS (ESI): m/z calcd for C20H26Cl2N2O3; found [M+Na] + 413.09. [0723] Scheme 6. Synthetic route for analog 68 (1075343) a chlorophenol (39), Cs2CO3, DMF, 80 oC, 2 h; (c) DIBAL-H, DCM, 0 oC, 2 h; (d) ZnEt2, CH2I2, DCM, 0 oC, 4 h; (e) DMP, DCM, rt, 1 h; (f) KMnO4, t-BuOH, acetone, rt, 2 h; (g) 4- (boc-aminomethyl)piperidine (2), HATU, DIPEA, DMF, 0 oC to rt, overnight; (h) TFA, DCM, 0 oC to rt, 2 h; (i) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0724] Procedure A. To a stirred a solution of 61 (2.2 g, 17.5 mmol, 1 equiv) in MeOH (20 ml), PyHBr3 (6.7 g, 21.5 mmol, 1.2 equiv) was added in one portion. The resulting red mixture was heated to 55 oC for 3 h before TLC analysis indicated full conversion. K2CO3 (4.8 g, 35 mmol, 2 equiv) was added and the reaction mixture was heated for another 3 h before TLC analysis showed full conversion. The reaction mixture was quenched with saturated aqueous Na2S2O3 (50 ml) and extracted with EtOAc (3x50 ml). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-20% EtOAc in hexane). [0725] Procedure B. Methyl (Z)-2-bromo-4-methylpent-2-enoate 62 (1.1 g, 5.5 mmol, 1 equiv) and 4-chlorophenol 39 (718 mg, 5.5 mmol, 1 equiv) were dissolved in DMF (10 ml). Cs2CO3 (3.6 g, 11 mmol, 1 equiv) was added in one portion and the resulting mixture was heated to 80 oC for 2 h. The reaction mixture was diluted with sat. NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (1 x 50 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-20% EtOAc in hexane). [0726] Procedure C. To a solution methyl (Z)-2-(4-chlorophenoxy)-4-methylpent-2-enoate 63 (1 g, 4 mmol, 1 equiv) in DCM (10 ml) cooled at 0 oC, DIBAL-H (1M in DCM, 4.8 ml) was added dropwise over 10 minutes. The mixture was stirred for 2 h, before TLC analysis indicated full conversion. The reaction was carefully quenched with 1 N HCl. The aqueous phase was extracted with DCM (3 ×10 ml) and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0 - 20% EtOAc in hexane). [0727] Procedure D. To a solution of Et2Zn (11 ml, 11 mmol, 1.0 M in hexane, 5 equiv) in dry DCM (10 ml) was added dropwise CH2I2 (887 ul, 11 mmol, 5 equiv) at 0 °C. After the reaction mixture became a white suspension, a solution of (Z)-2-(4-chlorophenoxy)-4- methylpent-2-en-1-ol 64 (500 mg, 2.2 mmol, 1 equiv) in DCM (5 ml) was added. The reaction was stirred for 4 h at 0 °C and quenched with sat. aq. NH4Cl (20 ml). The aqueous phase was extracted with DCM (3 ×10 ml) and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-20% EtOAc in hexane). [0728] Procedures E and F. To a solution of (±)-((1S,2S)-1-(4-chlorophenoxy)-2- isopropylcyclopropyl)methanol (65) (140 mg, 0.58 mmol, 1 equiv) in DCM (5 mL) was added Dess-Martin periodinane (295 mg, 0.7 mmol, 1.2 equiv) in small portions at room temperature. The resulting mixture was stirred for 1h and then it was quenched with sat. aq. Na2S2O3 (10 ml) and sat. aq. NaHCO3 (10 ml) and extracted with DCM (3 x 10ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was directly dissolved in t-BuOH (2 ml) and acetone (2 ml). KMnO4 (275 mg, 1.7 mmol, 3 equiv) was added in one portion and resulting the red mixture was stirred at room temperature for 2 h before TLC analysis indicated full conversion. The reaction was diluted with H2O (10 ml) and extracted with CH2Cl2 (3 x 10 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, DCM - MeOH, 0-20% MeOH in DCM). [0729] Procedure G. At 0 oC carboxylic acid 66 (63 mg, 0.25 mmol, 1 equiv) and HATU (114 mg, 0.3 mmol, 1.2 equiv) were dissolved in 2 ml dry DMF.4-(Boc- aminomethyl)piperidine 2 (64 mg, 0.3 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (134 μl, 0.75 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0730] Procedure H. The boc-protected intermediate 67 (80 mg, 0.18 mmol, 1 equiv) was dissolved in DCM (3ml) and cooled at 0oC. TFA (278 μl, 3.6 mmol, 20 equiv) was added dropwise. Stirring at 0 oC for 30 min, then rt for 2 h. Solvents were removed under reduced pressure and the obtained TFA salt was used directly in the next step. [0731] Procedure I. The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0732] Methyl (Z)-2-bromo-4-methylpent-2-enoate (62) [0733] Obtained using procedure on slight yellow oil, 3.2 g, 95% yield. 1H NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 9.3 Hz, 1H), 3.84 (s, 3H), 2.88 (ddt, J = 13.4, 9.3, 6.7 Hz, 1H), 1.12 – 1.09 (m, 6H).13C NMR (100 MHz, CDCl3) δ: 163.2, 152.4, 113.6, 53.1, 34.2, 20.9. LCMS (ESI): m/z calcd for C7H11BrO2; found [M+H]+ 207.01. [0734] Methyl (Z)-2-(4-chlorophenoxy)-4-methylpent-2-enoate (63) [0735] Obtained using procedure B cale, slight yellow oil, 1.1 g, 85% yield. 1H NMR (400 MHz, CDCl3) δ: 7.27 – 7.22 (m, 2H), 6.88 – 6.84 (m, 2H), 6.50 (d, J = 10.0 Hz, 1H), 3.73 (s, 3H), 2.85 – 2.67 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H).13C NMR (100 MHz, CDCl3) δ: 163.5, 156.2, 139.2, 129.5, 127.1, 116.9, 116.2, 52.2, 35.1, 21.9. LCMS (ESI): m/z calcd for C13H15ClO3; found [M+H]+ 255.09. [0736] (Z)-2-(4-chlorophenoxy)-4-methylpent-2-en-1-ol (64) [0737] Obtained using procedure colorless oil, 587 mg, 65% yield.1H NMR (400 MHz, CDCl3) δ: 7.28 – 7.23 (m, 2H), 6.98 – 6.89 (m, 2H), 5.22 (d, J = 9.7 Hz, 1H), 4.11 (t, J = 4.1 Hz, 2H), 2.74 – 2.50 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H).13C NMR (100 MHz, CDCl3) δ: 155.5, 147.2, 129.5, 125.2, 117.1, 116.7, 61.2, 24.8, 22.6. LCMS (ESI): m/z calcd for C12H15ClO2; found [M - OH]+ 209.11. [0738] (±)-((1S,2S)-1-(4-chlorophenoxy)-2-isopropylcyclopropyl)methanol (65) [0739] Obtained using procedure colorless oil, 158 mg, 30% yield. 1H NMR (400 MHz, CDCl3) δ: 7.26 – 7.21 (m, 2H), 7.01 – 6.94 (m, 2H), 4.18 (d, J = 12.3 Hz, 1H), 3.36 (d, J = 12.3 Hz, 1H), 1.92 (s, 1H), 1.53 – 1.34 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.11 – 1.02 (m, 4H), 0.85 (td, J = 9.6, 7.0 Hz, 1H), 0.67 (t, J = 6.5 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 156.0, 129.3, 126.0, 117.7, 66.1, 64.7, 31.0, 27.9, 22.7, 22.3, 16.6. LCMS (ESI): m/z calcd for C13H17ClO2; found [M + Na]+ 264.14. [0740] (±)-(1S,2S)-1-(4-chlorophenoxy)-2-isopropylcyclopropane-1-carboxylic acid (66) [0741] Obtained using procedure F cale, yellow oil, 66 mg, 45% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.25 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 1.84 (dd, J = 9.5, 5.4 Hz, 1H), 1.69 – 1.49 (m, 2H), 1.15 (d, J = 6.3 Hz, 3H), 1.09 (t, J = 6.3 Hz, 3H), 0.93 (dd, J = 7.7, 5.4 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 178.4, 156.2, 129.3, 126.7, 116.9, 60.8, 38.4, 31.1, 28.3, 22.3, 22.0. [0742] (±)-tert-butyl ((1-((1S,2S)-1-(4-chlorophenoxy)-2-isopropylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)carbamate (67) [0743] Obtained using oil, 84 mg, 75% yield. 1H NMR (400 MHz, CDCl3) δ: 7.24 – 7.16 (m, 2H), 7.00 – 6.90 (m, 2H), 4.62 (s, 2H), 4.42 (s, 1H), 3.11 – 2.44 (m, 4H), 1.94 – 1.79 (m, 2H), 1.75 – 1.57 (m, 4H), 1.43 (s, 9H), 1.19 – 1.09 (m, 4H), 1.03 (dd, J = 18.9, 6.2 Hz, 3H), 0.95 – 0.76 (m, 1H), 0.58 – 0.48 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.2, 168.8, 156.2, 129.4, 126.5, 116.7, 79.3, 64.6, 60.4, 45.6, 36.8, 28.9, 27.4, 22.7, 22.7, 21.1, 16.9, 14.2. [0744] (±)-2-chloro-N-((1-((1S,2S)-1-(4-chlorophenoxy)-2-isopropylcyclopropane-1- carbonyl)piperidin-4-yl)methyl) acetamide (68) 1075343 [0745] Obtained using on oil, 38 mg, 50% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.23 (d, J = 8.9 Hz, 2H), 7.01 – 6.90 (m, 2H), 6.62 (s, 1H), 4.73 – 4.34 (m, 2H), 4.04 (d, J = 3.5 Hz, 2H), 3.38 – 2.79 (m, 3H), 2.60 (d, J = 24.1 Hz, 1H), 2.13 – 1.53 (m, 6H), 1.45 (d, J = 6.2 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 25.6 Hz, 1H), 0.54 (s, 1H).13C NMR (100 MHz, CDCl3) δ: 168.7, 166.0, 156.4, 129.4, 126.5, 116.6, 63.8, 44.9, 43.1, 42.7, 36.3, 30.1, 27.4, 20.6, 17.0. LCMS (ESI): m/z calcd for C21H28Cl2N2O3; found [M + H]+ 427.09. [0746] Scheme 7. Synthetic route for analog 74 (1075314) a DMF, 80 oC, 2 h; (c) LDA, MeI, THF, -78oC to rt, 2 h; (d) LiOH, MeOH/H2O, reflux, 4 h; (e) 4-(boc-aminomethyl)piperidine (2), HATU, DIPEA, DMF, 0 oC to rt, overnight; (f) TFA, DCM, 0 oC to rt, 2 h; (g) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 2 h. [0747] Procedures A and B. To a stirred a solution of 69 (500 mg, 3.2 mmol, 1 equiv) in MeOH (5 ml), PyHBr3 (1.1 g, 3.5 mmol, 1.2 equiv) was added in one portion. The resulting red mixture was heated to 55 oC for 3 h before TLC analysis indicated full conversion. The reaction mixture was allowed to reach room temperature and solvents were removed under reduced pressure. The residue was dissolved in DMF (5 ml).4-Chlorophenol 39 (448 mg, 3.5 mmol, 1.1 equiv) and Cs2CO3 (1.6 g, 4.8 mmol, 1.5 equiv) were added in one portion. The resulting mixture was heated to 80 oC for 2 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 (30 ml) and extracted with EtOAc (3x30 ml). The combined organic phases were washed with 1 N HCl, brine, dried over over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-10% EtOAc in hexane). [0748] Procedure C. To a stirred a solution of (±)-methyl 2-(4-chlorophenoxy)-2- cyclohexylacetate (71) (300 mg, 1.1 mmol, 1 equiv) in THF (3 ml) at -78 oC, LDA (1M in THF, 1.3 ml) was added dropwise. The reaction mixture was stirred for 1h and then MeI (80 μl, 1.3 mmol, 1.18 equiv) was added. The reaction was allowed to reach rt and stirred for 2h. The reaction was quenched with sat. NH4Cl (10 ml) and extracted with EtOAc (3x10ml). The combined organic phases were washed with brine, dried over over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-10% EtOAc in hexane). [0749] Procedure D. (±)-Methyl 2-(4-chlorophenoxy)-2-cyclohexylpropanoate 72 (150 mg, 0.5 mmol, 1 equiv) was dissolved in a mixture of MeOH – H2O (1:1, 4 ml) and LiOH (60 mg, 2.5 mmol, 5 equiv) was added. The reaction mixture was heated to reflux for 4 h. Solvents were removed under reduced pressure. The residue was dissolved in 10 ml H2O and extracted with EtOAc (1 x 10ml). The aqua phase was separated, cooled at 0 oC and acidified with 2 N HCl until pH = 1. Extraction with EtOAc (3x 20 ml), drying over MgSO4, filtration and evaporation under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0750] Procedure E. At 0oC carboxylic acid 73 (80 mg, 0.3 mmol, 1 equiv) and HATU (137 mg, 0.36 mmol, 1.2 equiv) were dissolved in 2 ml dry DMF.4-(Boc- aminomethyl)piperidine 2 (77 mg, 0.36 mmol, 1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (156 μl, 0.9 mmol, 3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt overnight. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0751] Procedure F. The boc-protected intermediate 74 (75 mg, 0.15 mmol, 1 equiv) was dissolved in DCM (2 ml) and cooled at 0 oC. TFA (230 μl, 3.0 mmol, 20 equiv) was added dropwise. Stirring at 0 oC for 30 min, then rt for 2 h. Solvents were removed under reduced pressure and the obtained TFA salt was used directly in the next step. [0752] Procedure G. The TFA salt (1 equiv) was suspended in 2 ml dry DCM. At 0 oC, DIPEA (4 equiv) was added. After 10 min, chloroacetyl chloride 25 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0753] (±)-Methyl 2-(4-chlorophenoxy)-2-cyclohexylacetate (71) [0754] Obtained using procedure ale, colorless oil, 406 mg, 45% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.26 – 7.20 (m, 2H), 6.86 – 6.78 (m, 2H), 4.36 (d, J = 5.8 Hz, 1H), 3.76 (s, 3H), 2.10 – 1.78 (m, 4H), 1.75 – 1.65 (m, 2H), 1.40 – 1.05 (m, 5H).13C NMR (100 MHz, CDCl3) δ: 171.5, 156.9, 129.5, 126.4, 116.4, 81.6, 52.1, 41.0, 28.9, 28.2, 26.1, 25.9, 25.9. LCMS (ESI): m/z calcd for C15H19ClO3; found [M+Na]+ 306.39. [0755] (±)-Methyl 2-(4-chlorophenoxy)-2-cyclohexylpropanoate (72) [0756] Obtained using colorless oil, 220 mg, 70% yield.1H NMR (400 MHz, CDCl3) δ: 7.24 – 7.15 (m, 2H), 6.87 – 6.75 (m, 2H), 3.78 (s, 3H), 2.09 – 1.78 (m, 4H), 1.76 – 1.55 (m, 2H), 1.39 (s, 3H), 1.33 – 0.99 (m, 5H).13C NMR (100 MHz, CDCl3) δ: 174.3, 154.2, 129.1, 127.2, 120.8, 85.0, 52.2, 46.2, 27.2, 26.9, 26.4, 26.4, 17.1. LCMS (ESI): m/z calcd for C16H21ClO3; found [M+K]+ 334.09. [0757] (±)-Methyl 2-(4-Chlorophenoxy)-2-cyclohexylpropanoic acid (73) [0758] Obtained using procedure colorless oil, 112 mg, 80% yield. 1H NMR (400 MHz, CDCl3) δ: 7.26 – 7.17 (m, 2H), 6.96 – 6.84 (m, 2H), 2.09 – 1.64 (m, 6H), 1.40 (s, 3H), 1.36 – 1.07 (m, 5H).13C NMR (100 MHz, CDCl3) δ: 179.2, 153.8, 129.2, 128.0, 121.8, 85.1, 46.8, 27.0, 26.4, 26.3, 26.3, 17.5. [0759] (±)-tert-butyl ((1-(2-(4-chlorophenoxy)-2-cyclohexylpropanoyl)piperidin-4- yl)methyl)carbamate (74) [0760] Obtained using pro ow oil, 81 mg, 60% yield.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 8.7 Hz, 2H), 6.80 – 6.73 (m, 2H), 4.78 – 4.72 (m, 2H), 4.58 – 4.49 (m, 1H), 3.01 – 2.79 (m, 3H), 2.60 – 2.48 (m, 1H), 2.13 – 2.11 (m, 1H), 1.90 – 1.82 (m, 3H), 1.78 – 1.62 (m, 4H), 1.53 – 1.50 (m, 1H), 1.43 (s, 9H), 1.40 – 1.38 (m, 3H), 1.30 – 1.04 (m, 7H).13C NMR (100 MHz, CDCl3) δ: 176.9, 170.9, 153.7, 129.9, 128.0, 121.6, 86.3, 47.3, 46.0, 45.1, 43.3, 29.9, 28.4, 28.1, 27.1, 26.4, 26.3, 17.1. [0761] (±)-2-Chloro-N-((1-(2-(4-chlorophenoxy)-2-cyclohexylpropanoyl)piperidin-4- yl)methyl)acetamide (75) 1075314 [0762] Obtained using oil, 37 mg, 55% yield (over 2 steps).1H NMR (400 MHz, CDCl3) δ: 7.18 – 7.14 (m, 2H), 6.80 – 6.72 (m, 2H), 6.64 – 6.56 (m, 1H), 4.76 – 4.71 (m, 2H), 4.03 (b, 2H), 3.24 – 3.20 (m, 1H), 3.05 – 2.77 (m, 2H), 2.62 – 2.48 (m, 1H), 2.13 – 2.10 (m, 1H), 1.95 – 1.64 (m, 7H), 1.53 – 1.43 (m, 1H), 1.41 – 1.38 (m, 3H), 1.30 – 1.00 (m, 7H).13C NMR (100 MHz, CDCl3) δ: 170.9, 166.0, 153.9, 129.3, 126.3, 118.8, 87.0, 46.0, 45.5, 44.9, 44.7, 43.1, 42.6, 36.3, 36.0, 30.7, 29.9, 29.4, 28.0, 26.4, 17.0. LCMS (ESI): m/z calcd for C23H32Cl2N2O3; found [M+H]+ 455.10. [0763] Scheme 8. Procedures for the synthesis of carboxylic acids 76 – 104.a
a Reagents and cond t ons: (a) 2CO3, Cu (5 mo %), G- 00, - sobutyry cyclohexanone (ligand, 20 mol%), water, 130 oC, 7 h; (b) NaOH, CHCl3, THF, 0 oC to rt overnight. [0764] Procedure A. Carboxylic acids 76 – 84 were synthesized by modifying previously published procedures (16,17). with the exception of 80 and 82, which are commercially available. The corresponding amino acid (1.2 equiv), aryl bromide (1.0 equiv), potassium carbonate (2.5 equiv), 2-isobutyrylcyclohexan-1-one (20 mol%) and PEG-400 (1.5 equiv) were taken in water. After bubbling argon gas for 10 min, copper (I) iodide (5 mol%) was added to the mixture and heated to 130 oC for 7 h. The reaction mixture was diluted with water (10 ml), adjusted to pH 4 with glacial acetic acid and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-50% EtOAc in hexane). [0765] Procedure B. Carboxylic acids 85 – 104 were synthesized using the Bargellini reaction (18). Under argon: The appropriate phenol or aniline (3 mmol, 1 equiv) were dissolved in dry THF (40 ml) and cooled at 0oC. NaOH powder (581 mg, 15 mmol, 5equiv) and the appropriate ketone (9 mmol, 3equiv) were added as solids. Dry chloroform (1.16 ml, 15 mmol, 5 equiv) was added dropwise over 30 min at 0 oC. The reaction mixture was stirred at 0 oC for 1 h and then rt overnight. In the cases that solid formation was observed, the solid was filtered off and dissolved in water (50 ml). If solid formation was not observed, the reaction mixture was diluted with water (50 ml). In both cases, the aqua phase was extracted with EtOAc (3 x 50 ml). The combined organic phases were separated, and the aqua phase was cooled at 0 oC and acidified with 1 N acetic acid, until pH=3. The acidified aqua phase was extracted with EtOAc (3 x 50 ml). The combined organic phases were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Product formation was confirmed with LCMS. The obtained products were used directly in the next step. [0766] Scheme 9. General procedure for 1C-linker chloroacetamide derivatives 108 – 143 a , oC to rt, 4 h; (b) 4N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h; (d) 4 N HCl/dioxane, rt, 3 h. [0767] Procedure A.1-N-Boc-4-(aminomethyl)piperidine 105 (1.0 equiv, 3 mmol, 642 mg) was dissolved in 15 ml dry DCM. DIPEA (3 equiv, 9 mmol, 1.56 ml) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv, 4.2 mmol, 331 μl) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (15 ml) and extracted with DCM (3 x 20 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0768] Procedure B. The boc-protected intermediate was dissolved in 5 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained HCl salt was used directly in the next step. [0769] Procedure C. The appropriate carboxylic acid (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0770] Procedure D. The purified Boc-intermediate was suspended in 3 ml HCl/dioxane (4 N) Stirring rt for 3 h. The solvent was removed under reduced pressure and the deprotected product was dried under vacuum. [0771] tert-butyl 4-((2-chloroacetamido)methyl)piperidine-1-carboxylate (106) [0772] Obtained using on yellow oil, 520 mg, 60% yield. 1H NMR (400 MHz, CDCl3) δ: 6.67 (b, 1H), 4.13 – 4.11 (m, 2H), 4.06 (s, 2H), 3.21 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 12.4 Hz, 2H), 1.72 – 1.69 (m, 3H), 1.45 (s, 9H), 1.14 (qd, J = 12.9, 4.7 Hz, 2H).13C NMR (100 MHz, CDCl3) δ: 166.0, 154.8, 79.5, 45.1, 42.7, 36.2, 29.6, 28.4. LCMS (ESI): m/z calcd for C13H23ClN2O3; found 313.13 [M+Na]+. [0773] 2-chloro-N-((1-((4-chlorophenyl)-L-leucyl)piperidin-4-yl)methyl)acetamide (108) 1075321 [0774] Obtained using pr less oil, 42.8 mg, 34% yield. 1H NMR (400 MHz, CDCl3) δ 7.10 – 7.06 (m, 2H), 6.72 (b, 1H), 6.54 – 6.50 (m, 2H), 4.59 (d, J = 13.0 Hz, 1H), 4.29 (dd, J = 9.0, 4.4 Hz, 1H), 4.05 (s, 2H), 3.95 (d, J = 13.3 Hz, 1H), 3.28 – 3.05 (m, 4H), 2.60 – 2.53 (m, 1H), 1.87 – 1.69 (m, 4H), 1.57 – 1.49 (m, 2H), 1.16 – 1.05 (m, 2H), 0.96 (s, 3H), 0.95 (s, 3H).13C NMR (100 MHz, CDCl3) δ 171.8, 166.1, 146.3, 129.1, 122.7, 115.0, 52.3, 45.1, 44.8, 42.6, 42.1, 41.9, 36.2, 30.9, 30.5, 29.4, 24.6, 23.3, 21.9. LCMS (ESI): m/z calcd for C20H29Cl2N3O2; found 414.19. [0775] 2-chloro-N-((1-((4-chlorophenyl)-D-leucyl)piperidin-4-yl)methyl)acetamide (109) 1075322 [0776] Obtained using oil, 20.3 mg, 20% yield. 1H NMR (400 MHz, CDCl3) δ: 7.10 – 7.07 (m, 2H), 6.71 (b, 1H), 6.54 – 6.50 (m, 2H), 4.59 (d, J = 13.0 Hz, 1H), 4.29 (dd, J = 8.9, 4.2 Hz, 1H), 4.06 (s, 2H), 3.96 (d, J = 12.4 Hz, 1H), 3.30 – 3.05 (m, 4H), 2.60 – 2.54 (m, 1H), 1.84 – 1.70 (m, 4H), 1.58 – 1.54 (m, 1H), 1.48 – 1.42 (m, 1H), 1.20 – 1.11 (m, 2H), 0.95 (b, 6H).13C NMR (100 MHz, CDCl3) δ: 171.9, 166.1, 146.3, 129.1, 122.7, 115.0, 52.4, 45.1, 44.8, 42.6, 42.2, 41.9, 36.2, 30.5, 29.5, 29.4, 24.7, 23.3, 22.0. LCMS (ESI): m/z calcd for C20H29Cl2N3O2; found 414.24. [0777] (R)-2-chloro-N-((1-(2-((4-chlorophenyl)amino)-2-cyclohexylacetyl)piperidin-4- yl)methyl)acetamide (110) 1075319 [0778] Obtained using on oil, 20 mg, 22% yield.1H NMR (400 MHz, CDCl3) δ: 7.10 – 7.07 (m, 2H), 6.67 (b, 1H), 6.54 – 6.50 (m, 2H), 4.63 (t, J = 12.4 Hz, 1H), 4.06 (d, J = 7.7 Hz, 3H), 3.98 (d, J = 12.8 Hz, 1H), 3.30 – 3.02 (m, 3H), 2.60 – 2.55 (m, 1H), 1.82 – 1.64 (m, 10H), 1.25 – 1.05 (m, 7H).13C NMR (100 MHz, CDCl3) δ: 171.1, 166.1, 147.0, 129.0, 122.4, 115.1, 114.9, 58.7, 45.8, 45.2, 44.9, 42.7, 42.0, 36.2, 30.3, 29.5, 28.5, 26.2, 26.1. LCMS (ESI): m/z calcd for C22H31Cl2N3O2; found 440.19. [0779] (S)-2-chloro-N-((1-(2-((4-chlorophenyl)amino)-2-cyclohexylacetyl)piperidin-4- yl)methyl)acetamide (111) 1075320 [0780] Obtained using oil, 19.1 mg, 21% yield.1H NMR (400 MHz, CDCl3) δ: 7.10 – 7.07 (m, 2H), 6.69 (b, 1H), 6.54 – 6.50 (m, 2H), 4.62 (t, J = 12.6 Hz, 1H), 4.05 (d, J = 8.0 Hz, 3H), 3.97 (d, J = 12.8 Hz, 1H), 3.29 – 3.02 (m, 3H), 2.61 – 2.53 (m, 1H), 1.81 – 1.63 (m, 10H), 1.28 – 0.98 (m, 7H).13C NMR (100 MHz, CDCl3) δ: 171.1, 166.1, 146.9, 129.0, 122.4, 115.1, 114.9, 58.7, 45.7, 44.8, 42.0, 36.2, 30.3, 29.4, 28.5, 26.2, 26.1. LCMS (ESI): m/z calcd for C22H31Cl2N3O2; found 440.19. [0781] 2-chloro-N-((1-(2-((4-chlorophenyl)amino)-2-phenylacetyl)piperidin-4- yl)methyl)acetamide (112) 1080270 [0782] Obtained using oil, 29.6 mg, yield 28%. HPLC retention time 12.0 min.1H NMR (400 MHz, CDCl3, racemic mixture) δ: 7.40 – 7.28 (m, 5H), 7.05 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 8.6 Hz, 2H), 5.23 – 5.20 (m, 1H), 4.67 – 4.58 (m, 1H), 4.05 – 4.00 (m, 4H), 3.24 – 3.20 (m, 1H), 3.02 – 2.97 (m, 2H), 2.63 – 2.56 (m, 1H), 1.72 – 1.61 (m, 2H), 1.54 – 1.20 (m, 2H), 0.93 – 0.90 (m, 1H), 0.22 – 0.19 (m, 1H).13C NMR (100 MHz, CDCl3, racemic mixture) δ: 168.5, 166.0, 144.7, 137.7, 129.1, 129.0, 128.2, 127.6, 122.4, 114.8, 58.3, 45.1, 44.7, 42.6, 36.0, 30.1, 29.3, 29.0, 28.9. LCMS (ESI): m/z calcd for C22H25Cl2N3O2; found [M+H]+ 434.21. [0783] 2-chloro-N-((1-(2-methyl-2-(phenylamino)propanoyl)piperidin-4- yl)methyl)acetamide (113) 1080268 [0784] Obtained using oil, 21.8 mg, 42% yield. HPLC retention time 7.0 min.1H NMR (400 MHz, CDCl3) δ: 7.18 – 7.14 (m, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 7.8 Hz, 3H), 5.00 – 4.80 (m, 2H), 4.03 (s, 2H), 3.09 (t, J = 6.4 Hz, 2H), 2.98 – 2.90 (m, 1H), 1.76 – 1.67 (m, 3H), 1.57 (s, 6H), 1.56 – 1.41 (m, 2H) 1.03 – 0.90 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.6, 165.9, 141.6, 133.4, 129.2, 118.2, 114.4, 58.4, 44.9, 42.6, 36.2, 29.7, 27.1. LCMS (ESI): m/z calcd for C18H26ClN3O2; found [M+H]+ 352.13. [0785] 2-chloro-N-((1-(2-((4-chlorophenyl)amino)-2-methylpropanoyl)piperidin-4- yl)methyl)acetamide (114) 1080291 [0786] Obtained using solid, 14.3 mg, 20% yield. HPLC retention time 11.0 min.1H NMR (400 MHz, CDCl3) δ: 7.08 – 7.06 (m, 2H), 6.64 (t, J = 7.3 Hz, 1H), 6.47 – 6.44 (m, 2H), 4.90 – 4.76 (m, 2H), 4.01 (s, 2H), 3.10 – 3.03 (m, 5H), 1.72 – 1.66 (m, 3H), 1.52 (s, 6H), 1.02 – 0.88 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.4, 166.2, 143.8, 129.0, 122.7, 115.4, 58.5, 44.8, 42.6, 36.1, 29.8, 27.0. LCMS (ESI): m/z calcd for C18H25Cl2N3O2; found [M+H]+ 386.19. [0787] 2-chloro-N-((1-(1-((4-chlorophenyl)amino)cyclopropane-1-carbonyl)piperidin-4- yl)methyl)acetamide (115) 1076406 [0788] Obtained using procedure C on 0.17 mmol scale, white solid, 16.5 mg, 25% yield. HPLC retention time 10.5 min.1H NMR (400 MHz, CDCl3) δ: 7.12 – 7.08 (m, 2H), 6.72 – 6.68 (m, 2H), 6.64 (b, 1H), 4.40 (d, J = 13.2 Hz, 2H), 4.12 (b, 1H), 4.03 (s, 2H), 3.16 (t, J = 6.0 Hz, 2H), 2.85 – 2.80 (m, 2H), 1.73 – 1.69 (m, 3H), 1.41 (q, J = 4.7 Hz, 2H), 1.11 – 1.05 (m, 2H), 0.90 (q, J = 4.6 Hz, 2H).13C NMR (100 MHz, CDCl3) δ: 169.7, 166.1, 145.2, 129.0, 122.9, 114.4, 44.9, 42.6, 37.9, 36.3, 29.7, 15.1. LCMS (ESI): m/z calcd for C18H23Cl2N3O2; found [M+H]+ 384.23, [M+Na]+ 406.25. [0789] 2-chloro-N-((1-(1-(phenylamino)cyclobutane-1-carbonyl)piperidin-4- yl)methyl)acetamide (116) 1080269 [0790] Obtained using oil, 24.6 mg, 46.0% yield. HPLC retention time 8.5 min. 1H NMR (400 MHz, CDCl3) δ: 7.15 – 7.11 (m, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.58 – 6.55 (m, 3H), 4.62 – 4.59 (m, 1H), 4.20 – 4.18 (m, 1H), 3.99 (s, 2H), 3.10 – 3.00 (m, 2H), 2.90 – 2.83 (m, 2H), 2.58 – 2.54 (m, 1H), 2.17 (s, 1H), 2.08 – 1.87 (m, 4H), 1.74 – 1.60 (m, 4H), 1.00 – 0.96 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 172.0, 166.0, 145.4, 129.2, 118.1, 113.8, 61.1, 44.9, 42.6, 36.2, 32.9, 32.1, 29.7, 14.7. LCMS (ESI): m/z calcd for C19H26ClN3O2; found [M+H]+ 364.24, [M+Na]+ 386.19. [0791] 2-Chloro-N-((1-(1-phenoxycyclopentane-1-carbonyl)piperidin-4- yl)methyl)acetamide (117) 1075300 [0792] Obtained using on oil, 23.0 mg, 30.0% yield.1H NMR (400 MHz, CDCl3) δ: 7.25 – 7.17 (m, 2H), 6.94 – 6.88 (m, 1H), 6.81 – 6.79 (m, 2H), 6.56 (b, 1H), 4.61 (dd, J = 13.1, 2.6 Hz, 2H), 3.98 (s, 2H), 3.05 – 3.00 (m, 2H), 2.87 – 2.80 (m, 1H), 2.53 – 2.46 (m, 2H), 2.35 – 2.31 (m, 1H), 2.16 – 2.08 (m, 2H), 1.75 – 1.62 (m, 6H), 1.51 (d, J = 13.2 Hz, 1H), 0.94 (qd, J = 12.6, 3.8 Hz, 1H), 0.70 (qd, J = 12.6, 3.9 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 171.4, 165.9, 155.6, 129.2, 120.9, 116.3, 90.1, 45.4, 44.8, 42.9, 42.5, 37.4, 36.8, 36.1, 29.9, 29.4, 24.7. LCMS (ESI): m/z calcd for C20H27ClN2O3; found [M+H]+ 379.19. [0793] 2-Chloro-N-((1-(1-(4-chlorophenoxy)cyclopentane-1-carbonyl)piperidin-4- yl)methyl)acetamide (118) 1075297 [0794] Obtained using oil, 25.0 mg, 30.0% yield.1H NMR (400 MHz, CDCl3) δ: 7.18 – 7.14 (m, 2H), 6.77 – 6.73 (m, 2H), 6.57 (b, 1H), 4.58 (t, J = 12.6 Hz, 2H), 4.01 (s, 2H), 3.17 – 3.00 (m, 2H), 2.89 – 2.82 (m, 1H), 2.55 – 2.45 (m, 2H), 2.38 – 2.32 (m, 1H), 2.13 – 2.03 (m, 2H), 1.80 – 1.69 (m, 6H), 1.68 – 1.66 (m, 1H), 0.97 (qd, J = 12.6, 3.8 Hz, 1H), 0.77 (qd, J = 12.6, 3.9 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 171.0, 166.0, 154.3, 129.2, 125.9, 117.6, 90.6, 45.4, 44.8, 43.0, 42.6, 37.3, 36.8, 36.2, 30.1, 29.5, 24.7. LCMS (ESI): m/z calcd for C20H26Cl2N2O3; found [M+H]+ 413.09. [0795] 2-chloro-N-((1-(1-(phenylamino)cyclopentane-1-carbonyl)piperidin-4- yl)methyl)acetamide (119) 1080271 [0796] Obtained using oil, 18.0 mg, 32% yield. HPLC retention time 13.5 min.1H NMR (400 MHz, CDCl3) δ: 7.12 (t, J = 7.3 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.8 Hz, 3H), 4.72 – 4.70 (m, 2H), 4.00 (s, 2H), 3.07 – 3.05 (m, 2H), 2.94 – 2.93 – 2.38 (m, 4H), 1.90 – 1.87 (m, 2H), 1.76 – 1.62 (m, 7H), 0.96 – 0.93 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.9, 166.0, 145.6, 129.0, 117.6, 113.8, 68.3, 44.8, 42.5, 36.1, 29.7, 24.1. LCMS (ESI): m/z calcd for C20H28ClN3O2; found [M+H]+ 378.24. [0797] 2-Chloro-N-((1-(1-((4-chlorophenyl)amino)cyclopentane-1-carbonyl)piperidin-4- yl)methyl)acetamide (120) 1075306 [0798] Obtained using p rless oil, 30.0 mg, 35% yield.1H NMR (400 MHz, CDCl3) δ: 7.05 (d, J = 8.8 Hz, 2H), 6.60 (b, 1H), 6.47 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 12.8 Hz, 2H), 3.99 (s, 2H), 3.86 – 3.85 (m, 1H), 3.09 – 3.07 (m, 2H), 2.91 – 2.90 (m, 1H), 2.51 – 2.36 (m, 3H), 1.85 – 1.58 (m, 9H), 0.94 – 0.92 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 172.5, 166.0, 144.3, 129.0, 122.3, 115.0, 68.4, 44.8, 42.6, 36.2, 29.8, 24.1. LCMS (ESI): m/z calcd for C20H27Cl2N3O2; found [M+H]+ 412.14. [0799] 2-chloro-N-((1-(1-(phenylamino)cyclohexane-1-carbonyl)piperidin-4- yl)methyl)acetamide (121) 1080272 O Cl [0800] Obtained using oil, 12.7 mg, 22% yield. HPLC retention time 11.5 min.1H NMR (400 MHz, CDCl3) δ: 7.12 (t, J = 7.7 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 3H), 5.00 – 4.89 (m, 2H), 4.00 (s, 2H), 3.92 – 3.90 (m, 1H), 3.05 (t, J = 6.0 Hz, 2H), 2.08 – 2.04 (m, 2H), 1.98 – 1.94 (m,2H), 1.70 – 1.62 (m, 6H), 1.44 – 1.25 (m, 5H), 1.05 – 0.79 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 173.3, 165.9, 144.9, 129.1, 117.8, 114.3, 60.0, 44.9, 42.6, 36.2, 32.8, 29.8, 25.1, 21.3. LCMS (ESI): m/z calcd for C21H30ClN3O2; found [M+H]+ 392.29. [0801] 2-chloro-N-((1-(1-(4-chlorophenoxy)cyclohexane-1-carbonyl)piperidin-4- yl)methyl)acetamide (122) 1080273 O Cl [0802] Obtained using on oil, 15.1 mg, 24% yield. HPLC retention time 13.5 min.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.58 (t, J = 5.0 Hz, 1H), 4.72 – 4.69 (m, 2H), 4.02 (s, 2H), 3.10 (td, J = 6.2, 3.1 Hz, 2H), 2.85 (t, J = 12.5 Hz, 1H), 2.53 (t, J = 12.3 Hz, 1H), 2.21 – 2.17 (m, 2H), 1.92 – 1.82 (m, 2H), 1.73 – 1.63 (m, 4H), 1.60 – 1.54 (m, 4H), 1.31 – 1.26 (m, 1H), 1.08 – 1.00 (m, 1H), 0.80 – 0.71 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.8, 166.0, 153.6, 129.2, 126.1, 118.3, 81.9, 45.2, 44.8, 43.0, 42.6, 36.2, 32.5, 32.1, 30.1, 29.5, 25.1, 21.0. LCMS (ESI): m/z calcd for C21H28Cl2N2O3; found [M+H] + 427.20, [M+Na]+ 449.09. [0803] 2-chloro-N-((1-(1-((4-chlorophenyl)amino)cyclohexane-1-carbonyl)piperidin-4- yl)methyl)acetamide (123) 1076403 [0804] Obtained using solid, 43.7 mg, 52% yield, HPLC retention time 12.5 min.1H NMR (400 MHz, CDCl3) δ: 7.06 (d, J = 8.8 Hz, 2H), 6.59 (b, 1H), 6.47 (d, J = 8.8 Hz, 2H), 4.91 – 4.79 (m, 2H), 4.01 (s, 2H), 3.95 (b, 1H), 3.08 (t, J = 5.9 Hz, 2H), 2.87 – 2.86 (m, 1H), 2.61 – 2.56 (m, 1H), 2.04 – 1.93 (m, 4H), 1.70 – 1.62 (m, 6H), 1.40 – 1.25 (m, 3H), 1.01 – 0.89 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.9, 166.0, 143.5, 129.0, 122.4, 115.4, 60.1, 44.8, 42.6, 36.2, 32.2, 29.9, 25.1, 21.3. LCMS (ESI): m/z calcd for C21H29Cl2N3O2; found [M+H]+ 426.30. [0805] 2-Chloro-N-((1-(1-(4-chlorophenoxy)-4,4-difluorocyclohexane-1- carbonyl)piperidin-4-yl)methyl)acetamide (124) 1075299 [0806] Obtained using oil, 28.0 mg, 30% yield.1H NMR (400 MHz, CDCl3) δ: 7.24 – 7.17 (m, 2H), 6.82 – 6.78 (m, 2H), 6.59 (b, 1H), 4.68 (t, J = 11.2 Hz, 2H), 4.02 (s, 2H), 3.11 (dd, J = 11.0, 6.2 Hz, 2H), 2.90 (t, J = 11.9 Hz, 1H), 2.57 (t, J = 11.9 Hz, 1H), 2.30 – 2.16 (m, 4H), 2.09 – 2.00 (m, 4H), 1.76 – 1.69 (m, 2H), 1.59 – 1.56 (m, 1H), 1.10 – 1.06 (m, 1H), 0.80 – 0.75 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 170.0, 166.0, 153.0, 129.6, 127.0, 118.1, 80.2, 45.3, 44.7, 43.2, 42.6, 36.1, 30.1, 29.5, 29.3, 29.1, 28.8. LCMS (ESI): m/z calcd for C21H26Cl2F2N2O3; found [M+H]+ 463.00. [0807] 2-Chloro-N-((1-(1-((4-chlorophenyl)amino)-4,4-difluorocyclohexane-1- carbonyl)piperidin-4-yl)methyl)acetamide (125) 1075311 [0808] Obtained using oil, 28. 1 0 mg, 30% yield. H NMR (400 MHz, CDCl3) δ: 7.13 – 7.07 (m, 2H), 6.58 (b, 1H), 6.55 – 6.49 (m, 2H), 4.85 – 4.80 (m, 2H), 4.02 (s, 2H), 3.76 – 3.75 (m, 1H), 3.09 (t, J = 6.1 Hz, 2H), 2.42 – 2.40 (m, 2H), 2.16 – 2.12 (m, 2H), 2.00 – 1.92 (m, 4H), 1.75 – 1.58 (m, 5H), 1.00 – 0.88 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 170.9, 166.0, 143.1, 129.3, 123.3, 115.4, 59.2, 44.8, 42.6, 36.1, 30.7, 30.0. LCMS (ESI): m/z calcd for C21H27Cl2F2N3O2; found [M+H]+ 462.10. [0809] 2-Chloro-N-((1-(4-(4-chlorophenoxy)tetrahydro-2H-pyran-4-carbonyl)piperidin-4- yl)methyl)acetamide (126) 1075305 [0810] Obtained using oil, 30.0 mg, 35% yield.1H NMR (400 MHz, CDCl3) δ: 7.21 – 7.18 (m, 2H), 6.81 – 6.79 (m, 2H), 6.59 (b, 1H), 4.70 – 4.68 (m, 2H), 4.02 (s, 2H), 3.78 – 3.69 (m, 4H), 3.10 (dd, J = 11.6, 6.1 Hz, 2H), 2.88 (t, J = 12.0 Hz, 1H), 2.56 (t, J = 12.1 Hz, 1H), 2.34 – 2.21 (m, 2H), 2.09 – 2.05 (m, 2H), 1.75 – 1.69 (m, 2H), 1.57 – 1.54 (m, 1H), 1.07 – 1.05 (m, 1H), 0.78 – 0.73 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 170.2, 166.0, 153.2, 129.5, 126.7, 118.2, 79.4, 63.0, 62.9, 45.1, 44.7, 43.1, 42.6, 36.1, 33.0, 32.6, 30.1, 29.5. LCMS (ESI): m/z calcd for C20H26Cl2N2O4; found [M+H]+ 429.09. [0811] 2-Chloro-N-((1-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4- carbonyl)piperidin-4-yl)methyl)acetamide (127) 1075310 [0812] Obtained using procedure C on 0.2 mmol scale, yellow oil, 25.0 mg, 30% yield.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.8 Hz, 2H), 6.60 (b, 1H), 6.51 (d, J = 8.8 Hz, 2H), 4.80 – 4.78 (m, 2H), 4.00 (s, 2H), 3.82 – 3.80 (m, 2H), 3.72 – 3.67 (m, 2H), 3.10 – 3.08 (m, 2H), 2.87 – 2.62 (m, 2H), 2.38 – 2.37 (m, 2H), 1.83 (d, J = 13.7 Hz, 2H), 1.70 – 1.65 (m, 4H), 0.95 – 0.90 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.3, 166.0, 143.0, 129.2, 123.0, 115.4, 63.6, 58.0, 44.8, 42.6, 36.1, 33.9, 29.8. LCMS (ESI): m/z calcd for C20H27Cl2N3O3; found [M+H]+ 428.14. [0813] tert-butyl 4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4-(4- chlorophenoxy)piperidine-1-carboxylate (128) 1076395 [0814] Obtained using solid, 48.0 mg, 30% yield. HPLC retention time 14 min.1H NMR (400 MHz, CDCl3) δ: 7.19 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.61 (b, 1H), 4.67 (d, J = 13.1 Hz, 2H), 4.01 (s, 2H), 3.87 – 3.82 (m, 2H), 3.10 – 3.09 (m, 4H), 2.88 (t, J = 12.3 Hz, 1H), 2.55 (t, J = 12.3 Hz, 1H), 2.14 – 2.13 (m, 4H), 1.74 – 1.68 (m, 2H), 1.59 – 1.54 (m, 1H), 1.43 (s, 9H), 1.07 – 1.04 (m, 1H), 0.76 – 0.75 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 170.3, 166.0, 154.7, 153.1, 129.5, 126.7, 118.2, 80.1, 79.7, 45.1, 44.7, 43.1, 42.6, 36.1, 30.1, 29.4, 28.4. LCMS (ESI): m/z calcd for C25H35Cl2N3O5; found [M+Na]+ 550.24. [0815] 2-chloro-N-((1-(4-(4-chlorophenoxy)piperidine-4-carbonyl)piperidin-4- yl)methyl)acetamide hydrochloride (129) 1076397 [0816] Obtained using on oil, 37.4 mg, 90% yield 1H NMR (400 MHz, DMSO) δ: 9.16 (b, 2H), 8.26 (t, J = 5.4 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.64 – 4.63 (m, 1H), 4.43 (d, J = 12.7 Hz, 2H), 4.01 (s, 2H), 3.72 – 3.65 (m, 4H), 3.50 – 3.43 (m, 4H), 3.18 – 3.15 (m, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.25 – 2.24 (m, 2H), 1.63 – 1.61 (m, 1H), 1.50 – 1.47 (m, 1H). 13C NMR (100 MHz, DMSO) δ: 168.1, 166.0, 152.8, 129.6, 125.9, 118.7, 77.9, 72.2, 70.5, 60.2, 44.6, 43.9, 43.6, 42.6, 35.4, 29.8. LCMS (ESI): m/z calcd for C20H27Cl2N3O3; found [M+H]+ 428.35. [0817] tert-butyl 4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4- (phenylamino)piperidine-1-carboxylate (130) 1076396 [0818] Obtained using solid, 51 mg, 33% yield. HPLC retention time 12 min.1H NMR (400 MHz, CDCl3) δ: 7.12 (t, J = 7.9 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 7.9 Hz, 3H), 4.84 – 4.83 (m, 2H), 3.99 (s, 2H), 3.90 – 3.89 (m, 1H), 3.72 (d, J = 12.7 Hz, 2H), 3.27 – 3.25 (m, 2H), 3.05 – 3.04 (m, 2H), 2.25 – 2.23 (m, 2H), 1.92 – 1.89 (m, 3H), 1.69 – 1.64 (m, 4H), 1.43 (s, 9H), 0.96 – 0.95 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 171.7, 166.0, 154.7, 144.4, 129.3, 118.4, 114.3, 79.7, 58.6, 44.8, 42.6, 36.1, 29.7, 28.4. LCMS (ESI): m/z calcd for C25H37ClN4O4; found [M+H] + 493.37, [M+Na]+ 515.28. [0819] 2-chloro-N-((1-(4-(phenylamino)piperidine-4-carbonyl)piperidin-4- yl)methyl)acetamide hydrochloride (131) 1076398 [0820] Obtained using 38.8 mg, 98% yield.1H NMR (400 MHz, DMSO) δ: 9.08 (b, 1H), 8.92 (b, 1H), 8.22 (t, J = 5.5 Hz, 1H), 7.06 (t, J = 7.8 Hz, 2H), 6.56 (t, J = 8.3 Hz, 3H), 6.34 (s, 1H), 4.62 (b, 1H), 4.44 (b, 1H), 4.00 (s, 2H), 3.73 – 3.65 (m, 4H), 3.52 – 3.44 (m, 4H), 3.13 – 3.11 (m, 2H), 2.86 – 2.77 (m, 2H), 2.22 – 2.14 (m, 2H), 1.54 – 1.53 (m, 2H), 0.80 – 0.65 (m, 1H).13C NMR (100 MHz, DMSO) δ: 170.6, 165.9, 145.2, 128.8, 116.5, 113.0, 72.2, 70.5, 60.2, 56.6, 43.6, 42.6, 35.5. LCMS (ESI): m/z calcd for C20H29ClN4O2; found [M+H]+ 393.2. [0821] tert-butyl 4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4-((4- chlorophenyl)amino)piperidine-1-carboxylate (132) 1075480 [0822] Obtained using solid, 32 mg, 30% yield. 1H NMR (400 MHz, CDCl3) δ: 7.09 (d, J = 8.9 Hz, 2H), 6.58 (b, 1H), 6.50 (d, J = 8.9 Hz, 2H), 4.81 – 4.80 (m, 2H), 4.01 (s, 2H), 3.86 – 3.85 (m, 1H), 3.72 – 3.69 (m, 2H), 3.26 – 3.25 (m, 2H), 3.09 – 3.08 (m, 2H), 2.24 – 2.23 (m, 2H), 1.89 – 1.85 (m, 2H), 1.72 – 1.58 (m, 5H), 1.44 (s, 9H), 1.02 – 0.86 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.3, 166.0, 154.7, 143.0, 129.2, 123.2, 115.4, 79.8, 58.8, 44.8, 42.6, 36.2, 29.7, 28.4. LCMS (ESI): m/z calcd for C25H36Cl2N4O4; found [M+Na]+ 549.24. [0823] 2-chloro-N-((1-(4-(4-chloro phenylamino)piperidine-4-carbonyl)piperidin-4- yl)methyl)acetamide hydrochloride (133) 1075481 [0824] Obtained using solid, 11.8 mg, 92% yield. 1H NMR (400 MHz, DMSO) δ: 8.99 (b, 2H), 8.24 (t, J = 5.3 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 4.56 – 4.42 (m, 2H), 4.00 (s, 2H), 3.71 – 3.65 (m, 4H), 3.49 – 3.42 (m, 4H), 3.32 – 3.29 (m, 2H), 3.00 – 2.97 (m, 2H), 2.82 – 2.80 (m, 2H), 2.30 – 2.26 (m, 1H), 2.05 – 2.01 (m, 1H), 1.56 – 1.54 (m, 2H).13C NMR (100 MHz, DMSO) δ: 170.2, 165.9, 151.1, 144.2, 128.6, 119.9, 114.4, 108.9, 77.9, 72.2, 70.5, 60.2, 56.7, 43.6, 42.6, 35.5, 27.6. LCMS (ESI): m/z calcd for C20H28Cl2N4O2; found [M+H]+ 427.14. [0825] tert-butyl (4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4- phenoxycyclohexyl)carbamate (134) 1076404
[0826] Obtained using procedure C on 0.2 mmol scale, white solid, 36.0 mg, 35% yield.1H NMR (400 MHz, CDCl3) δ: 7.24 - 7.20 (m, 2H), 6.94 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.9 Hz, 2H), 6.55 (t, J = 5.6 Hz, 1H), 4.75 – 4.69 (m, 3H), 4.00 (s, 2H), 3.75 (b, 1H), 3.06 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 12.2 Hz, 1H), 2.53 (t, J = 12.2 Hz, 1H), 2.24 – 2.10 (m, 2H), 2.03 – 2.00 (m, 2H), 1.92 – 1.88 (m, 2H), 1.70 – 1.65 (m, 5H), 1.51 – 1.48 (m, 1H), 1.42 (s, 9H), 1.06 – 1.02 (m, 1H), 0.68 – 0.64 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 171.3, 165.9, 155.3, 154.9, 129.4, 121.5, 116.9, 80.8, 79.1, 45.6, 45.3, 44.8, 43.0, 42.6, 36.1, 29.9, 29.4, 29.1, 28.7, 28.4, 26.4. LCMS (ESI): m/z calcd for C26H38ClN3O5; found [M+Na]+ 530.19. [0827] N-((1-(4-amino-1-phenoxycyclohexane-1-carbonyl)piperidin-4-yl)methyl)-2- chloroacetamide hydrochloride (135) 1076405 [0828] Obtained using oil, 26.4 mg, 92% yield. 1H NMR (400 MHz, DMSO) δ: 8.25 (b, 1H), 8.08 (b, 3H), 7.27 (t, J = 7.8 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 2H), 4.64 – 4.63 (m, 2H), 4.50 – 4.49 (m, 2H), 4.00 (s, 2H), 3.72 – 3.65 (m, 4H), 3.50 – 3.34 (m, 4H), 2.82 (t, J = 5.7 Hz, 2H), 2.33 – 2.30 (m, 2H), 1.89 – 1.81 (m, 2H), 1.74 – 1.68 (m, 2H).13C NMR (100 MHz, DMSO) δ: 169.2, 165.9, 154.8, 129.5, 121.6, 117.1, 80.2, 72.2, 70.5, 60.2, 46.6, 44.0, 43.6, 42.6, 35.5, 29.8. LCMS (ESI): m/z calcd for C21H30ClN3O3; found [M+H]+ 408.30. [0829] tert-butyl (4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4-(4- chlorophenoxy)cyclohexyl) carbamate (136) 1076401 [0830] Obtained using on solid, 34.6 mg, 32% yield. HPLC retention time 14 min.1H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.58 (t, J = 5.9 Hz, 1H), 4.68 (d, J = 12.6 Hz, 3H), 4.02 (s, 2H), 3.74 (b, 1H), 3.10 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 12.1 Hz, 1H), 2.54 (t, J = 12.1 Hz, 1H), 2.20 – 2.12 (m, 2H), 2.00 – 1.96 (m, 2H), 1.88 – 1.85 (m, 2H), 1.75 – 1.66 (m, 4H), 1.58 – 1.53 (m, 1H), 1.43 (s, 9H), 1.06 – 1.04 (m, 1H), 0.75 – 0.73 (m, 1H).13C NMR (100 MHz, CDCl3) δ: 170.9, 166.0, 155.3, 153.5, 129.4, 126.5, 118.2, 81.3, 79.2, 45.3, 44.7, 43.04, 42.6, 36.1, 30.1, 29.5, 28.8, 28.4, 26.3. LCMS (ESI): m/z calcd for C26H37Cl2N3O5; found [M+Na]+ 564.25. [0831] N-((1-(4-amino-1-(4-chlorophenoxy)cyclohexane-1-carbonyl)piperidin-4- yl)methyl)-2-chloroacetamide hydrochloride (137) 1076402 [0832] Obtained using solid, 23.3 mg, 90% yield. 1H NMR (400 MHz, DMSO) δ: 8.24 (b, 1H), 8.00 (b, 3H), 7.34 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 4.46 (d, J = 12.4 Hz, 2H), 4.01 (s, 2H), 3.73 – 3.67 (m, 4H), 3.52 – 3.45 (m, 4H), 2.86 – 2.84 (m, 2H), 2.33 – 2.31 (m, 2H), 1.89 – 1.81 (m, 3H), 1.66 – 1.63 (m, 3H).13C NMR (100 MHz, DMSO) δ: 169.0, 166.0, 153.6, 129.4, 125.4, 118.8, 80.7, 72.2, 70.5, 60.2, 43.6, 42.6, 35.5, 29.8. LCMS (ESI): m/z calcd for C21H29Cl2N3O3; found [M+H]+ 442.26. [0833] tert-butyl (4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4- (phenylamino)cyclohexyl) carbamate (138) 1076399 [0834] Obtained using solid, 30.5 mg, 30% yield. HPLC retention time 12 min.1H NMR (400 MHz, CDCl3) δ: 7.10 (t, J = 7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.9 Hz, 3H), 4.92 – 4.76 (m, 2H), 4.64 (d, J = 7.2 Hz, 1H), 3.98 (s, 2H), 3.62 (b, 1H), 3.04 (t, J = 6.2 Hz, 2H), 2.88 - 2.87 (m, 1H), 2.40 – 2.39 (m, 3H), 1.81 – 1.80 (m, 2H), 1.66 – 1.64 (m, 7H), 1.43 (s, 9H), 1.03 – 0.77 (m, 3H).13C NMR (100 MHz, CDCl3) δ: 172.0, 165.9, 155.3, 145.0, 129.2, 118.1, 114.2, 79.1, 59.5, 46.9, 44.8, 42.6, 36.1, 31.8, 29.8, 28.3, 27.8. LCMS (ESI): m/z calcd for C26H39ClN4O4; found [M+H] + 507.33, [M+Na]+ 529.29. [0835] N-((1-(4-amino-1-(phenylamino)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-2- chloroacetamide hydrochloride (139) 1076400 [0836] Obtained using oil, 17.4 mg, 92% y 1 ield. H NMR (400 MHz, DMSO) δ: 8.25 (t, J = 5.6 Hz, 1H), 8.04 (b, 3H), 7.02 (t, J = 7.9 Hz, 2H), 6.56 – 6.50 (m, 3H), 4.00 (s, 2H), 3.71 – 3.68 (m, 4H), 3.52 – 3.45 (m, 4H), 3.10 – 3.09 (m, 1H), 2.79 – 2.78 (m, 2H), 2.41 – 2.40 (m, 2H), 1.91 – 1.89 (m, 2H), 1.76 – 1.70 (m, 2H), 1.57 – 1.54 (s, 4H).13C NMR (100 MHz, DMSO) δ: 171.1, 165.9, 146.2, 128.7, 116.1, 113.2, 72.2, 70.5, 60.2, 58.6, 48.0, 43.6, 42.6, 35.6. LCMS (ESI): m/z calcd for C21H31ClN4O2; found [M+H]+ 407.30. [0837] tert-butyl (4-(4-((2-chloroacetamido)methyl)piperidine-1-carbonyl)-4-((4- chlorophenyl)amino) cyclohexyl) carbamate (140) 1076393 [0838] Obtained using solid, 37.8 mg, 35% yield. HPLC retention time 14min.1H NMR (400 MHz, CDCl3) δ: 7.06 (d, J = 8.8 Hz, 2H), 6.58 (t, J = 5.7 Hz, 1H), 6.49 (d, J = 8.8 Hz, 2H), 4.82 – 4.80 (m, 2H), 4.60 (d, J = 6.7 Hz, 1H), 4.01 (s, 2H), 3.62 (b, 1H), 3.08 (t, J = 6.1 Hz, 2H), 2.90 – 2.87 (m, 1H), 2.41– 2.40 (m, 2H), 1.81 – 1.58 (m, 11H), 1.42 (s, 9H), 1.01 – 0.85 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.6, 166.0, 155.3, 143.6, 129.1, 122.8, 115.3,79.2, 59.7, 47.0, 44.8, 42.6, 36.1, 31.8, 30.0, 28.4, 27.9. LCMS (ESI): m/z calcd for C26H38Cl2N4O4; found [M+H] + 541.29, [M+Na]+ 563.25. [0839] N-((1-(4-amino-1-((4-chlorophenyl)amino)cyclohexane-1-carbonyl)piperidin-4- yl)methyl)-2-chloroacetamide hydrochloride (141) 1076394 [0840] Obtained using less oil, 30.4 mg, 98% yield. 1H NMR (400 MHz, DMSO) δ: 8.26 (t, J = 5.5 Hz, 1H), 8.03 (b, 3H), 7.05 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 6.18 (s, 1H), 4.64 – 4.59 (m, 2H), 4.01 (s, 2H), 3.73 – 3.65 (m, 5H), 3.52 – 3.45 (m, 5H), 3.11 – 3.10 (m, 1H), 2.83 – 2.81 (m, 2H), 2.41 – 2.40 (m, 2H), 1.90 – 1.89 (m, 2H), 1.58 – 1.57 (m, 2H), 1.24 – 1.23 (m, 1H), 0.87 – 0.80 (m, 1H). 13C NMR (100 MHz, DMSO) δ: 170.5, 165.9, 145.1, 128.5, 119.4, 114.5, 72.2, 70.5, 60.2, 58.6, 47.7, 43.6, 42.6, 35.6, 31.6. LCMS (ESI): m/z calcd for C21H30Cl2N4O2; found [M+H]+ 441.26. [0841] 2-chloro-N-((1-(4-((4-chlorophenyl)amino)-2,6-dimethyltetrahydro-2H-pyran-4- carbonyl)piperidin-4-yl)methyl)acetamide (142) 1080299 [0842] Obtained using oil, 4.8 mg, 10% yield. HPLC retention time 10.0 min.1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 8.4 Hz, 2H), 6.57 (b, 1H), 6.52 (d, J = 8.4 Hz, 2H), 4.82 – 4.80 (m, 2H), 4.01 (s, 2H), 3.86 – 3.84 (m, 2H), 3.15 – 3.09 (m, 2H), 2.60 – 2.55 (m, 4H), 1.72 – 1.69 (m, 4H), 1.18 (s, 6H), 0.90 – 0.85 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 171.0, 166.0, 143.6, 129.2, 123.1, 115.7, 69.9, 66.6, 59.7, 44.8, 43.7, 42.6, 36.2, 29.9, 22.0. LCMS (ESI): m/z calcd for C22H31Cl2N3O3; found [M+H]+ 456.26. [0843] 2-chloro-N-((1-(4-((4-chlorophenyl)amino)-2,2,6,6-tetramethyltetrahydro-2H- pyran-4-carbonyl)piperidin-4-yl)methyl)acetamide (143) 1080300 [0844] Obtained using procedure C on 0.2 mmol scale, off-white solid, 12.2 mg, 13% yield. HPLC retention time 11.0 min.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.9 Hz, 2H), 6.57 (b, 1H), 6.44 (d, J = 8.9 Hz, 2H), 4.76 – 4.64 (m, 2H), 4.01 (s, 2H), 3.08 – 3.06 (m, 2H), 2.36 – 2.34 (m, 2H), 2.06 – 2.02 (m, 2H), 1.75 – 1.52 (m, 3H), 1.48 – 1.37 (m, 3H), 1.27 (s, 12H), 0.94 – 0.92 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 172.2, 166.0, 143.6, 129.2, 122.7, 115.1, 71.3, 70.8, 59.3, 44.8, 42.6, 36.2, 32.7, 29.7. LCMS (ESI): m/z calcd for C24H35Cl2N3O3; found [M+H]+ 484.32. [0845] Scheme 10. Synthetic route for vinylsulfonamide analog 145 (1075479) a 0 oC to rt, 2 h; (b) 4 N HCl/dioxane, rt, 4 h; (c) ethenesulfonyl chloride (144), DIPEA, DCM, 0 oC to rt, 2 h. [0846] Procedure A. At 0 oC carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in dry DMF (2 ml for 1 mmol reaction scale).4-(Boc-aminomethyl)piperidine 2 (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). The product was confirmed with LCMS and used directly in the next step. [0847] Procedure B. The Boc-protected amine was dissolved in 3 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained HCl salt was used directly in the next step. [0848] Procedure C. The HCl salt (1 equiv) was suspended in 2 ml dry DCM. At 0oC, Et3N (4 equiv) was added. After 10 min, ethenesulfonyl chloride 144 was added slowly (1.2 equiv). Stirring at 0 oC for 30 min and then at rt for 2 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0849] N-((1-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)piperidin-4- yl)methyl)ethenesulfonamide (145) 1075479 [0850] Obtained using oil, 2.0 mg, 2.3% yi 1 eld. H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.9 Hz, 2H), 6.45 (dd, J = 16.5, 9.9 Hz, 1H), 6.22 (d, J = 16.5 Hz, 1H), 5.93 (d, J = 9.8 Hz, 1H), 4.79 – 4.78 (m, 2H), 4.18 (t, J = 6.0 Hz, 1H), 3.82 – 3.81 (m, 2H), 3.73 – 3.68 (m, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.38 – 2.37 (m, 2H), 1.86 – 1.82 (m, 2H), 1.68 – 1.65 (m, 3H), 1.25 – 1.24 (m, 3H), 0.88 – 0.87 (m, 2H). LCMS (ESI): m/z calcd for C20H28ClN3O4S; found [M+H]+ 442.19. [0851] Scheme 11. Synthetic route for α-chloroketone 146 (1075351) a [0852] Procedure A. At 0 oC carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in dry DMF (2 ml for 1 mmol reaction scale). TFA amine salt 36 (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0853] 1-chloro-4-(1-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4- carbonyl)piperidin-4-yl)butan-2-one (146) 1075351 [0854] Obtained using procedure C on 0.2 mmol scale, yellow oil, 20.0 mg, 23% yield.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 7.7 Hz, 2H), 6.52 (d, J = 8.1 Hz, 2H), 4.74 – 4.71 (m, 2H), 4.03 (s, 2H), 3.82 – 3.80 (m, 2H), 3.73 – 3.71 (m, 2H), 2.82 – 2.81 (m, 1H), 2.62- 2.61 (m, 1H), 2.52 – 2.50 (m, 2H), 2.39 – 2.37 (m, 2H), 1.84 (d, J = 11.1 Hz, 2H), 1.60 – 1.57 (m, 2H), 1.46 – 1.44 (m, 4H), 0.85 – 0.83 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 202.5, 171.1, 143.1, 129.2, 122.9, 115.4, 63.7, 63.7, 58.0, 48.1, 36.3, 35.2, 34.1, 34.0, 32.0, 31.9, 29.4. LCMS (ESI): m/z calcd for C21H29Cl2N2O3; found [M+H]+ 427.14. [0855] Scheme 12. General procedure for 2C- and 3C-linker chloroacetamide derivatives 153 - 158 a oC to rt, 4 h; (b) 4N HCl/dioxane, rt, 3h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h; (d) 4 N HCl/dioxane, rt, 3 h. [0856] Procedure A. Tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate 147 or 1-Boc-4- (3-aminopropyl)piperidine 148 (1 mmol, 1.0 equiv) was dissolved in 5 ml dry DCM. DIPEA (3 mmol, equiv) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 mmol, 1.2 equiv) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified with flash column chromatography (Biotage, hexane - EtOAc, 0-100% EtOAc in hexane). [0857] Procedure B. The Boc-protected intermediate was dissolved in 3 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained HCl salt was used directly in the next step. [0858] Procedure C. The appropriate carboxylic acid (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring at 0 oC for 30 min, then rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0859] Procedure D. The purified Boc-intermediate was suspended in 3 ml HCl/dioxane (4 N). Stirring rt for 3 h. The solvent was removed under reduced pressure and the deprotected product was dried under vacuum. [0860] Tert-butyl 4-(2-(2-chloroacetamide)ethyl)piperidine-1-carboxylate (149) [0861] Obtained using oil, 237.4 mg, 0.78 mmol, 78% yield.1H NMR (400 MHz, CDCl3) δ: 6.71 (b, 1H), 4.00 – 3.98 (m, 2H), 3.97 (s, 2H), 3.26 (dd, J = 13.6, 6.6 Hz, 2H), 2.60 (t, J = 12.3 Hz, 2H), 1.60 (d, J = 12.8 Hz, 2H), 1.45 – 1.38 (m, 3H), 1.37 (s, 9H), 1.08 – 1.00 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 165.7, 154.6, 79.1, 43.7, 42.4, 37.2, 33.4, 31.7, 28.2. LCMS (ESI): m/z calcd for C14H25ClN2O3; found [M+Na]+ 327.18. [0862] Tert-butyl 4-(3-(2-chloroacetamido)propyl)piperidine-1-carboxylate (150) [0863] Obtained using procedure A on 1 mmol scale, yellow oil, 280 mg, 88% yield. 1H NMR (400 MHz, CDCl3) δ: 6.68 (b, 1H), 3.99 (s, 4H), 3.27 – 3.21 (m, 2H), 2.62 – 2.60 (m, 2H), 1.61 – 1.50 (m, 4H), 1.40 (s, 9H), 1.37 – 1.32 (m, 1H), 1.25 – 1.21 (m, 2H), 1.06 – 1.00 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 165.8, 154.7, 79.2, 43.8, 42.5, 39.8, 35.5, 33.4, 31.9, 28.3, 26.4. LCMS (ESI): m/z calcd for C15H27ClN2O3; found [M+Na]+ 341.0. [0864] 2-chloro-N-(2-(1-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4- carbonyl)piperidin-4-yl)ethyl)acetamide (153) 1080267 [0865] Obtained using oil, 16.0 mg, 24% yield. HPLC retention time 11.0 min.1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.3 Hz, 2H), 4.75 – 4.74 (m, 2H), 4.01 (s, 2H), 3.83 – 3.80 (m, 2H), 3.72 – 3.70 (m, 2H), 3.27 – 3.23 (m, 2H), 2.38 – 2.37 (m, 3H), 1.86 – 1.82 (m, 3H), 1.64 – 1.62 (m, 3H), 1.48 – 1.33 (m, 4H), 1.10 - 0.88 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.2, 165.8, 143.1, 129.2, 122.9, 115.3, 63.6, 58.0, 42.6, 37.2, 35.8, 34.1, 33.6, 32.1. LCMS (ESI): m/z calcd for C21H29Cl2N3O3; found [M+H]+ 442.16. [0866] 2-chloro-N-(3-(1-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4- carbonyl)piperidin-4-yl)propyl)acetamide (154) 1075478 [0867] Obtained oil, 21.8 mg, 24% yield. 1H NMR (400 MHz, CDCl3) δ: 7.06 (d, J = 8.7 Hz, 2H), 6.57 (b, 1H), 6.51 (d, J = 8.7 Hz, 2H), 4.74 – 4.73 (m, 2H), 4.01 (s, 2H), 3.82 – 3.79 (m, 2H), 3.72 – 3.68 (m, 3H), 3.57 (t, J = 6.4 Hz, 1H), 3.22 (dd, J = 13.4, 6.8 Hz, 2H), 2.36 (b, 2H), 1.89 – 1.82 (m, 3H), 1.75 – 1.73 (m, 1H), 1.60 – 1.53 (m, 2H), 1.48 – 1.40 (m, 3H), 1.15 – 1.08 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 170.9, 170.4, 165.8, 142.7, 129.1, 123.1, 115.6, 78.2, 67.0, 63.6, 62.6, 58.2, 44.8, 42.6, 39.8, 35.6, 33.8, 33.1, 32.2, 29.4, 27.4, 26.2. LCMS (ESI): m/z calcd for C22H31Cl2N3O3; found [M+H]+ 456.15, [M+Na]+ 478.10. [0868] tert-butyl 4-(4-(2-(2-chloroacetamido)ethyl)piperidine-1-carbonyl)-4-((4- chlorophenyl)amino) piperidine-1-carboxylate (155) 1080292 [0869] Obtained using solid, 31.8 mg, 24% yield. HPLC retention time 13.0 min.1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 8.7 Hz, 2H), 4.75 (b, 2H), 4.01 (s, 2H), 3.72 -3.69 (m, 2H), 3.29 – 3.24 (m, 4H), 2.25 – 2.23 (m, 2H), 1.90 – 1.85 (m, 3H), 1.67 – 1.59 (m, 3H), 1.48 – 1.42 (m, 3H), 1.44 (s, 9H), 1.40 – 1.34 (m, 2H), 1.10 – 0.88 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.3, 165.9, 154.7, 151.3, 143.1, 129.1, 122.9, 121.2, 115.3, 79.8, 58.7, 42.6, 39.9, 37.2, 35.7, 33.6, 32.1, 28.3. LCMS (ESI): m/z calcd for C26H38Cl2N4O4; found [M+H]+ 541.29. [0870] 2-chloro-N-(2-(1-(4-((4-chlorophenyl)amino)piperidine-4-carbonyl)piperidin-4- yl)ethyl)acetamide hydrochloride (156) 1080293 [0871] Obtained using oil, 18.5 mg, 98% yield. 1H NMR (400 MHz, DMSO) δ: 8.92 (b, 2H), 8.17 (b, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 4.54 – 4.46 (m, 2H), 3.99 (s, 2H), 3.73 – 3.65 (m, 4H), 3.52 – 3.44 (m, 4H), 3.03 – 3.01 (m, 2H), 2.83 – 2.81 (m, 1H), 2.28 – 2.24 (m, 1H), 2.11 – 2.02 (m, 2H), 1.60 – 1.58 (m, 1H), 1.40 – 1.38 (m, 1H), 1.18 – 1.15 (m, 2H), 0.77 – 0.60 (m, 2H).13C NMR (100 MHz, DMSO) δ: 170.1, 165.6, 144.2, 128.6, 119.9, 114.4, 72.2, 70.5, 60.2, 56.6, 43.6, 42.6, 36.2, 35.3, 32.6. LCMS (ESI): m/z calcd for C21H30Cl2N4O2; found [M+H]+ 441.21. [0872] tert-butyl 4-(4-(3-(2-chloroacetamido)propyl)piperidine-1-carbonyl)-4-((4- chlorophenyl)amino) piperidine-1-carboxylate (157) 1076391
[0873] Obtained using procedure C on 0.2 mmol scale, colorless oil, 22.2 mg, 20% yield. HPLC retention time 14 min.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.8 Hz, 2H), 6.54 (b, 1H), 6.50 (d, J = 8.8 Hz, 2H), 4.75 – 4.74 (m, 2H), 4.03 (s, 2H), 3.87 – 3.86 (m, 1H), 3.71 (d, J = 14.1 Hz, 2H), 3.27 – 3.21 (m, 4H), 2.26 – 2.25 (m, 2H), 2.01 (b, 1H), 1.87 (d, J = 14.0 Hz, 2H), 1.60 – 1.58 (m, 7H), 1.44 (s, 9H), 1.27 – 1.25 (m, 1H), 1.15 – 1.13 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 171.2, 165.8, 154.7, 143.1, 129.2, 123.0, 115.4, 79.8, 58.7, 42.7, 39.9, 35.6, 33.2, 32.5, 32.1, 28.4, 26.3. LCMS (ESI): m/z calcd for C27H40Cl2N4O4; found [M+Na]+ 555.57. [0874] 2-chloro-N-(3-(1-(4-((4-chlorophenyl)amino)piperidine-4-carbonyl)piperidin-4- yl)propyl)acetamide hydrochloride (158) 1076392 [0875] Obtained 15.6 mg, 85% yield. 1H NMR (400 MHz, DMSO) δ: 9.02 (b, 2H), 8.19 (t, J = 5.5 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.60 (s, 1H), 6.54 (d, J = 8.9 Hz, 2H), 4.55 – 4.46 (m, 2H), 4.00 (s, 2H), 3.71– 3.64 (m, 4H), 3.49– 3.44 (m, 4H), 3.01 – 2.96 (m, 2H), 2.83 – 2.80 (m, 1H), 2.12 – 2.10 (m, 2H), 1.58 – 1.54 (m, 2H), 1.34 – 1.26 (m, 2H), 1.00 – 0.98 (m, 2H), 0.78 – 0.75 (m, 1H), 0.60 – 0.55 (s, 1H).13C NMR (100 MHz, DMSO) δ: 170.1, 165.7, 144.2, 128.6, 119.9, 114.4, 72.2, 70.5, 60.2, 56.7, 43.6, 42.7, 34.8, 33.0, 25.8. LCMS (ESI): m/z calcd for C22H32Cl2N4O2; found [M+H]+ 455.26. [0876] Scheme 13. Synthetic route for spiro analog 162 (1080265) a
a Reagents and conditions: (a) tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (159), chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h. [0877] Procedure A. tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride 159 (1 mmol, 1.0 equiv) was dissolved in 5 ml dry DCM. DIPEA (3 equiv, 3 mmol) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv, 1.2 mmol) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with flash column chromatography [Biotage, hexane – EA, 0-100% EtOAc in hexane]. [0878] Procedure B. The residue was suspended in 3 ml HCl/dioxane (4 N) for Boc- deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the white solid oil was used directly in the next step. [0879] Procedure C.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.2 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0880] Tert-butyl 2-(2-chloroacetyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (160) [0881] Obtained using mg, 35% yield.1H NMR (400 MHz, CDCl3) δ: 3.93 (s, 2H), 3.86 (s, 2H), 3.73 (s, 2H), 3.34 – 3.28 (m, 4H), 1.69 (t, J = 5.5 Hz, 4H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 166.2, 154.5, 79.7, 60.4, 58.0, 40.5, 39.4, 34.9, 34.1, 28.3. LCMS (ESI): m/z calcd for C14H23ClN2O3; found [M+H]+ 303.07. [0882] 2-chloro-1-(7-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)-2,7- diazaspiro[3.5]nonan-2-yl)ethan-1-one (162) 1080265 [0883] Obtained using oil, 10.0 mg, 15% yield. HPLC retention time 10.5 min.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.9 Hz, 2H), 6.51 (d, J = 8.9 Hz, 2H), 3.89 (s, 2H), 3.86 (s, 2H), 3.83 – 3.79 (m, 4H), 3.72 – 3.67 (m, 6H), 2.39 – 2.37 (m, 2H), 1.85 – 1.82 (m, 2H), 1.62 – 1.55 (m, 5H). 13C NMR (100 MHz, CDCl3) δ: 171.6, 166.3, 143.0, 129.3, 123.3, 115.4, 63.6, 60.5, 58.1, 39.4, 35.4, 34.3, 33.9. LCMS (ESI): m/z calcd for C21H27Cl2N3O3; found [M+H]+ 440.11. [0884] Scheme 14. Synthetic route for spiro analog 163 (1080266) a a hydrochloride 159, HATU, DIPEA, DMF, 0 oC to rt, 2 h; (b) 4N HCl/dioxane, rt, 3 h; (c) chloroacetyl chloride 25, DIPEA, DCM, 0 oC to rt, 4 h. [0885] Procedure A.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (0.3 mmol, 1 equiv) and HATU (0.36 mmol, 1.2 equiv) were dissolved in 1 ml DMF. Tert- butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride 159 (0.33 mmol.1.1 equiv) and DIPEA (0.9 mmol, 3 equiv) were dissolved in 2 ml DMF. The solution of the carboxylic acid and HATU was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step. The obtained product was suspended in 1.5 ml HCl/dioxane (4N) for Boc-deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step. The HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv) was added. The reaction mixture was cooled at 0oC and chloroacetyl chloride 25 (1.2 equiv) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0886] 2-chloro-1-(2-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)-2,7- diazaspiro[3.5]nonan-7-yl)ethan-1-one (163) 1080266 [0887] Obtained using oil, 10.7 mg, 10% yield (over 3 steps). HPLC retention time 10.0 min.1H NMR (400 MHz, CDCl3) δ: 7.13 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 8.6 Hz, 2H), 4.02 – 4.00 (m, 2H), 3.95 – 3.92 (m, 2H), 3.86 – 3.83 (m, 2H), 3.75 (s, 2H), 3.68 – 3.62 (m, 2H), 3.56 – 3.52 (m, 1H), 3.36 – 3.32 (m, 3H), 2.34 – 2.27 (m, 2H), 1.78 – 1.74 (m, 2H), 1.64 – 1.56 (m, 5H).13C NMR (100 MHz, CDCl3) δ: 173.1, 165.1, 142.7, 129.4, 123.4, 115.1, 63.3, 63.1, 62.6, 58.2, 57.1, 43.4, 40.9, 39.3, 35.3, 34.4, 34.1, 32.6, 32.0. LCMS (ESI): m/z calcd for C21H27Cl2N3O3; found [M+H]+ 440.16. [0888] Scheme 15. Synthetic route for spiro analog 165 (1080294) a a nonane- , HATU, DIPEA, DMF, 0 oC to rt, 2 h; (b) 4N HCl/dioxane, rt, 3 h; (c) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h. [0889] Procedure A.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (0.3 mmol, 1equiv) and HATU (0.36 mmol, 1.2 equiv) were dissolved in 1ml DMF. Tert- butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate 164 (0.33 mmol.1.1 equiv) and DIPEA (0.9 mmol, 3 equiv) were dissolved in 2 ml DMF. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step. The obtained product was suspended in 1.5 ml HCl/dioxane (4 N) for Boc-deprotection. Stirring rt for 3h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step. The HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0890] N-(7-(2-chloroacetyl)-7-azaspiro[3.5]nonan-2-yl)-4-((4- chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxamide (165) 1080294 [0891] Obtained using 18.0 mg, 15% yield (over 3 steps). HPLC retention time 11.5 min.1H NMR (400 MHz, CDCl3) δ: 7.15 – 7.13 (m, 2H), 7.03 (b, 1H), 6.53 – 6.51 (m, 2H), 4.41 – 4.33 (m, 1H), 4.04 – 4.02 (m, 2H), 3.86 – 3.83 (m, 2H), 3.57 – 3.52 (m, 3H), 3.42 – 3.40 (m, 2H), 3.30 – 3.28 (m, 1H), 2.33 – 2.29 (m, 5H), 1.74 – 1.69 (m, 3H), 1.63 – 1.56 (m, 3H), 1.53 – 1.51 (m, 1H), 1.47 – 1.45 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 173.9, 165.0, 141.9, 129.1, 124.6, 117.1, 67.0, 63.1, 57.8, 43.7, 43.4, 41.0, 39.8, 39.3, 38.6, 36.0, 35.2, 32.5, 32.0. LCMS (ESI): m/z calcd for C22H29Cl2N3O3; found [M+H]+ 454.26. [0892] Scheme 16. Synthetic route for spiro analog 168 (1080295) a 64), chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h. [0893] Procedure A. Tert-Butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate 164 (1 mmol, 1 equiv) was dissolved in 5 ml dry DCM. DIPEA (3 mmol, 3 equiv) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.1 mmol, 1.1 equiv) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with flash column chromatography [Biotage, hexane – EA, 0-100% EtOAc in hexane]. [0894] Procedure B. The residue was suspended in 3 ml HCl/dioxane (4 N) for Boc- deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the white solid oil was used directly in the next step. [0895] Procedure C.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.1 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0896] Tert-butyl 2-(2-chloroacetamido)-7-azaspiro[3.5]nonane-7-carboxylate (166) [0897] Obtained using proced , 98% yield.1H NMR (400 MHz, CDCl3) δ: 6.95 (b, 1H), 4.26 (dd, J = 16.2, 8.1 Hz, 1H), 3.87 (s, , 3.24 – 3.21 (m, 2H), 3.16 – 3.14 (m, 2H), 2.22 – 2.17 (m, 2H), 1.64 – 1.59 (m, 2H), 1.47 – (m, 2H), 1.40 – 1.37 (m, 2H), 1.32 (s, 9H).13C NMR (100 MHz, CDCl3) δ: 165.0, 154.5, 79.0, 42.2, 39.9, 39.4, 38.9, 35.2, 32.1, 28.1. LCMS (ESI): m/z calcd for C15H25ClN2O3; found [M-Boc]+ 217.21. [0898] 2-chloro-N-(7-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)-7- azaspiro[3.5]nonan-2-yl)acetamide (168) 1080295 [0899] Obtained using solid, 25.5 mg, 20% yield. HPLC retention time 11.5 min.1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 8.7 Hz, 2H), 6.62 (b, 1H), 6.50 (d, J = 8.8 Hz, 2H), 4.35 – 4.29 (m, 1H), 3.99 (s, 2H), 3.83 – 3.78 (m, 3H), 3.73 – 3.64 (m, 3H), 3.60 – 3.48 (m, 2H), 2.39 – 2.33 (m, 2H), 2.28 – 2.23 (m, 2H), 1.84 – 1.81 (m, 2H), 1.65 – 1.60 (m, 2H), 1.48 – 1.30 (m, 5H). 13C NMR (100 MHz, CDCl3) δ: 171.3, 165.1, 143.1, 129.2, 123.0, 115.4, 63.6, 58.0, 42.4, 40.1, 39.9, 35.9, 33.9, 32.6. LCMS (ESI): m/z calcd for C22H29Cl2N3O3; found [M+H]+ 454.16. [0900] Scheme 17. Synthetic route for spiro analog 172 (1080296) a
a Reagents and conditions: (a) tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (169), chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h. [0901] Procedure A. Tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 169 (1 mmol, 1 equiv) was dissolved in 5 ml dry DCM. DIPEA (4 mmol, 4 equiv) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.1 mmol, 1.1 equiv) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with flash column chromatography [Biotage, hexane – EA, 0-100% EtOAc in hexane]. [0902] Procedure B. The residue was suspended in 3 ml HCl/dioxane (4 N) for Boc- deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the white solid oil was used directly in the next step. [0903] Procedure C.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.1 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0904] Tert-butyl 9-(2-chloroacetyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (170) N N Boc [0905] Obtained using 62% yield.1H NMR (400 MHz, CDCl3) δ: 3.99 (s, 2H), 3.50 – 3.46 (m, 2H), 3.40 -3.37 (m, 2H), 3.32 – 3.26 (m, 4H), 1.49 – 1.47 (m, 2H), 1.43 – 1.38 (m, 6H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 164.7, 154.6, 79.2, 41.9, 40.9, 38.9, 37.7, 35.5, 34.8, 34.3, 29.9, 28.2. LCMS (ESI): m/z calcd for C16H27ClN2O3; found [M-Boc]+ 231.12. [0906] 2-chloro-1-(9-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)-3,9- diazaspiro[5.5] undecan-3-yl)ethan-1-one (172) 1080296 [0907] Obtained using solid, 12.9 mg, 10% yield. HPLC retention time 11.5 min.1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 4.03 (s, 2H), 3.85 – 3.80 (m, 4H), 3.73 – 3.68 (m, 4H), 3.53 – 3.50 (m, 2H), 3.40 – 3.38 (m, 2H), 3.30 – 3.29 (m, 1H), 2.38 – 2.36 (m, 2H), 1.86 – 1.82 (m, 2H), 1.42 – 1.40 (m, 6H), 1.25 – 1.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 171.3, 165.0, 143.1, 129.2, 123.1, 115.3, 63.6, 58.0, 42.1, 41.0, 37.9, 36.1, 35.4, 34.3, 34.0, 30.2. LCMS (ESI): m/z calcd for C23H31Cl2N3O3; found [M+H]+ 468.32. [0908] Scheme 18. Synthetic route for spiro analog 176 (1080297) a - nonane- carboxylate 173, chloroacetyl chloride 25, DIPEA, DCM, 0 oC to rt, 4 h; (b) 4N HCl/dioxane, rt, 3 h; (c) HATU, DIPEA, DMF, 0 oC to rt, 2 h. [0909] Procedure A. Tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (173) (1 mmol, 1 equiv) was dissolved in 5 ml dry DCM. DIPEA (3 equiv, 3 mmol) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride (25) (1.1 mmol, 1.1 equiv) was added dropwise. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (15 ml) and extracted with DCM (3 x 20 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained oil was purified with flash column chromatography [Biotage, hexane – EA, 0-100% EtOAc in hexane]. [0910] Procedure B. The residue was suspended in 3 ml HCl/dioxane (4 N) for Boc- deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the white solid oil was used directly in the next step. [0911] Procedure C.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (1 equiv) and HATU (1.2 equiv) were dissolved in 2 ml dry DMF at 0 oC. The amine HCl salt (1.1 equiv) was dissolved in 1 ml DMF, and DIPEA (3 equiv) was added. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0912] Tert-butyl 2-((2-chloroacetamido)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (173) [0913] Obtained using 75% yield.1H NMR (400 MHz, CDCl3) δ: 6.74 (s, 1H), 3.93 (s, 2H), 3.24 – 3.20 (m, 4H), 3.16 – 3.14 (m, 2H), 2.40 – 2.36 (m, 1H), 1.87 – 1.71 (m, 2H), 1.46 – 1.35 (m, 6H), 1.33 (s, 9H).13C NMR (100 MHz, CDCl3) δ: 165.8, 154.6, 79.0, 45.4, 42.4, 40.3, 39.0, 36.1, 35.1, 33.7, 28.2, 27.9. LCMS (ESI): m/z calcd for C16H27ClN2O3; found [M+Na]+ 353.23. [0914] N-((7-(2-chloroacetyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-4-((4- chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxamide (176) 1080297
[0915] Obtained using procedure C on 0.22 mmol scale, colorless oil, 9.4 mg, 10% yield. HPLC retention time 13.0 min.1H NMR (400 MHz, CDCl3) δ: 7.08 – 7.06 (m, 2H), 6.51 – 6.49 (m, 3H), 4.02 (s, 2H), 3.85 – 3.76 (m, 3H), 3.72 – 3.67 (m, 4H), 3.60 – 3.56 (m, 1H), 3.32 – 3.29 (m, 2H), 2.44 – 2.34 (m, 3H), 1.90 – 1.81 (m, 5H), 1.45 – 1.28 (m, 6H). 13C NMR (100 MHz, CDCl3) δ: 171.3, 165.9, 143.1, 129.2, 123.0, 115.4, 63.6, 58.0, 45.5, 42.7, 35.4, 34.2, 34.0, 28.0. LCMS (ESI): m/z calcd for C23H31Cl2N3O3; found [M+H]+ 468.22. [0916] Scheme 19. Synthetic route for spiro analog 177 (1080298) a carboxylate (173), HATU, DIPEA, DMF, 0 oC to rt, 2 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h. [0917] Procedure A.4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid 95 (0.3 mmol, 1 equiv) and HATU (0.36 mmol, 1.2 equiv) were dissolved in 1ml DMF. Tert- butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate 173 (0.33 mmol, 1.1 equiv) and DIPEA (0.9 mmol, 3 equiv) were dissolved in 2 ml DMF. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step. The obtained product was suspended in 1.5 ml HCl/dioxane (4N) for Boc-deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step. The HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0918] 2-chloro-N-(7-(4-((4-chlorophenyl)amino)tetrahydro-2H-pyran-4-carbonyl)-7- azaspiro[3.5]nonan-2-yl)acetamide (177) 1080298 [0919] Obtained using solid, 23.8 mg, 17% yield (over 3 steps). HPLC retention time 11.5 min.1H NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 8.8 Hz, 2H), 6.93 (b, 1H), 6.53 (d, J = 8.8 Hz, 2H), 4.03 (s, 2H), 3.85 (dt, J = 12.0, 4.0 Hz, 2H), 3.60 – 3.48 (m, 3H), 3.42 – 3.36 (m, 2H), 3.31 – 3.27 (m, 3H), 2.35 (ddd, J = 14.6, 12.3, 6.9 Hz, 3H), 1.86 – 1.79 (m, 2H), 1.78 – 1.72 (m, 3H), 1.64 – 1.62 (m, 1H), 1.57 – 1.55 (m, 1H), 1.51 – 1.49 (m, 1H), 1.46 – 1.41 (m, 3H).13C NMR (100 MHz, CDCl3) δ: 174.5, 164.9, 141.9, 129.1, 124.5, 117.1, 63.1, 58.0, 45.3, 43.3, 41.1, 39.5, 39.1, 36.7, 35.8, 35.3, 34.0, 32.2, 28.3. LCMS (ESI): m/z calcd for C23H31Cl2N3O3; found [M+H]+ 468.42. [0920] Scheme 20. Synthetic route for spiro analog 178 (1083743) a carboxylate (173), HATU, DIPEA, DMF, 0 oC to rt, 2 h; (b) 4 N HCl/dioxane, rt, 3 h; (c) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h. [0921] Procedure A.4-((4-chlorophenyl)amino)-2,6-dimethyltetrahydro-2H-pyran-4- carboxylic acid 103 (0.41 mmol, 1 equiv) and HATU (0.49 mmol, 1.2 equiv) were dissolved in 2 ml DMF. Tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate 173 (0.45 mmol.1.1 equiv) and DIPEA (1.23 mmol, 3 equiv) were dissolved in 3 ml DMF. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (20 ml) and extracted with ethyl acetate (3x20ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step. The obtained product was suspended in 2.0 ml HCl/dioxane (4 N) for Boc-deprotection. Stirring rt for 3 h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step. The HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv, 50 μl) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv, 20 μl) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0922] N-((7-(2-chloroacetyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-4-((4- chlorophenyl)amino)-2,6-dimethyltetrahydro-2H-pyran-4-carboxamide (178) 1083743 [0923] Obtained using solid, 32.2 mg, 18% yield (over 3 steps). HPLC retention time 12.0 min.1H NMR (400 MHz, CDCl3) δ: 7.09 (d, J = 8.8 Hz, 2H), 6.92 – 6.90 (m, 1H), 6.52 (d, J = 8.8 Hz, 2H), 4.04 – 3.99 (m, 3H), 3.91 – 3.80 (m, 1H), 3.55 (t, J = 6.5 Hz, 1H), 3.50 – 3.47 (m, 1H), 3.41 – 3.30 (m, 2H), 3.29 – 3.26 (m, 3H), 2.40 – 2.34 (m, 1H), 2.28 – 2.25 (m, 2H), 1.94 – 1.91 (m, 1H), 1.83 – 1.78 (m, 2H), 1.69 – 1.67 (m, 1H), 1.63 – 1.60 (m, 1H), 1.55 – 1.46 (m, 3H), 1.44 – 1.39 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 174.7, 164.9, 142.3, 129.0, 124.5, 117.1, 78.0, 69.8, 62.0, 59.0, 45.1, 43.3, 41.3, 41.0, 39.4, 38.7, 36.7, 35.8, 35.3, 33.9, 29.4, 28.3, 27.4, 21.9. LCMS (ESI): m/z calcd for C25H35Cl2N3O3; found [M+H]+ 496.23. [0924] Scheme 21. Synthetic route for spiro analog 179 (1083744) a O O Cl a Reagents and conditions: (a) tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (169), HATU, DIPEA, DMF, 0 oC to rt, 2 h; (b) 4N HCl/dioxane, rt, 3 h; (c) chloroacetyl chloride (25), DIPEA, DCM, 0 oC to rt, 4 h. [0925] Procedure A.4-((4-chlorophenyl)amino)-2,6-dimethyltetrahydro-2H-pyran-4- carboxylic acid 103 (0.41 mmol, 1equiv) and HATU (0.49 mmol, 1.2 equiv) were dissolved in 2 ml DMF. Tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 169 (0.45 mmol, 1.1 equiv) and DIPEA (1.23 mmol, 3 equiv) were dissolved in 3 ml DMF. The solution of the amine was added to the reaction mixture under stirring. Stirring rt for 2 h. The reaction mixture was diluted with sat. NH4Cl (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with Brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (Biotage, hexane – EA, 0-100% EtOAc in hexane), confirmed with LCMS and was used directly in the next step. The obtained product was suspended in 2.0 ml HCl/dioxane (4 N) for Boc-deprotection. Stirring rt for 3h. The solvent was removed under reduced pressure and the obtained salt was used directly in the next step. The HCl salt was suspended in 2 ml dry DCM. DIPEA (4 equiv, 50 μl) was added. The reaction mixture was cooled at 0 oC and chloroacetyl chloride 25 (1.2 equiv, 20 μl) was added slowly. Stirring rt for 4 h. The reaction mixture was quenched with sat. NaHCO3 (10 ml) and extracted with DCM (3 x 10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was purified by HPLC (column C18, H2O – CH3CN + 0.05% formic acid, gradient 30-100% CH3CN in H2O, 20 min total). [0926] 2-chloro-1-(9-(4-((4-chlorophenyl)amino)-2,6-dimethyltetrahydro-2H-pyran-4- carbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one (179) 1083744 [0927] Obtained using on white solid, 47.0 mg, 24% yield (over 3 steps). HPLC retention time 11.0 min.1H NMR (400 MHz, CDCl3) δ: 7.05 (d, J = 8.9 Hz, 2H), 6.51 (d, J = 8.9 Hz, 2H), 4.01 (s, 2H), 3.85 – 3.80 (m, 3H), 3.68 – 3.64 (m, 2H), 3.58 – 3.52 (m, 2H), 3.50 – 3.45 (m, 1H), 3.37 – 3.32 (m, 2H), 2.52 – 2.50 (m, 2H), 2.23 – 2.20 (m, 1H), 1.83 – 1.78 (m, 1H), 1.69 – 1.65 (m, 1H), 1.58 – 1.48 (m, 3H), 1.44 – 1.36 (m, 4H), 1.27 – 1.24 (m, 1H), 1.17 (s, 3H), 1.16 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 171.0, 170.4, 164.9, 143.7, 129.1, 123.0, 115.5, 79.6, 70.3, 70.0, 62.1, 59.6, 44.8, 43.6, 42.0, 41.7, 41.0, 37.9, 36.1, 34.2, 30.2, 29.3, 27.3, 21.9. LCMS (ESI): m/z calcd for C25H35Cl2N3O3; found [M+H]+ 496.28. REFERENCES FOR EXAMPLES 2 AND 3 [0928] 1. Hallenbeck, K. K.; Davies, J. L.; Merron, C.; Ogden, P.; Sijbesma, E.; Ottmann, C.; Renslo, A. R.; Wilson, C.; Arkin, M. R. SLAS Discov.2018, 23 (2), 183–192. doi.org/10.1177/2472555217732072. 2. Geertjens, N. H. J.; de Vink, P. J.; Wezeman, T.; Markvoort, A. J.; Brunsveld, L. 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Chem.2015, 13 (16), 4637–4641. doi.org/10.1039/C5OB00288E. 18. Butcher, K. J.; Hurst, J. Tetrahedron Lett.2009, 50 (21), 2497–2500. doi.org/10.1016/j.tetlet.2009.03.044. Example 4: Cellular activity evaluation of stabilizers of the estrogen receptor α– 14-3-3 interaction [0929] Fully synthetic covalent stabilizers of the ERα–14-3-3 PPI induce ERα inhibition [0930] We investigated the effect of the chloroacetamides on the transcriptional activity of ERα. For this, we performed a reporter assay in MCF-7 ERα WT cells (Table 1). After transfection of ERE-luc and Renilla, the cells were treated with either 1 or 30 µM of each compound followed by 10 nM E2 stimulation. While for 30 µM FC-A and FC-NAc the luciferase signal was reduced as observed previously (42% and 62%, respectively), no effect was visible at 1 µM of either FC. The inactive compound 1080268 showed no effect in the reporter assay, as well as its phenyl-Cl derivative, 1080291. Some reduced signal was observed at 30 µM of the improved stabilizers, 1075310, 1075478, and 1075481, although this was only significant for 1075478 (47%). Impressively, 1 µL of the hit compound 1083744 reduced the luciferase signal by 57%, thereby reaching the same levels of reduction as 30 µM of FC-NAc (62%) and 100 nM of ICI (56%). Higher concentrations (30 µM) of the spiro-containing compounds (1080294, 1083744) appeared to be toxic for the MCF-7 cells. To assess the IC50 value in MCF-7 (ERα positive) and MDA-MB-231 (ERα negative cells) of each compound, a cell titer blue (CTB) viability assay was performed (Table 2). Noticeably, all chloroacetamides did affect MCF-7 cellular viability. However, for most compounds this was accompanied with a similar, or slightly reduced, effect in MDA-MB-231 cells, indicating possible off-target or cytotoxic effects. Only the spiro-containing compounds (1080294 and 1083744) did not affect the viability of MDA-MB-231 cells at their corresponding IC50 value concentration in MCF-7 cells (4 µM and 1 µM, respectively), resulting in a higher specificity. This was reflected by proliferation experiments, showing a reduction in MCF-7 cell proliferation for 1 µM of 1083744 while this concentration did not affect MDA-MB-231 cell proliferation (Table 3). The apparent cytotoxic effect at higher concentrations of the chloro- acetamides might be related to their higher affinity for 14-3-3 apo compared to the fusicoccanes. [0931] Table 1. Normalized transactivation activity (ERE-luciferase assay) of MCF-7 cells transfected with ERE-luc and Renilla in the presence of 1 µM or 30 µM of the fusicoccanes (FC-A) or the chloroacetamides. Crosses indicate dead cells. 100 nM ICI added as positive control and DMSO as negative control (n = 3 ± SD, biologically independent). Compound 1 µM 30 µM DMSO (neg. control) 8.43 ± 0.82 [0932] Table 2. Cell Titer Blue (CTB) viability assay for the selected chloro-acetamides in MDA-MB-231 cells and in MCF-7 cells (mean, n = 3 biologically independent). Compound Concentration (µM) Concentration (µM) d d f 50% ll l d d f 50% ll l [0933] Table 3. Cellular proliferation assay at 160 hours with 1 µM of 1083744 in MCF-7 or MDA-MB-231 cells (n = 2 ± SD biologically independent replicates, with each 2 technical replicates). Percentage of viable cells (%) normalized to DMSO control. Cell line 1 µM 1083744 MCF7 GR 54.3 ± 23.9 [0934] Experimental procedures [0935] Cell lines [0936] Cell lines were maintained in regular Dulbecco’s modified Eagle’s medium (DMEM) supplied with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin, and cultured at 37 °C and with 5% CO2.. Three days before all experiments requiring an E2 induction, cells were placed in hormone-depleted media. Hormone-depleted media consisted of phenol-red free DMEM (Thermo Fisher Scientific), 5% dextran and charcoal-stripped fetal bovine serum, 1% penicillin-streptomycin and 1% L-glutamate. All cell lines were tested negative for mycoplasma contamination. [0937] Cell Titer Blue (CTB) viability assay [0938] Hormone-deprived MCF-7 and MDA-MB-231 cells were seeded at 2,500 cells per well in a 96-well plate. Cells were pretreated 1h with the indicated concentration of fusicoccanes or chloro-acetamides (starting at a concentration of 50 µM, dilution 1:3) or ICI (starting at a concentration of 1 µM, dilution 1:3). After 1 hour of incubation, 10 nM of E2 was added to the wells containing the MCF-7 cells to induce proliferation. After one week of incubation, cell viability was measured by addition of resazurin according to manufacturer’s instructions (Promega). [0939] Luciferase Reporter Assay [0940] Hormone-deprived MCF-7 cells were seeded at 10,000 cells per well in a 96-well plate. Cells were transfected for 6 hours with 80 ng 3xERRE-ERE-luciferase (Addgene #37852) and 16 ng pRL-SV40P (Addgene #27163) per well using lipofectamine 3000 (Thermo Fisher), followed by an overnight treatment with the indicated concentration of fusicoccanes, chloroacetamides or ICI. The following day the cells were stimulated with the indicated concentration of E2 for 24 h, after which the ERα activity was determined with a Dual-Luciferase Reporter Assay (Promega), according to the manufacturer’s instructions. The ERE-luciferase signal was first normalized over the Renilla-luciferase signal. [0941] Proliferation assay [0942] Hormone-deprived MCF-7 cells and MDA-MB-231 cells were seeded at 2,500 cells per well in a 96-well plate. Cells were pretreated 1 h with the indicated concentration of fusicoccanes (FC) or DMSO as control, before the addition of 10 nM E2. Cell proliferation was measured kinetically every 4 hours as an increase in cell confluence. Cell confluence was determined by analysis of phase-contrast images, using the IncuCyte FLR (Essen BioScience). The algorithm used to analyze images for cell confluence was from the IncuCyte software, build 1001A Rev2. Example 5: Linked-fragment stabilizers of 14-3-3 protein-protein interactions [0943] Pharmacological intervention of PPIs is an attractive approach to modulate protein function. Whereas both convincing success stories and proven strategies exist for developing PPI inhibitors, conceptually validated approaches for targeted and specific stabilization of PPIs are scarce. However, adding to the initial description of natural product therapeutics like rapamycin and FK506 as ‘molecular glues’ (1), the tremendous success of PROTACs (PROteolysis Targeting Chimeras) and IMiDs (Immunomodulatory Drugs) have sparked significant interest in the ‘three-body-challenge’ of small-molecule PPI stabilization (1-3). While there are examples of bioactive small molecules that act by stabilizing PPIs, in the majority of cases their discovery was due to serendipity rather than prospective mechanistic insight (4). [0944] One protein class attractive for PPI stabilization is the 14-3-3 family of phosphoserine/threonine-recognizing adapter proteins. These proteins interact with several hundred partner proteins (5) and modulate the activity of disease-driving proteins e.g., Raf kinases (6-8), p53 (9-12) (cancer), Tau (13-15) (Alzheimer’s), LRRK2 (16,17) (Parkinson’s), NFκB (18,19) (Inflammation), and ExoS (20,21) (Infection). Not surprisingly, molecules able to modulate these interactions have been of significant interest for chemical biology and increasingly as guiding principles for potential therapeutic intervention (22,23). In addition to natural products (24-26), supramolecular ligands (27), and more ‘conventional’ molecules (28,29), our groups have recently proposed fragments as starting points for the development of 14-3-3 PPI stabilizers (30-33). [0945] Fragment-based drug discovery (FBDD) is a widely applied technology to find initial chemical matter in drug discovery projects. In FBDD, molecules with a molecular weight below 200 Da, which bind with low affinities in the mM range, are identified by sensitive biophysical techniques like NMR, SPR-, and X-ray crystallography. Approved drugs like the B-RAF inhibitor vemurafenib (34) and Bcl-2 inhibitor venetoclax (35) have been developed using FBDD. Although one of the promises of fragment-based development was to link neighboring fragments (36), this strategy has been described in only a few cases (37,38). Two challenging factors are identifying linking chemistry that conserves the binding orientation of the initial fragment hits and the lack of suitable neighboring pockets in many protein targets (36,39). Consequently, the vast majority of fragment optimization is achieved by ‘fragment-growing’ rather than ‘fragment-linking’ (40,41). Nonetheless, when fragment linking has worked, high affinity was rapidly achieved (36,42,43). [0946] In two previous screening campaigns, we identified fragments that bound near the interface of the adapter protein 14-3-3 with a phospho-peptide derived from the C-termini of the transcription factors ERα and p53. One class of fragments (class I) were covalent molecules identified via ‘tethering’, which employed an engineered cysteine in 14-3-3 near the ERα phospho-peptide binding site (30) (FIG.9A). These fragments stabilized the 14-3- 3/ERα complex up to 40-fold by engaging the C-terminal residue of ERα, Val595. The second group of fragments (class II), identified via soaking of 14-3-3/p53 crystals with fragment cocktails, bound to 14-3-3 further from the peptide binding site (33) (FIG.9B). Herein, we demonstrate an approach for linking a tethered and non-covalent fragment designed by co-crystallography (FIG.9C). The resulting non-covalent molecules stabilized the 14-3-3γ/ERα- phospho-peptide complex efficiently and selectively. Such compounds are promising starting points for medicinal chemistry optimization, and to the best of our knowledge, the first examples of molecular glues discovered by fragment linking. [0947] The first class of fragments, exemplified by compound 1, was ‘tethered’ via an engineered cysteine at position 42 in the 14-3-3 protein and extended a halogenated benzyl ring (chlorophenyl) into a deep composite pocket formed between 14-3-3 and the C-terminal valine of the ERα phospho-peptide (FIG.9A, FIG.9D). The other class of fragments consisted of a benzo[b]thiophene-2-carboximidamide (Core A) or a 4-phenylthiophene-2- carboximidamide (Core B) (FIG.9B, FIG.9D, FIG.14). Soaking the thiophene-containing fragments (A-1–A-3 and B-1–B-3) into 14-3-3/ERα co-crystals revealed engagement of their amidine functional group with Glu14 of 14-3-3 via a salt-bridge, defining the primary anchoring point of these fragments (44) (FIGS.15A-15G). To determine if fragments bound compatibly with compound 1, 14-3-3/ERα crystals were soaked with compound 1 and the class II fragments. Comparison of the single benzothiophene soaks with their compound 1 co- soaks, revealed a slight tilt of the benzo[b]thiophene fragments to prevent a steric clash, while the conformation of compound 1 remained unchanged (FIGS.16A-16C). In this turned conformation, the binding sites of the two fragment groups lay next to each other, with a distance of 3 to 4 Å (FIG.9E, FIGS.16D-16F). [0948] Based on the structural information of the co-soaks, we designed four benzothiophene-containing linkers with varying linker length and rigidity (fragments 2-5), to retain key binding elements, including the amidine-mediated binding to Glu14 of 14-3-3 and the positioning of the p-chlorophenyl ring towards the C-terminal valine of ERα (FIG.10A). Only 5 showed partial electron density for the benzothiophene and the p-chlorophenyl building blocks of the hybrid molecule (FIG.10B). Overlaying its structure with the single and co-soaks of the benzothiophene cores (FIG.17) revealed that the orientation of the benzothiophene in the hybrid molecule was partway between its orientation in single and co- soaked structures. The p-chlorophenyl ring of 5 also adopted a different conformation than compound 1 (FIG.10C). These slightly different positions of the building blocks compared to their single soaks were likely not their preferred conformations, explaining the lack of density found for the linker of 5. [0949] To increase flexibility, we designed three alternative linkers (fragments 6-8) containing phenylthiophene constructs (FIG.10D). Excitingly, continuous electron density was visible for the phenylthiophene compound 6 (FIG.10E), which also showed modest stabilization of 14-3-3/ERα in the high μM to mM range (FIG.18A). Of note, the synthesis intermediate 7 amidoxime was not active in the assay tested nor was the carboxamide replacement of the amidine (8) (FIG.18A). A crystallographic overlay of the hybrid molecule 6 with the single phenyl-thiophene soaks (FIG.18B) and compound 1 (FIG.10F) revealed that indeed the primary binding modes of the original individual fragments were largely conserved in the linked fragment. We therefore synthesized analogs of the scaffold with the aim of improving its stabilization properties. A Fluorescence Anisotropy (FA) assay was used to analyze the stabilizing properties of the linked fragments. Compounds were titrated in the presence of 14-3-3σ and FAM-labeled ERα phospho-peptide. For stabilizers, a dose- dependent increase in anisotropy was expected. It is noteworthy that for several linked fragments we observed an increase in anisotropy in the absence of 14-3-3, indicative of spectroscopic interference or compound-induced aggregation of the peptide. We crystallized twenty of the synthesized linked fragments; hence chemical optimization was mainly guided by crystallography. Improved compounds from the series stabilized 14-3-3/ERα binding without significantly interfering with anisotropy in the absence of protein. [0950] We evaluated the structure-activity relationships (SAR) by inspection of the crystal structure of 6 (FIGS.19A-19B). We hypothesized that a modification of the chlorophenyl building block was most likely to improve stabilization efficiency because it interacted with both 14-3-3 and the ERα phospho-peptide. The gem-dimethyl made hydrophobic interactions with the side chain of Val595 of ERα as well as Leu218 and Ile219 of 14-3-3. Furthermore, the chlorophenyl moiety was buried in a hydrophobic pocket formed by Phe119, Pro167, Ile168 and Gly171 of 14-3-3 and Val595 of ERα. Based on these observations, we made the following chemical modifications: introducing an amine instead of an ether (Y), changing the chemical nature of the para (W) and meta (V) substituent on the phenyl ring and, finally, replacing the gem-dimethyl group with larger cyclic groups (X) (FIG.11). [0951] Exchanging the ether to an amine at position Y (9) resulted in a similar binding conformation with a slightly weaker stabilization effect (FIG.20A). The chlorophenyl moiety buried between the +1 amino acid of the ERα phospho-peptide and 14-3-3 appeared to play an important role for binding of the linked fragment to the protein/peptide complex. When removing this substituent in either the ether (10) or the amine variant (11) of the hybrid molecules, the phenyl ring was less anchored resulting in a reduction of electron density (FIGS.20B-20C). We tested the influence of the substitution of the phenyl ring by changing the chemical nature of the para substituent and preparing different combinations of halogen substituents. Exchanging the chloride with bromide (12) or trifluoromethyl (13), had no effect on the conformation of the linked fragment nor on that of Lys122 of 14-3-3 (FIGS.21A- 21B). The same held true for an additional halogen decoration in the meta position as in 14 (chloro) and 15 (fluoro) (FIGS.21C-21D). [0952] Deep in the chlorophenyl-accepting pocket, Lys122 was close (4 Å) to the chloride position in 6, hinting at the possibility that the introduction of an oxygen functionality could result in a positive polar contact with the terminal amino group of Lys122. However, changing the chloride substituent for an acetyl in 16 resulted in a substantial decline of the quality of the electron density map (FIG.21E) and did not lead to the engagement of Lys122. Substitution of a methoxy group at the para position (17) improved electron density (FIG. 21F), with the distance of the oxygen to the amine of Lys122 being reduced to3.3 Å. No density was visible for the para substitution of the carboxylic acid group (18). [0953] We next focused on the gem-dimethyl (position X) which was in close proximity to a hydrophobic patch in the ‘roof’ of the14-3-3 channel, including Leu218 and Ile219, and the hydrophobic side chain of Val595 of ERα (FIG.22A). Derivatives with successive extensions of the gem-dimethyl moiety- were synthesized and soaked into crystals of the 14- 3-3σ/ERα phospho-peptide complex. Four-, five-, and six-membered rings (19-21, respectively) were well tolerated and produced high-occupancy crystal structures with clear density for the entirety of the molecules (FIGS.22B-22D). [0954] In addition to purely hydrocarbon extensions, three compounds were synthesized with a heteroatom, including a tetrahydropyran moiety (22), a piperidine (23), and a 4- aminocyclohexyl group (24) at position X. All three compounds showed complete electron density coverage (FIG.23); however, the amino-cyclohexyl group in 24 seemed to be less well-defined. Interestingly, these compounds did not result in the undesirable increase in anisotropy in the control experiments lacking 14-3-3, while showing clear 14-3-3/ERα phospho-peptide stabilization (FIG.12A). The additional water-solubilizing functionality at position X might thus have enhanced solubility and decreased aggregation potential. The amine variant of the piperidine ring was also synthesized (25) and showed a similar stabilization efficiency and electron density (FIG.12A, FIG.23). A more detailed analysis of the binding modes revealed that the introduction of a hydrogen bond acceptor (22) or donor (23, 24, 25) in the cyclohexyl group allowed for participation in a water network, thereby enabling water-mediated interactions with the terminal carboxyl group of Val595 or the carbonyl oxygen of ERα (FIG.12B). These introduced polar interactions facilitated interactions with both 14-3-3 and ERα, likely leading to the stabilization observed in FA. [0955] Surprisingly, removal of the chloro group from the phenyl substituent in the presence of an unsubstituted cyclohexyl (26), 4,4-difluorocyclohexane (27) or a tetrahydropyran (28) resulted in a switch of the ring systems, wherein the unsubstituted terminal benzene moved out of the interface pocket between 14-3-3 and the peptide and was replaced by the ring introduced at the gem-dimethyl position (FIGS.24A-24C). In the case of the 4,4-difluorocyclohexane analog, even the re-introduction of the chloro-substituent with the 4,4-difluorocyclohexane at position X (29) was not able to reverse this switch (FIG.24D), again highlighting the strong preference for halogen decorations for this interface pocket. Additionally, this switch in ring systems caused three other structural effects: (i) in the case of the cyclohexyl (26) and the difluoro-cyclohexyl (27) compounds, density was observed for an alternative conformation of Val595 of ERα, pointing towards the compound (FIGS.24A- 24B); (ii) the ether and the nitrogen of the amine of the compounds lacking the p-chloro substitution were now able to participate in a water network, allowing for water-mediated bonds with the C-terminal carboxyl group of ERα (FIG.24E); and (iii) the difluoro-group of 27 interacted directly with Lys122 of 14-3-3 and the carboxy group of ERα, with a distance of 3.2 Å and 2.8 Å, respectively (FIG.24F). These compounds provide promising chemical starting points that could be matured into more potent stabilizers, for example, by introducing a hydrogen bond donor or acceptor in the phenyl ring of 27 to allow for more polar contacts with ERα and 14-3-3. [0956] We further evaluated the most potent analogs (23, 24, and 25; EC50 values 118 μM, 151 μM, and 143 μM, respectively) via FA 2D-protein titration with these compounds (FIG. 13A).14-3-3γ was titrated to FAM-labeled ERα phospho-peptide (10 nM) in the presence of varied concentrations of each compound, resulting in a 21-fold, 25-fold and 15-fold maximum increase in PPI stabilization at 500 µM of 23, 24 and 25, respectively. The most potent stabilizer, 24, was evaluated for its selectivity versus ten representative 14-3-3 client- derived phospho-peptide motifs (FIG.13B). These motifs were selected based on their distinct binding sequences. Compound titrations showed a high selectivity for ERα, which can be explained by the structural overlay of 24 with each peptide client (FIG.25), showing steric clashes with almost all other peptides. [0957] The stabilization of linked compounds with the 14-3-3/ERα interface is driven by a number of polar and hydrophobic contacts, as exemplified by compound 24 (FIG.13C). The most prominent polar interaction is the salt-bridge between compound 24’s amidine moiety and the side chain of 14-3-3’s Glu14. Furthermore, water-mediated contacts between compound 24’s amidine and Glu39 and Ser45 of 14-3-3 and the water network involving Glu115 and Asp215 are established by the carbonyl oxygen and the linker nitrogen and oxygens of 24. At the site of the ERα interface, the introduced amino group at the cyclohexyl of 24 interacts with a water network involving the backbone of 14-3-3 and the carboxyl terminus of ERα. Important hydrophobic interactions are mediated by the cyclohexyl and the side chains of Val595 of ERα as well as Leu218 and Ile219 of 14-3-3σ. The p-chlorophenyl moiety is buried in a hydrophobic pocket formed by Phe119, Pro167, Ile168 and Gly171 of 14-3-3 and Val595 of ERα phospho-peptide. Finally, the thiophene and linked benzyl ring is resting on a hydrophobic cushion formed by the hydrocarbon part of Asn42. [0958] We have illustrated the potential of fragment linking for the development of molecular glues. Our approach utilized one stabilizing covalent fragment and one neutral binding, non-covalent fragment as well as crystallography of the quaternary complex containing 14-3-3, ERα phospho-peptide, and both fragments. The co-crystallization allowed for a linker design that conserved the orientations of the individual fragments at the 14-3- 3/ERα interface. These initial linked compounds were rapidly developed into more potent and selective stabilizers of the 14-3-3/ERα interaction, making this approach very attractive for the rational design of PPI stabilizers for 14-3-3 PPIs and beyond. 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Example 6: Experimental procedures for Example 5 [0960] Protein expression and purification [0961] The 14-3-3γ and σ full-length isoforms (for fluorescence anisotropy assays) and 14- 3-3σ isoform lacking the C-terminus (amino acids 1-231; for crystallography) were cloned into pPROEX HTb expression vector with an N-terminal His6 tag. Plasmids were transformed following manufacturer’s instructions into RosettaTM 2(DE3)pLysS competent E. coli (Novagen). Single colonies were picked and inoculated in 30 mL precultures grown in LB media overnight at 37 °C. Inoculations were then added to 1.5 L terrific broth (TB) medium. Expression was induced upon reaching OD6001.9−2.1 by adding 400 μM IPTG. After overnight expression at 30°C, 150 rpm, cells were harvested by centrifugation at 6,500 rpm, resuspended in lysis buffer (50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 10% glycerol, 1 mM TCEP), and lysed by sonication. The His6-tagged protein was purified by Ni-affinity chromatography (Ni-NTA Agarose, Invitrogen) (Wash buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 1 mM TCEP; Elution buffer 50 mM HEPES pH 7.5, 500 mM NaCl, 500 mM imidazole, 1 mM TCEP) and analyzed for purity by SDS-PAGE and Q-Tof LC/MS. The protein was buffer exchanged (Storage buffer 25 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP) and concentrated to ~67 mg/mL and aliquotsflash-frozen for storage at −80 °C. After Ni-affinity chromatography, the crystallography construct was treated with TEV protease to cleave off the His6 tag during dialysis (25 mM HEPES, pH 7.5, 200 mM NaCl, 5% glycerol, 10 mM MgCl2, 250 µM TCEP) overnight at 4°C. The flow- through of a second Ni-affinity column was subjected to a final purification step by size exclusion chromatography (Superdex 75 pg 16/60 size exclusion column (GE Life Science) (SEC buffer: 25 mM HEPES pH 7.5, 100 mM NaCl, 10 mM MgCl2, 250 µM TCEP). The protein was concentrated to ~60 mg/mL, analyzed for purity by SDS-PAGE and Q-Tof LC/MS and aliquots were flash-frozen for storage at -80 °C. [0962] Peptide sequences [0963] Acetylated ERα phospho-peptide for X-ray crystallography and FAM-labeled peptides were ordered from GenScript Biotech Corp. Sequences were: ERα: Ac- or 5-FAM-AEGFPA(pT)V-COOH (SEQ ID NO: 2) p65: 5-FAM-EGRSAG(pS)IPGRRS-CONH2 (SEQ ID NO: 4) SOS1: 5-FAM-PRRRPE(pS)APAESS-CONH2 (SEQ ID NO: 5) USP8: 5-FAM-KLKRSY(pS)SPDITQ-CONH2 (SEQ ID NO: 6) B-RAF: 5-FAM-RDRSS(pS)APNVH-CONH2 (SEQ ID NO: 7) FOXO1: 5-FAM-RPRSC(pT)WPLPR-CONH2 (SEQ ID NO: 8) Pin1: 5-FAM-LVKHSQSRRPS(pS)WRQEK-CONH2 (SEQ ID NO: 9) EXOS: 5-FAM-KKLMFK(pT)EGPDSD-CONH2 (SEQ ID NO: 10) ChREBP: 5-FAM-RDIRLNNAIWRAWYIQYVQR-CONH2 (SEQ ID NO: 11) [0964] Compounds [0965] Compound 1 was synthesized and analyzed as described previously (1). [0966] Amidine fragments (Core A and Core B) were obtained from a library of AstraZeneca Pharma as 100 mM DMSO stocks, as described previously (2,3). [0967] Synthesis and analysis of linked fragments (compound 2 – 29) are described in Example 7. [0968] Fluorescence anisotropy measurements [0969] Fluorescein-labelled peptides (5-FAM), 14-3-3σ FL protein, the compounds (100 mM stock solution in DMSO) were diluted in buffer (10 mM HEPES, pH 7.5, 150 mM NaCl, 0.1% Tween20, 1 mg/mL Bovine Serum Albumin (BSA; Sigma-Aldrich). Final DMSO in the assay was always 1%. Dilution series of 14-3-3 proteins or compounds were made in black, round-bottom 384-microwell plates (Corning) in a final sample volume of 10 µL in triplicates. [0970] Compound titrations were made by titrating the compound in a 2-fold dilution series (starting at 1 mM) to a mix of fluorescein-labelled peptide (10 nM) and 14-3-3γ (concentration at EC20 value of the protein-peptide complex; 0.25 µM for ERα, 0.45 µM for C-RAF, 30 µM for p65, 0.35 µM for SOS1, 0.25 µM for USP8, 0.23 µM for B-RAF, 0.002 µM for FOXO1, 10 µM for PIN1, 4 µM for EXOs, 0.15 µM for ChREBP). Fluorescence anisotropy measurements were performed immediately after. [0971] Protein 2D titrations were made by titrating 14-3-3γ in a 2-fold dilution series (starting at 500 µM) to a mix of fluorescein-labelled peptide (10 nM) against varying fixed concentrations of compound (2-fold dilution, starting at 250 µM), or DMSO. Fluorescence anisotropy measurements were performed immediately after. [0972] Fluorescence anisotropy values were measured using a Tecan Infinite F500 plate reader (filter set lex: 485 ± 20 nm, lem: 535 ± 25 nm; mirror: Dichroic 510; flashes:20; integration time: 50 ms; settle time: 0 ms; gain: 55; and Z-position: calculated from well). Wells containing only FAM-peptide were used to set as G-factor at 35 mP. Data reported are at endpoint. EC50 and apparent Kd values were obtained from fitting the data with a four- parameter logistic model (4PL) in GraphPad Prism 7 for Windows. Data was obtained and averaged based on two independent experiments. [0973] X-Ray crystallography data collection and refinement [0974] 14-3-3σ protein (residues 1-231; 470 µM, 12.5 mg/mL) was mixed with ERα phospho-peptide (1:2 molar stoichiometry; 940 µM) and incubated in crystallization buffer (20 mM HEPES pH 7.4, 2 mM MgCl2, 2 mM BME) for a few minutes at RT before setting up sitting drop crystallization in MRC crystallization plates (Swissci) with a custom crystallization liquor grid (0.095 M HEPES (pH 7.1, 7.3, 7.5, 7.7), 0-19 M CaCl2, 5% glycerol, 24-29% PEG 400). Crystals grew at 4 °C within 1 week. Soaking of crystals was performed by mixing 0.4 µL of compound from 100 mM stock solutions in DMSO in 3.6 µL mother liquor and adding this to crystal-containing drops. Soaked crystals were fished after overnight incubation and flash-frozen in liquid nitrogen. X-ray diffraction (XRD) data were collected at either an in-house system Rigaku Micromax-003 (Rigaku, Europe, Kemsing Sevenoaks, UK) equipped with an Dectris Pilatus 200K detector, the Deutsche Elektronen- Synchrotron (DESY) Petra III beamline P11, Hamburg, Germany, the European Synchrotron Radiation Facility (ESRF Grenoble, France, beamline ID23-1 or ID30A-1/MASSIF-1), or at Diamond Light Source (DLS) (Oxfordshire, United Kingdom, beamline I 24). Data was processed using the CCP4i2 suite (version 8.0.002) (4). Data integration was done using Xia2Dials (5). The data was phased with MolRep (6), using 4JC3 as a template. Presence of soaked ligands was verified by visual inspection of the Fo-Fc and 2Fo-Fc electron density maps in COOT (version 0.9.6) (7). eLBOW (8) was used to generate the structures and restraints of the soaked ligands, followed by model rebuilding and refinement using phenix.refine (9,10) from the Phenix software suite (version 1.19.2-4158) and Coot. The images were created using the PyMOL Molecular Graphic System (Schrödinger LLC, version 2.2.3). [0975] The structures were deposited in the protein data bank (PDB) with IDs: 8BZ9 (A-1), 8BZ0 (A-2), 8BYZ (A-3), 8BZA (B-1), 8C4F (B-2), 8C4G (B-3), 8BZW (1+A-3), 8BZB (1+A-2), 8C04 (1+A-1), 8BYG (5) , 8BYF (6), 8BYY (9) 8BXI (10), 8BXM (11), 8BX3 (12), 8BWJ (13), 8BX4 (14), 8BYO (15), 8BWZ (16), 8BX0 (17), 8BYE (19), 8BYD (20), 8BYB (21), 8BXS (22), 8C0K (23), 8BWX (24), 8BYC (25), 8BXQ (26), 8BXO (27), 8BXN (28), 8BY9 (29). [0976] Software [0977] Prism (7.00), Adobe Illustrator (27.1), Pymol (2.2.3), CCP4i2 (8.0.003), COOT (0.9.8.1), Phenix (1.19.2 – 4158). Example 7: Synthetic procedures for Example 5 [0978] General methods [0979] Unless otherwise noted all chemical reagents and solvents used are commercially available. 1-(4-chlorophenoxy)cyclohexane-1-carboxylic acid and 4-phenoxytetrahydro-2H- pyran-4-carboxylic acid were purchased from Enamine. Compounds prepared using Method E were synthesized by ChemPartner, Chengdu (China). Air and/or moisture sensitive reactions were carried out under an argon atmosphere in oven-dried glassware using anhydrous solvents from commercial suppliers. Air and/or moisture sensitive reagents were transferred via syringe or cannula and were introduced into reaction vessels through rubber septa. Solvent removal was accomplished with a rotary evaporator at ca.10-50 Torr.1H NMR spectra were recorded on a Varian INOVA-400400 MHz spectrometerand Bruker Avance III HD 400 MHz spectrometer. Chemical shifts are reported in ^ units (ppm). NMR spectra were referenced relative to residual NMR solvent peaks. Coupling constants (J) are reported in hertz (Hz). Hydrogenation reactions were carried out in ThalesNano H-Cube reactor using 30 mm catalyst cartridges. Column chromatography was carried out using Isolera Four flash chromatography system and SiliaSep silica gel cartridges from Silicycle. Reverse phase chromatography was carried out on Waters 2535 Separation module with Waters 2998 Photodiode Array Detector. Separations were carried out on XBridge Preparative C18, 19 x 50 mm column at ambient temperature using a mobile phase of water- methanol containing a constant 0.05% formic acid. LC/MS data were acquired either on a Waters Micromass ZQ mass spectrometer equipped with Waters 2795 Separation Module, Waters 2424 Evaporative Light Scattering Detector and Waters 2996 Photodiode Array Detector Waters or Waters Acquity UPLC QDa mass spectrometer equipped with Quaternary Solvent Manager, Photodiode Array Detector and Evaporative Light Scattering Detector. Separations were carried out with XTerra ^ MS C18, 5 ^m, 4.6 x 50 mm column, at ambient temperature (unregulated) using a mobile phase of water-methanol containing a constant 0.1 % formic acid or Acquity UPLC ^ BEH C181.7 ^m, 2.1 x 50 mm column at 25 oC, using a mobile phase of water-acetonitrile containing a constant 0.1 % formic acid. [0980] Method A (Amide Synthesis) [0981] To a solution of amine (1 equiv.) in DMF, was added the carboxylic acid (1 equiv.), HATU (1.1 equiv.) and DIEA (3 equiv.). After stirring at room temperature for 18 h, the reaction mixture was diluted with ethyl acetate. Washed with saturated aqueous solution of ammonium chloride, water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography to obtain the product. [0982] Method B (Amidine deprotection) [0983] To a solution of the 1,2,4-oxadiazolin-5-one compound (1 equiv.) in glacial acetic acid, was added zinc (20 equiv.) and stirred at 70 oC for 18 h. The reaction mixture was diluted water, adjusted to pH 7 with 10% aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, concentrated under reduced pressure, and purified by reverse phase HPLC to obtain the product. [0984] Method C (2-(Phenoxy)-2-methylpropanoic acid building block synthesis) [0985] To a mixture of ethyl-2-bromobutyrate (1 equiv.) and potassium carbonate (2 equiv.) in DMF, was added the corresponding phenol (0.9 equiv.). After stirring at 70 oC for 18 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography to obtain the product. [0986] Method D (Ester hydrolysis) [0987] To a solution of the ester (1 equiv.) in a mixture of MeOH/THF/water (2:1:1), was added 1M aqueous solution of lithium hydroxide (2 equiv.) and stirred at 50 oC for 18 h. The reaction mixture was concentrated to remove the organic solvents, diluted with water, adjusted to pH 2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain the product carboxylic acid. [0988] Method E (Bargellini reaction) [0989] To a cooled (0 oC) solution of 4-chlorophenol or phenol (1 equiv.) in tetrahydrofuran, were added the ketone (3 equiv.), sodium hydroxide (5 equiv. ) and chloroform (5 equiv.) dropwise. After the stirring at room temperature for 18 h, the reaction mixture was diluted with water and extracted with dichloromethane. The aqueous layer was adjusted to pH 2 with 2N aqueous hydrochloric acid and extracted with dichloromethane/methanol (10:1), washed with brine, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude which was recrystallized with ethyl acetate/petroleum ether (1:4) to obtain the product. [0990] 2-(4-Bromophenoxy)-2-methylpropanoic acid [0991] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17 g, 1.26 mmol) in DMF (0.5 mL), was added 4-bromophenol (98 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 60 mg (37%) of ethyl 2-(4-bromophenoxy)-2-methylpropanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.3-7.4 (m, 2H, J=9.0 Hz), 6.7-6.8 (m, 2H, J=9.0 Hz), 4.24 (q, 2H, J=7.1 Hz), 1.60 (m, 6H), 1.26 (t, 3H, J=7.2 Hz). LC-MS: m/z = 287, 289 [M+H]+. [0992] To a solution of ethyl 2-(4-bromophenoxy)-2-methylpropanoate (57 mg, 0.2 mmol)) in a mixture of MeOH/THF/water (2:1:1, 2 mL), was added 1 M aqueous solution of lithium hydroxide (0.4 mL, 0.4 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 51 mg of crude 2-(4-bromophenoxy)-2- methylpropanoic acid as a pale yellow solid which was used without further purification.1H NMR (CDCl3, 400 MHz) δ 7.40 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=9.0 Hz), 1.63 (s, 6H). LC- MS: m/z = 282 [M+Na]+. [0993] 2-(4-Acetylphenoxy)-2-methylpropanoic acid [0994] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17g, 1.26 mmol) in DMF (0.5 mL), was added 4-acetylphenol (78 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 45 mg (31%) of ethyl 2-(4-acetylphenoxy)-2-methylpropanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.89 (d, 2H, J=8.0 Hz), 6.84 (d, 2H, J=8.0 Hz), 4.24 (d, 2H, J=7.1 Hz), 2.56 (s, 3H), 1.66 (s, 6H), 1.23 (t, 3H, J=7.1 Hz). LC-MS: m/z = 251 [M+H]+. [0995] To a solution of ethyl 2-(4-acetylphenoxy)-2-methylpropanoate (45 mg, 0.18 mmol)) in a mixture of MeOH/THF/water (2:1:1, 4 mL), was added 1 M aqueous solution of lithium hydroxide (0.36 mL, 0.36 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 40 mg of crude 2-(4- acetylphenoxy)-2-methylpropanoic acid as a brown oil which was used without further purification.1H NMR (CDCl3, 400 MHz) δ 7.92 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.8 Hz), 2.58 (s, 3H), 1.71 (s, 6H). [0996] 2-(4-Methoxyphenoxy)-2-methylpropanoic acid [0997] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17g, 1.26 mmol) in DMF (0.5 mL), was added 4-methoxyphenol (71 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 71 mg (52%) of ethyl 2-(4-methoxyphenoxy)-2-methylpropanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 6.78-6.87 (m, 4H), 4.26 (q, 2H, J=7.1 Hz), 3.77 (s, 3H), 1.30 (t, 3H, J=7.1 Hz). LC-MS: m/z = 239 [M+H]+. [0998] To a solution of ethyl 2-(4-methoxyphenoxy)-2-methylpropanoate (51 mg, 0.21 mmol)) in a mixture of MeOH/THF/water (2:1:1, 2 mL), was added 1 M aqueous solution of lithium hydroxide (0.42 mL, 0.42 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 45 mg of crude 2-(4- methoxyphenoxy)-2-methylpropanoic acid as a yellow oil which was used without further purification. [0999] 2-Methyl-2-(4-(trifluoromethyl)phenoxy)propanoic acid [1000] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17g, 1.26 mmol) in DMF (0.5 mL), was added 4-trifluoromethylphenol (92 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 21 mg (13%) of ethyl 2-methyl-2-(4- (trifluoromethyl)phenoxy)propanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.52 (m, 2H, J=8.5 Hz), 6.90 (m, 2H, J=8.5 Hz), 4.25 (q, 2H, J=7.1 Hz), 1.66 (s, 6H), 1.25 (t, 3H, J=7.2 Hz). [1001] To a solution of ethyl 2-methyl-2-(4-(trifluoromethyl)phenoxy)propanoate (21 mg, 0.076 mmol)) in a mixture of MeOH/THF/water (2:1:1, 1.2 mL), was added 1 M aqueous solution of lithium hydroxide (0.15 mL, 0.15 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 17 mg of crude 2- methyl-2-(4-(trifluoromethyl)phenoxy)propanoic acid as an off-white solid which was used without further purification.1H NMR (CDCl3, 400 MHz) δ 7.55 (br d, 2H, J=7.8 Hz), 6.99 (br d, 2H, J=8.3 Hz), 1.6-1.8 (m, 6H). [1002] 2-(4-(tert-Butoxycarbonyl)phenoxy)-2-methylpropanoic acid [1003] To a mixture of 0.63 mmol) and potassium carbonate (0.17 g, 1.26 mmol) in DMF (1 mL), was added tert-butyl 4-hydroxybenzoate (0.19 g, 0.98 mmol). After stirring at 70 oC for 60 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (0- 60% ethyl acetate/hexanes) to obtain 130 mg (43%) of tert-butyl 4-((1-ethoxy-2-methyl-1- oxopropan-2-yl)oxy)benzoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.90 (d, 3H, J=9.0 Hz), 6.82 (d, 2H, J=7.7 Hz), 4.24 (q, 2H, J=7.1 Hz), 1.65 (s, 6H), 1.59 (s, 9H), 1.24 (t, 3H, J=7.2 Hz). [1004] To a solution of tert-butyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)benzoate (0.13 g, 0.42 mmol)) in a mixture of MeOH/THF/water (2:1:1, 4 mL), was added 1 M aqueous solution of lithium hydroxide (0.84 mL, 0.84 mmol) and stirred at 50 oC for 5 h. The reaction mixture was treated to conditions described in Method D to obtain 80 mg of crude 2- (4-(tert-butoxycarbonyl)phenoxy)-2-methylpropanoic acid as a beige solid which was used without further purification.1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 2H, J=8.8 Hz), 6.90 (br d, 2H, J=8.8 Hz), 1.68 (m, 6H), 1.59 (s, 9H). [1005] 2-(4-Chloro-3-fluorophenoxy)-2-methylpropanoic acid O OH [1006] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17g, 1.26 mmol) in DMF (0.5 mL), was added 3-fluoro-4-chlorophenol (84 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 56 mg (38%) of ethyl 2-(4-chloro-3-fluorophenoxy)-2- methylpropanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.22-7.28 (m, 1H), 6.70 (dd, 1H, J=2.9, 10.7 Hz), 6.60 (td, 1H, J=1.4, 8.8 Hz), 4.26 (q, 2H, J=7.1 Hz), 1.61 (s, 6H), 1.27 (t, 3H, J=7.2 Hz). LC-MS: m/z = 260 [M+H]+. [1007] To a solution of ethyl 2-(4-chloro-3-fluorophenoxy)-2-methylpropanoate (53 mg, 0.2 mmol)) in a mixture of MeOH/THF/water (2:1:1, 2 mL), was added 1 M aqueous solution of lithium hydroxide (0.4 mL, 0.4 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 42 mg of crude 2-(4-chloro-3- fluorophenoxy)-2-methylpropanoic acid as a colorless oil which was used without further purification.1H NMR (CDCl3, 400 MHz) δ 7.26-2.28 (m, 1H), 6.77 (br d, 1H, J=9.5 Hz), 6.68 (br d, 1H, J=7.5 Hz), 1.64 (s, 6H). [1008] 2-(3,4-Dichlorophenoxy)-2-methylpropanoic acid O OH [1009] To a mixture of ethyl-2- mL, 0.63 mmol) and potassium carbonate (0.17g, 1.26 mmol) in DMF (0.5 mL), was added 3,4-dichlorophenol (93 mg, 0.57 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 48 mg (30%) of ethyl 2-(3,4-dichlorophenoxy)-2- methylpropanoate as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 7.28-7.32 (m, 1H), 7.00 (d, 1H, J=2.9 Hz), 6.72 (dd, 1H, J=2.8, 8.9 Hz), 4.26 (q, 2H, J=7.1 Hz), 1.61 (s, 6H), 1.28 (t, 3H, J=7.1 Hz). [1010] To a solution of ethyl 2-(3,4-dichlorophenoxy)-2-methylpropanoate (44 mg, 0.2 mmol)) in a mixture of MeOH/THF/water (2:1:1, 1.6 mL), was added 1 M aqueous solution of lithium hydroxide (0.32 mL, 0.32 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D to obtain 40 mg of crude 2-(3,4- dichlorophenoxy)-2-methylpropanoic acid as a yellow oil which was used without further purification. [1011] 2-((4-chlorophenyl)amino)-2-methylpropanoic acid [1012] To a mixture of 2- (65 mg, 0.62 mmol), 4- bromochlorobenzene (0.1 g, 0.52 mmol) and cesium carbonate (0.34 g, 1.04 mmol) in DMF (1 mL), was added 2-isobutyrylcyclohexan-1-one (17 mg, 0.1 mmol) and copper (I) iodide (5 mg, 0.026 mmol). After stirring at room temperature for 48 h, the reaction mixture was taken in ethyl acetate and water. The aqueous phase was adjusted to about pH 4 with 1 N aqueous hydrochloride solution and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash chromatography (0-10% methanol/dichloromethane) to obtain about 20 mg (18%) of 2-((4- chlorophenyl)amino)-2-methylpropanoic acid as a brown oil. LC-MS: m/z = 214,216 [M-H]+. [1013] 1-(4-Chlorophenoxy)cyclobutane-1-carboxylic acid [1014] To a mixture of ethyl 1- (0.2 g, 1.0 mmol) and potassium carbonate (0.3 g, 2.0 mmol) in DMF (5 mL), was added 4-chlorophenol (0.1 g, 1.0 mmol). After stirring at 70 oC for 18 h, the reaction mixture was treated to conditions described in Method C and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 95 mg of crude ethyl 1-(4-chlorophenoxy)cyclobutane-1- carboxylate which was used without further purification. [1015] To a solution of ethyl 1-(4-chlorophenoxy)cyclobutane-1-carboxylate (95 mg, 0.37 mmol)) in a mixture of MeOH/THF/water (2:1:1, 4 mL), was added 1 M aqueous solution of lithium hydroxide (0.75 mL, 0.75 mmol) and stirred at 50 oC for 5 h. The reaction mixture was treated to conditions described in Method D to obtain 70 mg of crude 1-(4- chlorophenoxy)cyclobutane-1-carboxylic acid which was used without further purification1H NMR (CDCl3, 400 MHz) δ 7.22-7.24 (m, 2H), 6.66 (d, 2H, J=9.0 Hz), 2.76-2.80 (m, 2H), 2.48-2.54 (m, 2H), 2.02-2.11 (m, 2H). LC-MS: m/z = 225,227 [M-H]+. [1016] 1-(4-Chlorophenoxy)cyclopentane-1-carboxylic acid [1017] 4-Chlorophenol (0.5 g, to conditions described in Method E to obtain 110 mg (10%) of 1-(4-chlorophenoxy)cyclopentane-1-carboxylic acid as a light yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 7.18 (d, 2H, J=9.2 Hz), 6.71 (d, 2H, J=9.0 Hz), 2.12-2.18 (m, 2H), 1.83-1.86 (m, 2H), 1.60-1.63 (m, 4H). [1018] 4-(4-Chlorophenoxy)tetrahydro-2H-pyran-4-carboxylic acid [1019] 4-Chlorophenol (0.5 g, to conditions described in Method E to obtain 110 mg (11%) of 4-(4-chlorophenoxy)tetrahydro-2H-pyran-4-carboxylic acid as a white solid.1H NMR (DMSO-d6, 400 MHz) δ 13.37 (br s, 1H), 7.35 (d, 2H, J=3.2 Hz), 6.88 (d, 2H, J=8.8 Hz), 3.57-3.68 (m, 4H), 1.92-2.08 (m, 4H). LC-MS: m/z = 255,257 [M-H]+. [1020] 1-(tert-Butoxycarbonyl)-4-(4-chlorophenoxy)piperidine-4-carboxylic acid [1021] 4-Chlorophenol (0.51 to conditions described in Method E to obtain 250 mg (18%) of 1-(tert-butoxycarbonyl)-4-(4- chlorophenoxy)piperidine-4-carboxylic acid as a white solid.1H NMR (DMSO-d6, 400 MHz) δ 13.45 (br s, 1H), 7.34 (d, 2H, J=6.8 Hz), 6.89 (d, 2H, J=6.8 Hz), 3.68-3.71 (m, 2H), 2.96- 3.14 (m, 2H), 1.98-2.03 (m, 2H), 1.83-1.92 (m, 2H), 1.39 (s, 9H). [1022] 4-((tert-Butoxycarbonyl)amino)-1-(4-chlorophenoxy)cyclohexane-1-carboxylic acid [1023] 4-Chlorophenol (0.38 g, to conditions described in Method E to obtain 110 mg (10%) of 4-((tert-butoxycarbonyl)amino)-1-(4- chlorophenoxy)cyclohexane-1-carboxylic acid as a white solid.1H NMR (DMSO-d6, 400 MHz) δ 13.14 (br s, 1H), 7.29-7.34(m, 2H), 6.84-6.94 (m, 2H), 3.44-3.45 (m, 1H), 2.14-2.20 (m, 2H), 1.67-1.77 (m, 4H), 1.37-1.48 (m, 11H). [1024] 1-(tert-Butoxycarbonyl)-4-((4-chlorophenyl)amino)piperidine-4-carboxylic acid [1025] To a cooled (0 oC) mg, 3.92 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (2.34 g, 11.76 mmol) and sodium hydroxide (0.78 g, 19.6 mmol) in tetrahydrofuran (50 mL) was added chloroform (2.34 g, 19.6 mmol) dropwise. After stirring at room temperature for 18 h, the reaction mixture was diluted with water and extracted with dichloromethane. The aqueous phase was adjusted to pH 2 with 2 N aqueous hydrochloric acid and extracted with dichloromethane/methanol (10:1), washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude, which was recrystallized from ethyl acetate/petroleum ether (1:4) to obtain 190 mg( 14%) of 1-(tert-butoxycarbonyl)-4-((4-chlorophenyl)amino)piperidine-4-carboxylic acid as a light yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 7.08 (d, 2H, J=8.8 Hz), 6.54 (d, 2H, J=8.8 Hz), 3.57-3.61 (m, 2H), 3.13-3.14 (m, 2H), 1.85-1.92 (m, 4H), 1.40 (s, 9H). [1026] 1-Phenoxycyclohexane-1-carboxylic acid [1027] Phenol (0.5 g, 5.32 mmol) was subjected to conditions described in Method E to obtain 122mg (10%) of 1-phenoxycyclohexane-1-carboxylic acid as a white solid.1H NMR (DMSO-d6, 400 MHz) δ 7.24 -7.26 (m, 2H), 6.94 (t, 1H, J=7.6 Hz), 6.82 (d, 2H, J=8.0 Hz), 2.01-2.04 (m, 2H), 1.75-1.81 (m, 2H), 1.44-1.56 (m, 5H), 1.29-1.33 (m, 1H). [1028] 4,4-Difluoro-1-phenoxycyclohexane-1-carboxylic acid [1029] Phenol (0.47 g, 5.32 conditions described in Method E to obtain 160mg (13%) of 4,4-difluoro-1-phenoxycyclohexane-1-carboxylic acid as a light brown solid.1H NMR (DMSO-d6, 400 MHz) δ 13.42 (br s, 1H), 7.27 -7.33 (m, 2H), 7.00 (t, 1H, J=7.6 Hz), 6.88 (d, 2H, J=8.8 Hz), 2.23-2.25 (m, 2H), 1.91-2.03 (m, 6H). [1030] 1-(4-Chlorophenoxy)-4,4-difluorocyclohexane-1-carboxylic acid [1031] 4-Chlorophenol (0.51 g, to conditions described in Method E to obtain 110 mg (9%) of 1-(4-chlorophenoxy)-4,4-difluorocyclohexane-1- carboxylic acid as a light yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 13.55 (br s, 1H), 7.33-7.37 (m, 2H), 6.89-6.93 (m, 2H), 2.04-2.24 (m, 2H), 1.90-2.00 (m, 6H). LC-MS: m/z = 289,291 [M-H]+.
[1032] Linked fragments [1033] Compound 2 mmol), tert-butyl carbamate (95 mg,0.81 mmol) and cesium carbonate (0.48 g, 1.48 mmol) in dioxane (4 mL) was bubbled argon gas for 15 min. To this mixture was added palladium(II) acetate (8 mg, 0.037 mmol) and XPhos (35 mg, 0.074 mmol) and stirred at 100 oC for 18 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 0.2 g (88%) of methyl 4- ((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylate as a beige colored solid. 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.89 (br d, 1H, J=7.5 Hz), 7.56 (d, 1H, J=8.3 Hz), 7.44 (t, 1H, J=8.0 Hz), 6.98 (br s, 1H), 3.97 (s, 3H), 1.58 (s, 9H).13C NMR (CDCl3, 100 MHz) δ 163.1, 152.7, 143.0, 134.5, 132.4, 130.1, 128.1, 125.9, 117.7, 115.1, 81.2, 52.6, 28.3. LC-MS: m/z = 330 [M+Na]+. [1035] To methyl 4-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylate (40 mg, 0.13 mmol) was added 4M HCl in dioxane (0.5 mL) and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and resuspended in DMF (0.5 mL). To this solution was added 2-(4-chlorophenoxy)-2-methylpropanoic acid (28 mg, 0.13 mmol), HATU (54 mg, 0.15 mmol) and DIEA (0.068 mL, 0.39 mmol). After stirring at room temperature for 24 h, the reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 30 mg (57%) of methyl 4-(2-(4-chlorophenoxy)-2- methylpropanamido)benzo[b]thiophene-2-carboxylate as colorless oil. LC-MS: m/z = 404, 406 [M+H]+. [1036] To a solution of methyl 4-(2-(4-chlorophenoxy)-2- methylpropanamido)benzo[b]thiophene-2-carboxylate (20 mg, 0.05 mmol) in a mixture of MeOH/THF/water (2:1:1, 2 mL), was added 1 M aqueous solution of lithium hydroxide (0.1 mL, 0.1 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D. (2-(4-Chlorophenoxy)-2-methylpropanamido)benzo[b]thiophene-2- carboxylic acid thus obtained was taken in DMF (0.5 mL). To this solution was added ammonium chloride (5 mg, 0.1 mmol), HATU (21 mg, 0.055 mmol) and DIEA (0.035 mL, 0.2 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced to obtain about 20 mg of crude 4-(2-(4-chlorophenoxy)-2- methylpropanamido)benzo[b]thiophene-2-carboxamide as a colorless oil that was used without further purification. [1037] To a cooled (0 oC) solution of 4-(2-(4-chlorophenoxy)-2- methylpropanamido)benzo[b]thiophene-2-carboxamide (20 mg, 0.05 mmol) in DCM (1 mL), was added triethyloxonium tetrafluoroborate (12 mg, 0.062 mmol) under argon. After stirring at room temperature for 2 h, the reaction mixture was diluted with DCM, saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain crude ethyl 4-(2-(4-chlorophenoxy)-2- methylpropanamido)benzo[b]thiophene-2-carbimidate. The crude imidate was taken in 0.5M solution of ammonia in dioxane (3 mL) and stirred at 70 oC for 5 days. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to obtain 2.4 mg (11% over 4 steps) of N-(2-carbamimidoylbenzo[b]thiophen-4-yl)-2-(4-chlorophenoxy)- 2-methylpropanamide (2) as a formate salt.1H NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.79- 7.81 (m, 1H), 7.72-7.74 (m, 1H), 7.53 (br t, 1H, J=7.9 Hz), 7.27-7.29 (m, 2H), 6.96-6.98 (m, 2H), 1.62 (m, 6H). LC-MS: m/z = 388, 390 [M+H]+.
[1038] Compound 3 mmol) in a mixture of MeOH/THF/water (2:1:1, 2 mL), was added 1M aqueous solution of lithium hydroxide (1.1 mL, 1.1 mmol) and stirred at 50 oC for 18 h. The reaction mixture was then treated to conditions described in Method D. The crude 4-bromobenzo[b]thiophene-2- carboxylic acid obtained was taken in DMF (1 mL). To this solution was added ammonium chloride (58 mg, 1.1 mmol), HATU (0.23 g, 0.6 mmol) and DIEA (0.174 mL, 1.1 mmol) and stirred at room temperature for 3 h. The reaction mixture was treated to conditions described in Method A to obtain 0.17 g of crude 4-bromobenzo[b]thiophene-2-carboxamide as a yellow solid. To a solution of crude 4-bromobenzo[b]thiophene-2-carboxamide (0.12 g, 0.47 mmol) in NMP (1 mL), was added copper(I) cyanide (0.17 g, 0.19 mmol) and the mixture was heated to 150 oC for 72 h. The reaction mixture was suspended in dichloromethane and water. The insoluble solids were filtered, the organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by flash column chromatography (0-50% ethyl acetate/hexanes) to obtain 30 mg (32%) of 4- cyanobenzo[b]thiophene-2-carboxamide as a beige solid.1H NMR (CDCl3, 400 MHz) δ 8.07-8.09 (m, 2H), 7.73 (d, 1H, J=7.5 Hz), 7.47 (t, 1H, J=7.8 Hz), 2.95 (s, 1H), 2.68 (s, 1H). LC-MS: m/z = 202 [M+H]+. [1040] To a solution of 4-cyanobenzo[b]thiophene-2-carboxamide (30 mg, 0.15 mmol) in methanol (1.5 mL), was added cobalt (II) chloride hexahydrate. After stirring at room temperature for 10 min, sodium borohydride (57 mg, 1.5 mmol) was added slowly to the reaction mixture which turned deep bluish black in color. After stirring at room temperature for an hour, the reaction mixture was acidified to pH 2 with 1N aqueous Hydrochloric acid. After removing methanol under reduced pressure, the mixture was adjusted to pH 10 with 10% ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extracts were dried over magnesium sulfate and concentrated under reduced pressure to obtain 19 mg of crude 4-(aminomethyl)benzo[b]thiophene-2-carboxamide as light brown oil which was used without further purification. To this crude 4- (aminomethyl)benzo[b]thiophene-2-carboxamide (19 mg, 0.09 mmol) was added 2-(4- chlorophenoxy)-2-methylpropanoic acid (20 mg, 0.09 mmol), HATU (38 mg, 0.099 mmol) and DIEA (0.031 mL, 0.18 mmol) in DMF (1 mL). After stirring at room temperature for 18 h, the reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 21 mg (35%) of 4-((2-(4-chlorophenoxy)-2-methylpropanamido)methyl)benzo[b]thiophene-2-carboxamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.02 (s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.39-7.43 (m, 1H), 7.31-7.32 (m, 1H), 7.13-7.16 (m, 2H), 6.75-6.77 (m, 2H), 4.85 (d, 2H, J=6.1 Hz), 1.53 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 174.4, 163.7, 152.4, 142.3, 138.3, 137.9, 134.1, 129.2, 128.7, 126.6, 125.0, 124.0, 122.6, 122.6, 81.9, 77.2,41.9. LC-MS: m/z = 403 [M+H]+. [1041] To a cooled (0 oC) solution of 4-((2-(4-chlorophenoxy)-2- methylpropanamido)methyl)benzo[b]thiophene-2-carboxamide (31 mg, 0.077 mmol) and pyridine (0.019 mL, 0.23 mmol) in dioxane (1 mL), was added trifluoroacetic anhydride (0.032 mL, 0.23 mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate, washed with, saturated aqueous ammonium chloride, water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 10 mg (33%) of 2-(4-chlorophenoxy)-N-((2-cyanobenzo[b]thiophen-4-yl)methyl)-2-methylpropanamide as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=0.7 Hz), 7.84 (d, 1H, J=8.3 Hz), 7.49-7.53 (m, 1H), 7.37 (d, 1H, J=7.3 Hz), 7.16-7.19 (m, 2H), 7.08 (br s, 1H), 6.77-6.79 (m, 2H), 4.84 (d, 2H, J=6.1 Hz), 1.54 (s, 6H). LC-MS: m/z = 385, 387 [M+H]+. [1042] To a mixture of 2-(4-chlorophenoxy)-N-((2-cyanobenzo[b]thiophen-4-yl)methyl)-2- methylpropanamide (10 mg, 0.026 mmol) and DIEA (0.009 mL, 0.052 mmol) in ethanol (0.5 mL), was added hydroxylamine hydrochloride (2 mg, 0.031 mmol). After stirring at room temperature for 60 h, the reaction mixture was diluted with ethyl acetate. Washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain the crude amidoxime product, which was suspended in glacial acetic acid (0.5 mL). To this mixture was added zinc (5 mg, 0.078 mmol) and stirred at 70 °C for 4 h. The reaction mixture was diluted water, adjusted to pH 7 with 10% aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, concentrated under reduced pressure, and purified by reverse phase HPLC to obtain 5.5 mg (46%) of N-((2-carbamimidoylbenzo[b]thiophen-4-yl)methyl)-2-(4-chlorophenoxy)-2- methylpropanamide (3) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.49 (s, 2H), 7.98 (d, 1H, J=8.3 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=7.1 Hz), 7.09 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 4.82 (s, 2H), 1.54 (s, 6H). LC-MS: m/z = 403, 405 [M+H]+. [1043] Compound 4 0.65 mmol) was added 4M HCl in dioxane (3.0 mL) and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extracts were dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.15 g of crude methyl 4-aminobenzo[b]thiophene-2-carboxylate as yellow solid. To a cooled (0 oC) mixture of methyl 4-aminobenzo[b]thiophene-2-carboxylate (27 mg, 0.13 mmol in AcOH (0.5 mL), was added sodium nitrite (10 mg, 0.14 mmol) in cold water (0.25 mL) and stirred at 0 oC for 30 min. To this mixture was added sodium azide (9 mg, 0.14 mmol) in cold water (0.25 mL) and stirred at 0 oC for 1 h. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (25% ethyl acetate/hexanes) to obtain 22 mg (73%) of methyl 4-azidobenzo[b]thiophene-2-carboxylate as a beige solid.1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.64 (d, 1H, J=8.3 Hz), 7.48 (t, 1H, J=7.9 Hz), 7.15 (d, 1H, J=7.8 Hz), 3.97 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 162.9, 143.8, 136.9, 133.4, 131.5, 127.8, 127.3, 119.0, 113.3, 52.6. [1045] To a mixture of methyl 4-azidobenzo[b]thiophene-2-carboxylate (20 mg, 0.086 mmol) and tert-butyl prop-2-yn-1-ylcarbamate (13mg, 0.086 mmol) in DMF/water (1:1, 2 mL), was added 0.3 M aqueous solution of copper(II) sulfate pentahydrate (0.029 mL, 0.009 mmol) and 1 M aqueous solution of sodium ascorbate (0.17 mL, 0.17 mmol). After stirring at 80 oC for 24 h, reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 33 mg (99%) of methyl 4-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)benzo[b]thiophene-2- carboxylate as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 7.98-8.1 (m, 2H), 7.60 (t, 1H, J=7.4 Hz), 7.54 (d, 1H, J=7.3 Hz), 5.26 (br s, 1H), 4.56 (d, 2H, J=6.1 Hz), , 3.97 (s, 3H), 1.49 (s, 9H).13C NMR (CDCl3, 100 MHz) δ 162.6, 144.1, 135.7, 133.3, 132.7, 127.9, 127.0, 123.9, 122.8, 119.5, 100.10, 79.81, 52.8, 36.2, 28.4. LC-MS: m/z = 389 [M+H]+. [1046] To methyl 4-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1- yl)benzo[b]thiophene-2-carboxylate (50 mg, 0.13 mmol) was added 4 M HCl in dioxane (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and resuspended in DMF (0.5 mL). To this solution was added 2-(4- chlorophenoxy)-2-methylpropanoic acid (28 mg, 0.13 mmol), HATU (54mg, 0.14 mmol) and DIEA (0.067 mL, 0.39 mmol). After stirring at room temperature for 18 h, the reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (50% ethyl acetate/hexanes) to obtain 55 mg (87%) of methyl 4-(4- ((2-(4-chlorophenoxy)-2-methylpropanamido)methyl)-1H-1,2,3-triazol-1- yl)benzo[b]thiophene-2-carboxylate as a tan solid.1H NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 7.98-8.00 (m, 2H), 7.60 (t, 1H, J=7.9 Hz), 7.52 (dd, 1H, J=1.0, 7.5 Hz), 7.45 (br s, 1H), 7.21-7.23 (m, 2H), 6.86-6.89 (m, 2H), 4.74 (d, 2H, J=5.8 Hz), 3.96 (s, 3H), 1.53 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 174.8, 162.6, 152.7, 145.0, 144.1, 135.7, 133.1, 132.6, 129.3, 128.7, 127.9, 127.0, 123.9, 122.9, 122.9, 119.4, 81.9, 52.8, 34.9, 24.9. LC-MS: m/z = 485, 487 [M+H]+. [1047] To a solution of methyl 4-(4-((2-(4-chlorophenoxy)-2-methylpropanamido)methyl)- 1H-1,2,3-triazol-1-yl)benzo[b]thiophene-2-carboxylate (55 mg, 0.11 mmol) in a mixture of MeOH/THF/water (2:1:1, 4 mL), was added 1 M aqueous solution of lithium hydroxide (0.22 mL, 0.22 mmol) and stirred at 50 oC for 18 h. The reaction mixture was treated to conditions described in Method D. The crude 4-(4-((2-(4-chlorophenoxy)-2- methylpropanamido)methyl)-1H-1,2,3-triazol-1-yl)benzo[b]thiophene-2-carboxylic acid obtained was taken in DMF (1 mL). To this solution was added ammonium chloride (12 mg, 0.22 mmol), HATU (47 mg, 0.12 mmol) and DIEA (0.08 mL, 0.45 mmol) and stirred at room temperature for 3 h. The reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (0-50% ethyl acetate/hexanes followed by 5% methanol/dichloromethane) to obtain 49mg (94%) of 4-(4-((2-(4- chlorophenoxy)-2-methylpropanamido)methyl)-1H-1,2,3-triazol-1-yl)benzo[b]thiophene-2- carboxamide as a white solid (contains residual DMF).1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 8.0-8.1 (m, 3H), 7.49-7.59 (m, 3H), 7.19-7.21 (m, 2H), 6.85-6.87 (m, 2H), 4.71 (d, 2H, J=5.8 Hz), 2.97 (s, 3H), 2.89 (s, 3H), 1.52 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 174.9, 163.6, 162.6, 152.6, 145.0, 143.6, 140.8, 132.8, 132.7, 129.3, 128.8, 126.5, 123.9, 123.3, 123.0, 122.9, 118.9, 81.9, 77.3, 36.5, 34.9, 31.5, 24.9. LC-MS: m/z = 470, 472 [M+H]+. [1048] To a cooled (0 oC) solution of 4-(4-((2-(4-chlorophenoxy)-2- methylpropanamido)methyl)-1H-1,2,3-triazol-1-yl)benzo[b]thiophene-2-carboxamide (55 mg, 0.12 mmol) and pyridine (0.028 mL, 0.36 mmol), was added trifluoroacetic anhydride (0.15 mL, 0.9 mmol) and stirred at room temperature for 6 days. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (0-75% ethyl acetate/hexanes) to obtain 50 mg (93%) of 2-(4-chlorophenoxy)-N-((1-(2- cyanobenzo[b]thiophen-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-methylpropanamide as yellow oil.1H NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 7.79-8.01 (m, 2H), 7.70 (t, 1H, J=7.9 Hz), 7.56 (dd, 1H, J=0.7, 7.5 Hz), 7.45 (br t, 1H), 7.21-7.23 (m, 2H), 6.86-6.88 (m, 2H), 4.73 (d, 2H, J=5.8 Hz), 1.53 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 174.8, 152.6, 145.3, 143.4, 133.5, 132.9, 131.2, 129.3, 128.8, 128.1, 123.4, 122.8, 122.7, 119.4, 113.7, 111.9, 81.8, 34.8, 24.9. LC-MS: m/z = 452, 454 [M+H]+. [1049] To a mixture of 2-(4-chlorophenoxy)-N-((1-(2-cyanobenzo[b]thiophen-4-yl)-1H- 1,2,3-triazol-4-yl)methyl)-2-methylpropanamide (50 mg, 0.11 mmol) and DIEA (0.039 mL, 0.22 mmol) in ethanol (1 mL), was added hydroxylamine hydrochloride (9 mg, 0.13 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with ethyl acetate. Washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain 64 mg of the crude amidoxime product. About half the material was suspended in glacial acetic acid (1 mL). To this mixture was added zinc (12 mg, 0.18 mmol) and stirred at 70 oC for 24 h. The reaction mixture was diluted water, adjusted to pH 7 with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (0-15% 0.7 N ammonia in methanol/dichloromethane) to obtain 1.4 mg (5%) of N-((1-(2- carbamimidoylbenzo[b]thiophen-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-chlorophenoxy)-2- methylpropanamide (4).1H NMR (METHANOL-d4, 400 MHz) δ 8.35 (s, 1H), 8.28 (s, 1H), 8.21 (d, 1H, J=8.0 Hz) 7.76 (m, 2H), 7.20 (d, 2H, J=9.0 Hz), 6.92 (d, 2H, J=9.0 Hz), 4.66 (s, 2H), 1.56 (s, 6H). LC-MS: m/z = 469, 471 [M+H]+. [1050] Compound 5 [1051] A mixture of 2-chloro-6-fluorobenzaldehyde (0.2 mg, 1.26 mmol), tert-butyl methyl(2-(methylamino)ethyl)carbamate (0.24 g, 1.26 mmol) and DIEA (0.44 mL, 2.52 mmol) in DMF (2 mL) were heated to 70 oC for 18 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 0.36 g (87%) of tert-butyl (2-((3-chloro-2- formylphenyl)(methyl)amino)ethyl)carbamate as a yellow oil.1H NMR (CDCl3, 400 MHz) δ 10.26 (br s, 1H), 7.25-7.28 (m, 1H), 6.93-6.99 (m, 2H), 3.42 (br s, 2H), 3.27 (br s, 2H), 2.89 (br s, 3H), 2.67-2.77 (br d, 3H), 1.40 (s, 9H). LC-MS: m/z = 327, 329 [M+H]+. [1052] To a mixture of tert-butyl (2-((3-chloro-2- formylphenyl)(methyl)amino)ethyl)carbamate (0.31 g, 0.95 mmol) and potassium carbonate (0.52 g, 3.8 mmol) in DMF (2 mL), was added ethyl thioglycolate (0.25 mL, 2.28 mmol) and stirred at 90 oC for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 0.2 g (54%) of ethyl 4-((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxylate as a reddish orange oil.1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.44 (br s, 1H), 7.35 (t, 1H, J=7.4 Hz), 6.90 (d, 1H, J=7.7 Hz), 4.42 (q, 2H, J=7.1 Hz), 3.40-3.46 (m, 4H), 3.01 (s, 3H), 2.76-2.88(br d, 3H), 1.41-1.45 (m, 12H). LC-MS: m/z = 415 [M+Na]+. [1053] To ethyl 4-((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxylate (150 mg mg, 0.38 mmol) was added 4M HCl in dioxane (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 120 mg of crude ethyl 4-(methyl(2-(methylamino)ethyl)amino)benzo[b]thiophene-2-carboxylate as a HCl salt. Resuspended this crude material (40 mg, 0.12 mmol) in DMF (0.5 mL). To this solution was added 2-(4-chlorophenoxy)-2-methylpropanoic acid (26 mg, 0.12 mmol), HATU (51 mg, 0.13 mmol) and DIEA (0.042 mL, 0.24 mmol). After stirring at room temperature for 18 h, the reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 50 mg (84%) of ethyl 4-((2-(2-(4-chlorophenoxy)-N,2- dimethylpropanamido)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxylate as yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.47 (d, 1H, J=8.3 Hz), 7.37 (t, 1H, J=7.8 Hz), 7.07-7.09 (m, 2H), 6.93 (d, 1H, J=7.5 Hz), 6.73-6.75 (m, 2H), 4.41 (q, 2H, J=7.1 Hz), 3.65 (t, 2H, J=6.8 Hz), 3.40 (t, 2H, J=6.8 Hz), 3.16 (s, 3H), 3.01 (m, 3H), 2.86 (s, 1H), 1.60 (s, 3H), 1.42 (t, 3H, J=7.2 Hz). LC-MS: m/z = 489, 491 [M+H]+. [1054] To a cooled (0 oC) mixture of ammonium chloride (38 mg, 0.72 mmol) in toluene (1 mL) with 4A molecular sieves under argon was added trimethylaluminum (0.36 mL, 0.72 mmol). After stirring at room temperature until fuming subsides, was added a solution of ethyl 4-((2-(2-(4-chlorophenoxy)-N,2- dimethylpropanamido)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxylate (70 mg, 0.14 mmol) in toluene (0.5 mL). After stirring at 80 °C for 18 h, methanol (1 mL) was added to the cooled (0 oC) reaction mixture. After stirring at room temperature for an hour, the precipitate formed was filtered and purified by silica gel flash column chromatography (0-75% ethyl acetate/hexanes) to obtain 27 mg of 4-((2-(2-(4-chlorophenoxy)-N,2- dimethylpropanamido)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxamide instead of the desired amidine product.1H NMR (METHANOL-d4, 400 MHz) δ 8.43 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.36 (t, 1H, J=7.9 Hz), 7.02-7.05 (m, 2H), 6.91-6.93 (m, 1H), 6.75-6.78 (m, 2H), 3.79-3.81 (m, 2H), 3.38-3.40 (m, 2H), 3.26 (s, 3H), 2.97 (s, 3H), 2.03 (s, 1H), 1.59 (s, 6H). LC-MS: m/z = 460, 462 [M+H]+. [1055] To a cooled (0 oC) solution of 4-((2-(2-(4-chlorophenoxy)-N,2- dimethylpropanamido)ethyl)(methyl)amino)benzo[b]thiophene-2-carboxamide (25 mg, 0.054 mmol) in DCM (1 mL), was added triethyloxonium tetrafluoroborate (12 mg, 0.065 mmol) under argon. After stirring at room temperature for 3 h, the reaction mixture was diluted with DCM, saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain crude 4-((2-(2-(4- chlorophenoxy)-N,2-dimethylpropanamido)ethyl)(methyl)amino)benzo[b]thiophene-2- carbimidate. The crude imidate was taken in 0.5 M solution of ammonia in dioxane (0.5 mL) and stirred at 50 oC for 18 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to obtain 12 mg (44%) of the N-(2-((2- carbamimidoylbenzo[b]thiophen-4-yl)(methyl)amino)ethyl)-2-(4-chlorophenoxy)-N,2- dimethylpropanamide (5) as a formate salt.1H NMR (CDCl3, 400 MHz) δ 8.97 (s, 1H), 8.65 (br s, 1H), 7.42-7.47 (m, 2H), 7.14-7.17 (m, 2H), 6.85 (dd, 1H, J=1.1, 7.4 Hz), 6.69-6.71 (m, 2H), 3.79-3.84 (m, 2H), 3.29-3.35 (m, 5H), 2.93 (s, 3H), 1.65 (s, 6H). LC-MS: m/z = 459, 461 [M+H]+. [1056] Compound 6 phenylboronic acid (1.09 g, 8 mmol) and cesium carbonate (5.2 g, 15.9 mmol) in dioxane/water (4:1, 50 mL), was added [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.43 g, 0.53 mmol). After stirring at 100 oC for 18 h, added water and ethyl acetate to the mixture, filtered through celite, separated the layers, washed organic layer with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 1.05 g (99%) of 4-(3- aminophenyl)thiophene-2-carbonitrile as yellowish brown oil.1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 1H), 7.62 (s, 1H), 7.21-7.25 (m, 1H), 6.92-6.94 (m, 1H), 6.85 (t, 1H, J=1.9 Hz), 6.72- 6.74 (m, 1H), 3.83 (br s, 2H).13C NMR (CDCl3, 100 MHz) δ 147.2, 143.3, 136.4, 134.7, 130.1, 126.9, 116.8, 115.1, 114.4, 112.9, 110.3. LC-MS: m/z = 201 [M+H]+. [1058] To a mixture of 4-(3-aminophenyl)thiophene-2-carbonitrile (1.05 g, 5.24 mmol) and di-tert-butyl dicarbonate (1.72 g, 7.86 mmol) in ethanol (10 mL) was added guanidine hydrochloride (75 mg, 0.78 mmol). After stirring at 50 oC for 60 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure. The crude obtained was washed with hexanes and dried to obtain 1.5 g of tert-butyl (3-(5-cyanothiophen-3-yl)phenyl)carbamate as a beige solid. To the crude tert-butyl (3-(5-cyanothiophen-3-yl)phenyl)carbamate (1.45 g, 4.8 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (0.4 g, 5.8 mmol) and DIEA (1.67 mL, 9.6 mmol). After stirring at 50 oC for 18 h, the reaction mixture was diluted with ethyl acetate. Washed with 10% aqueous ammonium hydroxide, water and brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain 1.8 g of the crude amidoxime product. To the crude amidoxime taken in dioxane (50 mL) was added 1,1′-carbonyldiimidazole (1.17 g, 7.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.07 mL, 7.2 mmol). After stirring at 100 oC for 18 h, the reaction mixture was diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, water and brine, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 1.3 g (46% over 3 steps) of tert-butyl (3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)carbamate as cream colored solid.1H NMR (CDCl3, 400 MHz) δ 7.87 (s, 1H), 7.76 (br s, 1H), 7.60 (s, 1H), 7.12-7.23 , 6.54 (br s, 1H), 1.55 (s, 9H). [1059] To tert-butyl (3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)carbamate (1.3 g, 3.6 mmol) was added 4 M HCl in dioxane (10 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain 0.9 g of crude 3-(4-(3-aminophenyl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one as a hydrochloride salt and was used without further purification. LC-MS: m/z = 260 [M+H]+. [1060] To a solution of 3-(4-(3-aminophenyl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.071 mmol) in DMF (0.5 mL), was added 2-(4-chlorophenoxy)- 2-methylpropanoic acid (15 mg, 0.071 mmol), HATU (30 mg, 0.078 mmol) and DIEA (0.037 mL, 0.21 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 26 mg (81%) of 2-(4-chlorophenoxy)-2-methyl-N- (3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propenamide as a white solid.1H NMR (DMSO-d6, 400 MHz) δ 10.15 (s, 1H), 8.08-8.15 (m, 2H), 7.62-7.64 (m, 1H), 7.31-7.43 (m, 3H), 6.83-6.99 (m, 2H), 1.51-1.57 (m, 6H). LC-MS: m/z = 455, 457 [M+H]+. [1061] To a solution of 2-(4-chlorophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)propenamide (20 mg, 0.044 mmol) in glacial acetic acid (1 mL), was added zinc (58 mg, 0.88 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 8 mg (40%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-2-(4- chlorophenoxy)-2-methylpropanamide (6) as a formate salt. [1062] Compound 7 methylpropanamido)phenyl)thiophene-2-carboxamide (36 mg, 0.09 mmol) in dioxane (1 mL) was added pyridine (0.022 mL, 0.27 mmol) and trifluoroacetic anhydride (0.036 mL, 0.27 mmol). After stirring at room temperature for 24 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography (0-35% ethyl acetate/hexanes) to obtain 33 mg (92%) of 2-(4-chlorophenoxy)-N-(3-(5-cyanothiophen-3- yl)phenyl)-2-methylpropanamide as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 8.03 (t, 1H, J=1.7 Hz), 7.90 (d, 1H, J=1.5 Hz), 7.72 (d, 1H, J=1.5 Hz), 7.42-7.46 (m, 2H), 7.28-7.35 (m, 3H), 6.95-6.98 (m, 2H), 1.61 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 172.9, 152.3, 142.6, 138.3, 136.3, 134.7, 129.9, 129.5, 129.4, 127.3, 123.3, 122.6, 119.4, 117.9, 114.1, 110.7, 82.4, 24.9. LC-MS: m/z = 397, 399 [M+H]+. [1064] To a solution of 2-(4-chlorophenoxy)-N-(3-(5-cyanothiophen-3-yl)phenyl)-2- methylpropanamide (28 mg, 0.07 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (6 mg, 0.08 mmol) and DIEA (0.025 mL, 0.14 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography (0-35% ethyl acetate/hexanes) to obtain 16 mg of 2-(4-chlorophenoxy)-N-(3-(5-(N'-hydroxycarbamimidoyl)thiophen-3-yl)phenyl)-2- methylpropanamide (7) as a white solid.1H NMR (METHANOL-d4, 400 MHz) δ 7.93 (t, 1H, J=1.8 Hz), 7.79 (d, 1H, J=1.5 Hz), 7.62 (d, 1H, J=1.5 Hz), 7.30-7.55 (m, 5H), 7.02 (d, 2H, J=8.0 Hz), 1.62 (s, 6H). LC-MS: m/z = 430 [M+H]+. [1065] Compound 8 g, 0.55 mmol), (5-(methoxycarbonyl)thiophen-3-yl)boronic acid (0.113 g, 0.6 mmol) and potassium carbonate (0.2 g, 1.4 mmol) in dioxane/water (1:1.2 mL) for 20 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol) and heated to 90 oC. After 18 h, the mixture was filtered through celite and washed with ethyl acetate. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography (35% ethyl acetate/hexanes) to obtain 76 mg of methyl 4-(3-((tert- butoxycarbonyl)amino)phenyl)thiophene-2-carboxylate with 25% methyl thiophene-2- carboxylate impurity. To this mixture was added was added 4 M HCl in dioxane (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to crude methyl 4-(3-aminophenyl)thiophene-2-carboxylate as hydrochloride salt. This methyl 4-(3-aminophenyl)thiophene-2-carboxylate salt (50 mg, 0.21 mmol) was suspended in DMF (1 mL). To this solution was added 2-(4-chlorophenoxy)-2- methylpropanoic acid (46 mg, 0.21 mmol), HATU (90 mg, 0.24 mmol) and DIEA (0.11 mL, 0.63 mmol). After stirring at room temperature for 18 h, the reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to obtain 90 mg (38% over 3 steps) of methyl 4-(3-(2-(4- chlorophenoxy)-2-methylpropanamido)phenyl)thiophene-2-carboxylate as pale yellow oil.1H NMR (CDCl3, 400 MHz) δ 8.62 (br s, 1H), 8.10 (s, 1H), 7.97-7.98 (m, 1H), 7.70 (d, 1H, J=1.5 Hz), 7.48-7.49 (m, 1H), 7.38-7.41 (m, 2H), 7.29-7.31 (m, 2H), 6.96-6.98 (m, 2H), 3.93 (s, 3H), 1.61 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 172.8, 162.6, 152.4, 142.4, 138.1, 135.8, 134.3, 132.2, 129.7, 129.6, 129.5, 127.4, 123.2, 122.5, 118.9, 117.7, 82.4, 52.3, 24.9. LC-MS: m/z = 430, 432 [M+H]+. [1067] To a solution of methyl 4-(3-(2-(4-chlorophenoxy)-2- methylpropanamido)phenyl)thiophene-2-carboxylate (82 mg, 0.19 mmol) in a mixture of MeOH/THF/water (2:1:1, 4 mL), was added 1 M aqueous solution of lithium hydroxide (0.38 mL, 0.38 mmol) and stirred at 50 oC for 18 h. The reaction mixture was then treated to conditions described in Method D. The crude 4-(3-(2-(4-chlorophenoxy)-2- methylpropanamido)phenyl)thiophene-2-carboxylic acid obtained was taken in DMF (1 mL). To this solution was added ammonium chloride (21 mg, 0.38 mmol), HATU (81 mg, 0.21 mmol) and DIEA (0.136 mL, 0.78 mmol) and stirred at room temperature for 2 h. The reaction mixture was treated to conditions described in Method A and purified by silica gel flash column chromatography (0-75% ethyl acetate/hexanes) to obtain 33 mg (42%) of 4-(3- (2-(4-chlorophenoxy)-2-methylpropanamido)phenyl)thiophene-2-carboxamide (8) as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.03 (s, 1H), 7.85 (d, 1H, J=1.5 Hz), 7.66 (d, 1H, J=1.2 Hz), 7.28-7.42 (m, 4H), 6.97 (d, 2H, J=8.0 Hz), 1.61 (s, 6H).13C NMR (CDCl3, 100 MHz) δ 172.9, 152.4, 142.5, 138.6, 138.0, 135.9, 129.7, 129.5, 129.3, 128.1, 126.0, 123.2, 122.5, 118.9, 117.7, 82.4, 24.9. LC-MS: m/z = 415 [M+H]+. [1068] Compound 9 [1069] To a solution of - oxadiazol-5(4H)-one hydrochloride salt (25 mg, 0.084 mmol) in DMF (0.5 mL), was added 2-((4- chlorophenyl)amino)-2-methylpropanoic acid (18 mg, 0.084 mmol), HATU (35 mg, 0.093 mmol) and DIEA (0.044 mL, 0.25 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A to obtain 48 mg of crude 2-((4- chlorophenyl)amino)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)propenamide as a brown oil. LC-MS: m/z = 455, 457 [M+H]+. [1070] To a solution of crude 2-((4-chlorophenyl)amino)-2-methyl-N-(3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (48 mg, 0.084 mmol) in glacial acetic acid (1 mL), was added zinc (110 mg, 1.7 mmol) and stirred at 70 oC for 24 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 9 mg (23%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-2- ((4-chlorophenyl)amino)-2-methylpropanamide (9) as a formate salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.46 (br s, 1H), 8.31 (d, 1H, J=1.2 Hz), 8.19 (s, 1H), 7.98 (s, 1H), 7.41-7.48 (m, 3H), 7.10-7.12 (m, 2H), 6.60-6.62 (m, 2H), 1.57 (s, 6H). LC-MS: m/z = 413, 415 [M+H]+. [1071] Compound 10 [1072] A solution of 2-(4- (5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (34 mg, 0.068 mmol) in ethyl acetate/glacial acetic acid (9:1, 10 mL) at 1 mL/min was passed through the H-Cube over 10% Pd/C at room temperature and atmospheric pressure which also resulted in debromination. The reaction mixture was concentrated under reduced pressure, and purified by reverse phase HPLC to obtain 13 mg (59%) of N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-2-methyl-2-phenoxypropanamide (10) as a formate salt. 1H NMR (METHANOL- d4, 400 MHz) δ 8.57 (br s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.44-7.54 (m, 3H), 7.29-7.33 (m, 2H), 7.02-7.10 (m, 3H), 1.63 (m, 6H). LC-MS: m/z = 380 [M+H]+. [1073] Compound 11
[1074] To a solution of 3-(4-(3-aminophenyl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (33 mg, 0.11 mmol) in DMF (0.5 mL), was added 2-methyl-2- (phenylamino)propanoic acid (20 mg, 0.11 mmol), HATU (47 mg, 0.12 mmol) and DIEA (0.057 mL, 0.33 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A to obtain 45 mg of crude 2-methyl-N-(3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)-2-(phenylamino)propenamide as an off white solid. LC-MS: m/z = 421 [M+H]+. [1075] To a solution of 2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)thiophen-3-yl)phenyl)-2-(phenylamino)propanamide (45 mg, 0.11 mmol) in glacial acetic acid (2 mL), was added zinc (140 mg, 2.1 mmol) and stirred at 70 oC for 24 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 19 mg (40%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-2-methyl-2- (phenylamino)propanamide (11) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.43 (br s, 1H), 8.31 (d, 1H, J=1.2 Hz), 8.18 (s, , 7.97 (s, 1H), 7.35-7.46 (m, 3H), 7.11- 7.15 (m, 2H), 6.64-6.73 (m, 3H), 1.57 (m, 6H). LC-MS: m/z = 379 [M+H]+. [1076] Compound 12 [1077] To a solution of 1,2,4-oxadiazol-5(4H)-one hydrochloride salt (16 mg, 0.054 mmol) in DMF (0.5 mL), was added 2-(4-bromophenoxy)- 2-methylpropanoic acid (14 mg, 0.054 mmol), HATU (23 mg, 0.059 mmol) and DIEA (0.028 mL, 0.16 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes followed by 5% methanol/dichloromethane) to obtain 17 mg (63%) of 2-(4-bromophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)thiophen-3-yl)phenyl)propenamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.45 (d, 2H, J=9.0 Hz), 7.32-7.35 (m, 2H), 6.92 (d, 2H, J=8.8 Hz), 1.61 (s, 6H). LC-MS: m/z = 500, 502 [M+H]+. [1078] To a solution of 2-(4-bromophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (17 mg, 0.034 mmol) in glacial acetic acid (0.5 mL), was added zinc (20 mg, 0.3 mmol) and stirred at 70 oC for 96 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 10 mg (59%) of 2-(4-bromophenoxy)-N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-2-methylpropanamide (12) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.33 (d, 1H, J=1.5 Hz), 8.21 (d, 1H, J=1.5 Hz), 8.06 (t, 1H, J=1.7Hz), 7.44-7.52 (m, 5H), 6.95-6.97 (m, 2H), 1.63 (s, 6H). LC-MS: m/z = 458, 460 [M+H]+. [1079] Compound 13 [1080] To a solution of oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 2-methyl-2-(4- (trifluoromethyl)phenoxy)propanoic acid (17 mg, 0.068 mmol), HATU (28 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 13 mg (39%) of 2-methyl-N-(3-(5- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)-2-(4- (trifluoromethyl)phenoxy)propanamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.59-7.63 (m, 3H), 7.33-7.34 (m, 2H), 7.10 (d, 2H, J=8.5 Hz), 1.67 (s, 6H). LC-MS: m/z = 490 [M+H]+. [1081] To a solution of 2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)thiophen-3-yl)phenyl)-2-(4-(trifluoromethyl)phenoxy)propanamide (13 mg, 0.026 mmol) in glacial acetic acid (0.5 mL), was added zinc (36 mg, 0.52 mmol) and stirred at 70 oC for 48 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 4.2 mg (33%) of N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-2-methyl-2-(4-(trifluoromethyl)phenoxy)propanamide (13) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.32 (d, 1H, J=1.2 Hz), 8.20 (d, 1H, J=1.5 Hz), 8.05 (t, 1H, J=1.6 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.41-7.49 (m, 3H), 7.15 (d, 2H, J=8.5 Hz), 1.71 (s, 6H). LC-MS: m/z = 448 [M+H]+. [1082] Compound 14 [1083] To a solution of 1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 2-(3,4- dichlorophenoxy)-2-methylpropanoic acid (17 mg, 0.068 mmol), HATU (28 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes followed by 5% methanol/dichloromethane) to obtain 22 mg (67%) of 2-(3,4-dichlorophenoxy)-2-methyl-N- (3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.34-7.38 (m, 3H), 7.12-7.13 (m, 1H), 6.84 (dd, 1H, J=2.7, 8.8 Hz), 1.59 (s, 6H). LC-MS: m/z = 490 [M+H]+. [1084] To a solution of 2-(3,4-dichlorophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (22 mg, 0.045 mmol) in glacial acetic acid (0.5 mL), was added zinc (90 mg, 1.35 mmol) and stirred at 70 oC for 96 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 4.2 mg (19%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-2-(3,4- dichlorophenoxy)-2-methylpropanamide (14) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.40 (br s, 2H) 8.33 (s, 1H), 8.21 (d, 1H, J=1.5 Hz), 8.06 (t, 1H, J=1.7 Hz), 7.74- 7.53 (m, 4H), 7.22 (d, 1H, J=2.9 Hz), 6.97 (dd, 1H, J=2.8, 8.9 Hz), 1.66 (m, 6H). LC-MS: m/z = 448, 450 [M+H]+. [1085] Compound 15 [1086] To a solution of 1,2,4-oxadiazol-5(4H)-one hydrochloride salt (19 mg, 0.064 mmol) in DMF (0.5 mL), was added 2-(4-chloro-3- fluorophenoxy)-2-methylpropanoic acid (15 mg, 0.064 mmol), HATU (27 mg, 0.07 mmol) and DIEA (0.033 mL, 0.19 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes followed by 5% methanol/dichloromethane) to obtain 16 mg (53%) of 2-(4-chloro-3-fluorophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propenamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.73 (br s, 1H), 8.07 (br s, 1H), 7.85 (br s, 1H), 7.67 (s, 1H), 7.30-7.39 (m, 4H), 6.84 (dd, 1H, J=2.7, 10.0 Hz), 6.74 (d, 1H, J=9.0 Hz), 1.60 (s, 6H). LC-MS: m/z = 474 [M+H]+. [1087] To a solution of 2-(4-chloro-3-fluorophenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (12 mg, 0.025 mmol) in glacial acetic acid (0.5 mL), was added zinc (34 mg, 0.5 mmol) and stirred at 70 oC for 24 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 2.4 mg (20%) of N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-2-(4-chloro-3-fluorophenoxy)-2-methylpropanamide (15) as a formate salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.33 (d, 1H, J=1.5 Hz), 8.21 (d, 1H, J=1.2 Hz), 8.06 (t, 1H, J=1.7 Hz), 7.38-7.52 (m, 4H), 6.95 (dd, 1H, J=2.7, 10.7 Hz), 6.84-6.86 (m, 1H), 1.66 (s, 5H). LC-MS: m/z = 432, 434 [M+H]+.
[1088] Compound 16 [1089] To a solution of oxadiazol-5(4H)-one hydrochloride salt (30 mg, 0.1 mmol) in DMF (0.5 mL), was added 2-(4-acetylphenoxy)-2- methylpropanoic acid (23 mg, 0.1 mmol), HATU (43 mg, 0.11 mmol) and DIEA (0.052 mL, 0.3 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 20 mg (43%) of 2-(4-acetylphenoxy)-2-methyl-N-(3-(5-(5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propenamide as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 7.93-7.97 (m, 3H), 7.64 (m, 1H), 7.37 (m, 3H), 7.04-7.06 (m, 2H), 2.59 (s, 3H), 1.70 (m, 6H). LC-MS: m/z = 464 [M+H]+. [1090] To a solution of 2-(4-acetylphenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (20 mg, 0.043 mmol) in glacial acetic acid (1 mL), was added zinc (57 mg, 0.86 mmol) and stirred at 70 oC for 48 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 4.2 mg (21%) of 2-(4-acetylphenoxy)-N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-2-methylpropanamide (16) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.53 (s, 1H), 8.32 (d, 1H, J=1.5 Hz), 8.20 (d, 1H, J=1.7 Hz), 8.04 (br s, 1H), 7.97- 7.99 (m, 2H), 7.40-7.50 (m, 3H), 7.07-7.09 (m, 2H), 2.56 (s, 3H), 1.72 (m, 6H). LC-MS: m/z = 422 [M+H]+. [1091] Compound 17
[1092] To a solution of 3-(4-(3-aminophenyl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (24 mg, 0.08 mmol) in DMF (0.5 mL), was added 2-(4-methoxyphenoxy)- 2-methylpropanoic acid (17 mg, 0.08 mmol), HATU (33 mg, 0.088 mmol) and DIEA (0.042 mL, 0.24 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 17 mg (47%) of 2-(4-methoxyphenoxy)-2-methyl- N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propenamide as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 8.92 (s, 1H), 7.95-8.07 (m, 3H), 7.63 (s, 1H), 7.30-7.40 (m, 2H), 6.96-6.95 (m, 2H), 6.85-6.87 (m, 2H), 3.81 (s, 3H), 1.57 (m, 6H). LC-MS: m/z = 452 [M+H]+. [1093] To a solution of 2-(4-methoxyphenoxy)-2-methyl-N-(3-(5-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)propanamide (17 mg, 0.038 mmol) in glacial acetic acid (1 mL), was added zinc (50 mg, 0.75 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 9 mg (53%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-2-(4- methoxyphenoxy)-2-methylpropanamide (17) as a formate salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.34 (d, 1H, J=1.5 Hz), 8.22 (s, 1H), 8.09 (br s, 1H), 7.47-7.58 (m, 3H), 6.99- 7.01 (m, 2H), 6.87-6.89 (m, 2H), 3.78 (s, 3H), 1.56 (s, 6H). LC-MS: m/z = 410 [M+H]+. [1094] Compound 18 [1095] To a solution of - oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.071 mmol) in DMF (0.5 mL), was added 2-(4-(tert- butoxycarbonyl)phenoxy)-2-methylpropanoic acid (20 mg, 0.071 mmol), HATU (30 mg, 0.078 mmol) and DIEA (0.037 mL, 0.21 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 30 mg (81%) of tert-butyl 4-((2-methyl-1-oxo-1-((3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)amino)propan-2-yl)oxy)benzoate as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 7.91-7.98 (m, 4H), 7.65 (d, 1H, J=1.5 Hz), 7.33-7.34 (m, 3H), 7.01-7.03 (m, 2H), 1.67 (s, 6H), 1.59 (s, 9H). LC-MS: m/z = 544 [M+Na]+. [1096] To a solution of tert-butyl 4-((2-methyl-1-oxo-1-((3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)amino)propan-2-yl)oxy)benzoate (30 mg, 0.06 mmol) in glacial acetic acid (1 mL), was added zinc (80 mg, 1.2 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 11 mg (34%) of tert-butyl 4-((1-((3-(5- carbamimidoylthiophen-3-yl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)oxy)benzoate as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.38 (br s, 2H), 8.32 (d, 1H, J=1.5 Hz), 8.19 (s, 1H), 8.02 (s, 1H), 7.90-7.92 (m, 2H), 7.43-7.49 (m, 3H), 7.03-7.05 (m, 2H), 1.70 (m, 6H), 1.58 (s, 9H). LC-MS: m/z = 480 [M+H]+. [1097] To tert-butyl 4-((1-((3-(5-carbamimidoylthiophen-3-yl)phenyl)amino)-2-methyl-1- oxopropan-2-yl)oxy)benzoate (11 mg, 0.021) was added formic acid (0.5 mL). After stirring at room temperature for 4 h, the mixture was lyophilized to obtain 8mg (80%) of 4-((1-((3-(5- carbamimidoylthiophen-3-yl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)oxy)benzoic acid (18) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.49 (bs, 1H), 8.31 (d, 1H, J=1.7 Hz), 8.20 (d, 1H, J=1.5 Hz), 7.94-7.97 (m, 3H), 7.43-7.49 (m, 3H), 7.03 (br d, 2H, J=8.8 Hz), 1.70 (s, 6H). LC-MS: m/z = 424 [M+H]+. [1098] Compound 19 [1099] To a solution of -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1-(4- chlorophenoxy)cyclobutane-1-carboxylic acid (15 mg, 0.068 mmol), HATU (28 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A to obtain 21 mg of crude 1-(4- chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)cyclobutane-1-carboxamide as a colorless oil which was used without further purification. LC-MS: m/z = 468 [M+H]+. [1100] A solution of 1-(4-chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)thiophen-3-yl)phenyl)cyclobutane-1-carboxamide (21 mg, 0.045 mmol) in methanol/glacial acetic acid (9:110 mL) at 1 mL/min was passed through the H-Cube over 10% Pd/C at room temperature and atmospheric pressure. The reaction mixture was concentrated under reduced pressure, and purified by reverse phase HPLC to obtain 6 mg (29%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-1-(4-chlorophenoxy)cyclobutane-1- carboxamide (19) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.30 (d, 1H, J=1.5 Hz), 8.18 (d, 1H, J=1.5 Hz), 7.99 (s, 1H), 7.38-7.47 (m, 3H), 7.27 (d, 2H, J=9.0 Hz), 6.82 (d, 2H, J=9.3 Hz), 2.83-2.89 (m, 2H), 2.43-2.51 (m, 2H), 1.99-2.07 (m, 2H) . LC-MS: m/z = 426, 428 [M+H]+. [1101] Compound 20 [1102] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1-(4- chlorophenoxy)cyclopentane-1-carboxylic acid (17 mg, 0.068 mmol), HATU (28 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A to obtain 21 mg of 1-(4- chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)cyclopentane-1-carboxamide which was used without further purification. LC-MS: m/z = 482 [M+H]+. [1103] To a solution of 1-(4-chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)thiophen-3-yl)phenyl)cyclopentane-1-carboxamide (21 mg, 0.045 mmol) in glacial acetic acid (0.5 mL), was added zinc (58 mg, 0.87 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 5 mg (23%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-1-(4- chlorophenoxy)cyclopentane-1-carboxamide (20) as a formate salt.1H NMR (METHANOL- d4, 400 MHz) δ 8.52 (br s, 2H), 8.31 (d, 1H, J=1.5 Hz), 8.19 (d, 1H, J=1.5 Hz), 7.99 (s, 1H), 7.70 (d, 1H, J=1.5 Hz), 7.36-7.47 (m, 4H), 7.26-7.28 (m, 2H), 6.67-6.90 (m, 2H), 2.38-2.40 (m, 2H), 2.18-2.22 (m,2H), 1.84-1.87 (m, 4H). LC-MS: m/z = 440, 442 [M+H]+. [1104] Compound 21 [1105] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1-(4- chlorophenoxy)cyclohexane-1-carboxylic acid (18 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 21 mg (62%) of 1-(4- chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)cyclohexane-1-carboxamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.00 (s, 1H), 7.91 (d, 1H, J=1.2 Hz), 7.66 (s, 1H), 7.34-7.36 (m, 2H), 7.24-7.27 (m, 2H), 6.91-6.94 (m, 2H), 2.17 (br d, 2H, J=13.4 Hz), 1.98-2.04 (m, 2H), 1.54-1.72 (m, 4H), 1.31-1.40 (m, 2H). LC-MS: m/z = 496, 498 [M+H]+. [1106] To a solution of 1-(4-chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)thiophen-3-yl)phenyl)cyclohexane-1-carboxamide (25 mg, 0.05 mmol) in glacial acetic acid (0.5 mL), was added zinc (67 mg, 1 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 11 mg (23%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-1-(4- chlorophenoxy)cyclohexane-1-carboxamide (21) as a formate salt.1H NMR (METHANOL- d4, 400 MHz) δ 8.42 (br s, 2H), 8.32 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.41-7.50 (m, 3H), 7.27-7.29 (m, 2H), 6.95-6.97 (m, 2H), 2.24 (br d, 2H, J=13.6 Hz), 1.94-2.02 (m, 2H), 1.64- 1.73 (m, 4H), 1.31-1.41 (m, 2H). LC-MS: m/z = 454, 456 [M+H]+. [1107] Compound 22 [1108] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 4-(4- chlorophenoxy)tetrahydro-2H-pyran-4-carboxylic acid (17 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 22 mg (65%) of 4-(4- chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)tetrahydro-2H-pyran-4-carboxamide as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.00 (s, 1H), 7.91 (d, 1H, J=1.5 Hz), 7.69 (d, 1H, J=1.2 Hz), 7.39-7.41 (m, 2H), 7.27-7.29 (m, 2H), 6.93-6.95 (m, 2H), 3.87-3.90 (m, 2H), 3.72-3.76 (m, 2H), 2.37-2.45 (m, 2H), 2.05-2.08 (m, 2H). LC-MS: m/z = 497, 499 [M+H]+. [1109] To a solution of 4-(4-chlorophenoxy)-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)thiophen-3-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide (22 mg, 0.044 mmol) in glacial acetic acid (1 mL), was added zinc (59 mg, 0.88 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 11 mg (50%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-4- (4-chlorophenoxy)tetrahydro-2H-pyran-4-carboxamide (22) as a formate salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.57 (s, 1H), 8.32 (d, 1H, J=1.2 Hz), 8.20 (d, 1H, J=1.5 Hz), 8.04 (t, 1H, J=1.7 Hz), 7.40-7.51 (m, 3H), 7.29-7.32 (m, 2H), 6.98-7.00 (m, 2H), 3.80-3.85 (m, 4H), 2.30 (br dd, 2H, J=4.4, 10.2 Hz), 2.12-2.16 (m, 2H). LC-MS: m/z = 456, 458 [M+H]+. [1110] Compound 23 [1111] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1-(tert- butoxycarbonyl)-4-(4-chlorophenoxy)piperidine-4-carboxylic acid (24 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 24 mg (59%) of tert-butyl 4-(4-chlorophenoxy)-4-((3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)thiophen-3-yl)phenyl)carbamoyl)piperidine-1-carboxylate as a white solid.1H NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 7.93 (s, 2H), 7.66 (s, 1H), 7.36 (br s, 3H), 7.25-7.28 (m, 2H), 6.91 (d, 2H, J=8.1 Hz), 3.07 (br t, 2H, J=11.2 Hz), 2.21 (br d, 2H, J=3.7 Hz), 2.11-2.21 (m, 4H), 1.47 (m, 9H). [1112] To a solution of tert-butyl 4-(4-chlorophenoxy)-4-((3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)carbamoyl)piperidine-1-carboxylate (24 mg, 0.04 mmol) in glacial acetic acid (1 mL), was added zinc (53 mg, 0.8 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 9 mg (33%) tert-butyl 4-((3-(5- carbamimidoylthiophen-3-yl)phenyl)carbamoyl)-4-(4-chlorophenoxy)piperidine-1- carboxylate (25) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.32 (d, 1H, J=1.7 Hz), 8.20 (d, 1H, J=1.7 Hz), 8.04 (t, 1H, J=1.7 Hz), 7.72 (d, 1H, J=1.5 Hz), 7.38-7.51 (m, 3H), 7.30-7.32 (m, 2H), 6.98-7.01 (m, 2H), 3.96 (br d, 2H, J=13.6 Hz), 3.15-3.24 (m, 2H), 2.14-2.25 (m, 4H), 1.49 (s, 9H). LC-MS: m/z = 555, 557 [M+H]+. [1113] A mixture of tert-butyl 4-((3-(5-carbamimidoylthiophen-3-yl)phenyl)carbamoyl)-4- (4-chlorophenoxy)piperidine-1-carboxylate (6 mg, 0.01 mmol) in 4 M solution of hydrochloric acid in dioxane (0.1 mL) was stittred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate and dried to obtain 5 mg (96%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-4-(4- chlorophenoxy)piperidine-4-carboxamide (23) as a bis hydrochloride salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.34 (d, 1H, J=1.5 Hz), 8.21 (d, 1H, J=1.5 Hz), 8.01 (t, 1H, J=1.6 Hz), 7.42-7.55 (m, 3H), 7.35 (d, 2H, J=9.0 Hz), 7.03-7.05 (m, 2H), 3.60-3.76 (m, 4H), 3.41-3.44 (m, 2H), 2.46-2.50 (m, 4H). LC-MS: m/z = 455, 457 [M+H]+. [1114] Compound 24 [1115] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 4-((tert- butoxycarbonyl)amino)-1-(4-chlorophenoxy)cyclohexane-1-carboxylic acid (25 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 32 mg (76%) of tert-butyl (4-(4-chlorophenoxy)-4-((3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)carbamoyl)cyclohexyl)carbamate as a yellow oil.1H NMR (CDCl3, 400 MHz) δ 8.35 (br s, 1H), 8.05 (br s, 1H), 7.99 (br s, 1H), 7.69 (s, 1H), 7.34- 7.37 (m, 2H), 7.23-7.26 (m, 2H), 6.90-6.92 (m, 2H), 3.87 (br s, 1H), 2.24-2.33 (m, 2H), 1.95- 2.06 (m, 2H), 1.60-1.91 (m, 4H), 1.7-1.45 (m, 9H). [1116] To a solution of tert-butyl (4-(4-chlorophenoxy)-4-((3-(5-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)thiophen-3-yl)phenyl)carbamoyl)cyclohexyl)carbamate (14 mg, 0.023 mmol) in glacial acetic acid (0.5 mL), was added zinc (30 mg, 0.46 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 4 mg (33%) 4-amino-N-(3-(5-carbamimidoylthiophen-3- yl)phenyl)-1-(4-chlorophenoxy)cyclohexane-1-carboxamide (24) as a bisformate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.31 (d, 1H, J=1.5 Hz), 8.18 (d, 1H, J=1.5 Hz), 7.94 (d, 1H, J=1.7 Hz), 7.59 (br d, 1H, J=7.8 Hz), 7.44-7.51 (m, 2H), 7.28-7.31 (m, 2H), 6.98-7.00 (m, 2H), 3.37-3.45 (m, 1H), 2.44-2.53 (m, 2H), 1.87-2.17 (m, 6H). LC-MS: m/z = 469, 471 [M+H]+. [1117] Compound 25 [1118] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (30 mg, 0.1 mmol) in DMF (0.5 mL), was added 1-(tert-butoxycarbonyl)- 4-((4-chlorophenyl)amino)piperidine-4-carboxylic acid (36 mg, 0.1 mmol), HATU (42 mg, 0.11 mmol) and DIEA (0.053 mL, 0.3 mmol). After stirring at room temperature for 60 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 54 mg (90%) of tert-butyl 4-((4-chlorophenyl)amino)-4-((3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)carbamoyl)piperidine-1-carboxylate as a beige solid.1H NMR (CDCl3, 400 MHz) δ 9.05 (s, 1H), 7.99 (d, 1H, J=1.5 Hz), 7.86 (s, 1H), 7.63 (d, 1H, J=1.5 Hz), 7.34-7.45 (m, 3H), 7.14-7.16 (m, 2H), 6.63-6.65 (m, 2H), 4.37 (br s, 1H), 3.95-3.97 (m, 2H), 3.02-3.09 (m, 2H), 2.25-2.33 (m, 2H), 1.97 (br d, 2H, J=13.4 Hz), 1.47 (s, 9H). [1119] To a solution of tert-butyl 4-((4-chlorophenyl)amino)-4-((3-(5-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)carbamoyl)piperidine-1-carboxylate (54 mg, 0.09 mmol) in methanol/glacial acetic acid (9:110 mL) at 1 mL/min was passed through the H- Cube over 10% Pd/C at room temperature and atmospheric pressure. The reaction mixture was concentrated under reduced pressure, and purified by reverse phase HPLC to obtain 15 mg (30%) of tert-butyl 4-((3-(5-carbamimidoylthiophen-3-yl)phenyl)carbamoyl)-4-((4- chlorophenyl)amino)piperidine-1-carboxylate as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.31-8.34 (m, 3H), 8.19 (s, 1H), 8.00 (s, 1H), 7.40-7.49 (m, 3H), 7.12-7.14 (m, 2H), 6.68-6.70 (m, 2H), 3.87 (td, 2H, J=4.0, 13.8 Hz), 3.21-3.29 (m, 2H), 2.16-2.22 (m, 2H), 2.01-2.05 (m, 2H), 1.49 (s, 9H). LC-MS: m/z = 554 [M+H]+. [1120] A mixture of tert-butyl 4-((3-(5-carbamimidoylthiophen-3-yl)phenyl)carbamoyl)-4- ((4-chlorophenyl)amino)piperidine-1-carboxylate (12 mg, 0.021 mmol) in 4 M solution of hydrochloric acid in dioxane (0.1 mL) was stittred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate and dried to obtain 11 mg (98%) of N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-4-((4- chlorophenyl)amino)piperidin (25) as a bis hydrochloride salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.32 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.40-7.53 (m, 3H), 7.16(d, 2H, J=8.5 Hz), 6.75 (d, 2H, J=8.5 Hz), 3.60-3.77 (m, 4H), 3.37-3.41 (m, 2H), 2.50 (br d, 2H, J=10.0 Hz), 2.33 (br d, 2H, J=14.6 Hz). LC-MS: m/z = 454 [M+H]+. [1121] Compound 26 HN S [1122] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1- phenoxycyclohexane-1-carboxylic acid (15 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 60 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 23 mg (70%) of N-(3-(5-(5-oxo- 4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)-1-phenoxycyclohexane-1- carboxamide as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 8.45 (br s, 1H), 7.96-8.03 (m, 2H), 7.64 (s, 1H), 7.25-7.33 (m, 4H), 6.95-7.07 (m, 3H), 2.13-2.21 (m, 2H), 1.98-2.03 (m, 2H), 1.88-1.96 (m, 4H), 1.27-1.37 (m, 2H). LC-MS: m/z = 462 [M+H]+. [1123] To a solution of N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)-1-phenoxycyclohexane-1-carboxamide (23 mg, 0.046 mmol) in glacial acetic acid (1 mL), was added zinc (62 mg, 0.93 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 12 mg (57%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-1- phenoxycyclohexane-1-carboxamide (26) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.54 (br s, 1H), 8.32 (d, 1H, J=1.5 Hz), 8.19 (br s, 1H), 8.01 (s, 1H), 7.47-7.50 (m, 2H), 7.26-7.29 (m, 2H), 6.93-7.02 (m, 3H), 2.25 (br d, 2H, J=13.4 Hz), 1.96 (br t, 2H, J=13.0 Hz), 1.56-1.90 (m, 6H). LC-MS: m/z = 420 [M+H]+. [1124] Compound 27 HN S F [1125] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 4,4-difluoro-1- phenoxycyclohexane-1-carboxylic acid (18 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 26 mg (76%) of 4,4-difluoro-N-(3- (5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)-1-phenoxycyclohexane-1- carboxamide as a colorless oil.1H NMR (CDCl3 with few drops of d6-DMSO, 400 MHz) δ 12.65 (br d, 1H, J=4.4 Hz), 8.75 (br s, 1H), 7.94-7.96 (m, 2H), 7.56-7.58(m, 1H), 7.19-7.24 (m, 4H), 6.97-7.01 (m, 1H), 6.88-6.91 (m, 2H), 2.23-2.26 (m, 4H), 1.92-1.97 (m, 4H). LC- MS: m/z = 498 [M+H]+. [1126] To a solution of 4,4-difluoro-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)thiophen-3-yl)phenyl)-1-phenoxycyclohexane-1-carboxamide (20 mg, 0.04 mmol) in glacial acetic acid (1 mL), was added zinc (53 mg, 0.8 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 12 mg (60%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)- 4,4-difluoro-1-phenoxycyclohexane-1-carboxamide (27) as a formate salt. 1H NMR (METHANOL-d4, 400 MHz) δ 8.40 (br s, 2H), 8.32 (s, 1H), 8.20 (br s, 1H), 8.05 (br s, 1H), 7.31-7.51 (m, 5H), 7.00-7.07 (m, 3H), 2.40-2.43 (m, 2H), 2.24-2.30 (m, 2H), 2.15 (br s, 1H), 2.03-2.07 (m, 3H). LC-MS: m/z = 456 [M+H]+. [1127] Compound 28 [1128] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 4-phenoxytetrahydro- 2H-pyran-4-carboxylic acid (17 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-70% acetone/dichloromethane) to obtain 17 mg (53%) of N-(3-(5-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)-4-phenoxytetrahydro-2H-pyran-4-carboxamide as a colorless oil.1H NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H), 7.31-7.39 (m, 4H), 6.98-7.10 (m, 3H), 3.86-3.89 (m, 2H), 3.73-3.79 (m, 2H), 2.38- 2.45 (m, 2H), 2.07-2.10 (m, 2H). LC-MS: m/z = 464 [M+H]+. [1129] To a solution of N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)-4-phenoxytetrahydro-2H-pyran-4-carboxamide (17 mg, 0.037 mmol) in glacial acetic acid (1 mL), was added zinc (49 mg, 0.73 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 3 mg (18%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-4- phenoxytetrahydro-2H-pyran-4-carboxamide (28) as a formate salt.1H NMR (METHANOL- d4, 400 MHz) δ 8.47 (br s, 2H), 8.32 (d, 1H, J=1.5 Hz), 8.20 (d, 1H, J=1.5 Hz), 8.05 (s, 1H), 7.40-7.51 (m, 3H), 7.29-7.33 (m, 2H), 7.00-7.05 (m, 3H), 3.82-3.85 (m, 4H), 2.29-2.35 (m, 2H), 2.15-2.27 (m, 2H). LC-MS: m/z = 422 [M+H]+.
[1130] Compound 29 [1131] To a solution of 3- -1,2,4-oxadiazol-5(4H)-one hydrochloride salt (20 mg, 0.068 mmol) in DMF (0.5 mL), was added 1-(4-chlorophenoxy)- 4,4-difluorocyclohexane-1-carboxylic acid (20 mg, 0.068 mmol), HATU (30 mg, 0.075 mmol) and DIEA (0.036 mL, 0.2 mmol). After stirring at room temperature for 18 h, the reaction mixture was worked up as described in Method A and purified by silica gel flash column chromatography (0-100% ethyl acetate/hexanes) to obtain 28 mg (78%) of 1-(4- chlorophenoxy)-4,4-difluoro-N-(3-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-3- yl)phenyl)cyclohexane-1-carboxamide as a whit solid 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.94-7.95 (m, 2H), 7.68 (s, 1H), 7.28-7.39 (m, 4H), 6.93-6.95 (m, 2H), 2.30-2.38 (m, 4H), 1.91-2.03 (m, 4H). LC-MS: m/z = 532 [M+H]+. [1132] To a solution of 1-(4-chlorophenoxy)-4,4-difluoro-N-(3-(5-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)thiophen-3-yl)phenyl)cyclohexane-1-carboxamide (28 mg, 0.053 mmol) in glacial acetic acid (1 mL), was added zinc (70 mg, 1.1 mmol) and stirred at 70 oC for 18 h. The reaction mixture was subjected to conditions described in Method B and purified by reverse phase HPLC to obtain 13 mg (46%) N-(3-(5-carbamimidoylthiophen-3-yl)phenyl)-1- (4-chlorophenoxy)-4,4-difluorocyclohexane-1-carboxamide (29) as a formate salt.1H NMR (METHANOL-d4, 400 MHz) δ 8.48 (br s, 2H), 8.32 (d, 1H, J=1.5 Hz), 8.19 (br s, 1H), 8.03 (br s, 1H), 7.40-7.51 (m, 3H), 7.31-7.33 (m, 2H), 6.99-7.02 (m, 2H), 2.38-2.42 (m, 2H), 2.24- 2.30 (m, 2H), 2.02-2.09 (m, 4H). LC-MS: m/z = 490, 492 [M+H]+. REFERENCES FOR EXAMPLES 6 AND 7 [1133] 1. Sijbesma, E. et al. J. Am. Chem. Soc.141, 3524–3531 (2019). 2. Guillory, X. et al. J. Med. Chem.63, 6694–6707 (2020). 3. Centorrino, F., Andlovic, B., Cossar, P., Brunsveld, L. & Ottmann, C. Curr. Res. Struct. Biol.4, 21–28 (2022). 4. Potterton, L. et al. Acta Crystallogr. Sect. D Struct. Biol.74, 68–84 (2018). 5. Winter, G. et al. Acta Crystallogr. Sect. D Struct. Biol.74, 85–97 (2018). 6. Vagin, A. & Teplyakov, A. Acta Crystallogr. Sect. D 66, 22–25 (2010). 7. Emsley, P. & Cowtan, K. Acta Crystallogr. Sect. D Biol. Crystallogr.60, 2126–2132 (2004). 8. Moriarty, N. W., Grosse-Kunstleve, R. W. & Adams, P. D. Acta Crystallogr. Sect. D 65, 1074–1080 (2009). 9. Afonine, P. V et al. Acta Crystallogr. Sect. D 68, 352–367 (2012). 10. Adams, P. D. et al. Acta Crystallogr. Sect. D Biol. Crystallogr.66, 213–221 (2010). 11. Karplus, P. A. & Diederichs, K. Science (80-. ). 336, 1030–1034 (2012).

Claims

WHAT IS CLAIMED IS: 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; are a or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; each R10, R20, R30, and R40 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. 2. The compound of claim 1, having the formula: . formula: R1 L2 1 R2 L A R3 R4 . . is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. 6. The compound of claim 1, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. is , , , 9. The compound of claim 1, wherein R2 is -Cl. 10. The compound of claim 1, wherein R3 and R4 combine to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. 11. The compound of claim 1, wherein R3 and R4 combine to form a substituted or unsubstituted tetrahydropyranyl. 12. The compound of claim 1, wherein R3 and R4 combine to form: . claim 1, wherein L1 is a bond or unsubstituted C1-C4 alkylene. 14. The compound of claim 1, wherein L1 is a bond or unsubstituted methylene. 15. The compound of claim 1, wherein L2 is a bond. 16. The compound of claim 1, wherein R1 is E. 17. The compound of claim 16, wherein E is , O X11 N , -CBr3, - - - - - - - - - - - -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. 18. The compound of claim 17, wherein R11, R12, R13, and R14 are hydrogen. 19. The compound of claim 1, wherein R1 is O Cl . 1, having the formula: O , H N O 21. A compound, or a pharmaceutically acceptable salt thereof, having the formula:
L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L4 is –NR40- or -O-; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R5, R6, R7, and R8 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. 22. The compound of claim 21, having the formula: or formula: (IIIa). the formula: . formula:
or R2 is halogen. 27. The compound of claim 21, wherein R2 is -Cl. 28. The compound of claim 21, wherein L1 is a bond or unsubstituted C1- C4 alkylene. 29. The compound of claim 21, wherein L1 is a bond or unsubstituted methylene. 30. The compound of claim 21, wherein L2 is a bond. 31. The compound of claim 21, wherein R1 is E. 32. The compound of claim 31, wherein E is O R11 ,
R11, R12, R13, and R14 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. 33. The compound of claim 32, wherein R11, R12, R13, and R14 are hydrogen. 34. The compound of claim 21, wherein R1 is . of claim 21, having the formula: ,
, . p , p y p , g the formula: or (O 10 )NR -, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 4; z6 is an integer from 0 to 2; each R10, R20, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. 37. The compound of claim 36, having the formula: . 38. The compound of claim 36, having the formula: (VIIIa). . , e formula: . . O L4 . (VIIIe). 43. The compound of claim 36, having the formula: R3 R4 2 5 (R )z2 N L (VIIIf). -O-. 45. The compound of claim 36, wherein L4 is -NH-. 46. The compound of claim 36, wherein L5 is –NH- or substituted or unsubstituted 2 to 8 membered heteroalkylene. 47. The compound of claim 36, wherein L5 is –NH-, -CH2NH-, or . The compound of claim 36, wherein R2 is independently halogen, -CX23, -C(O)R2C, -C(O)OR2C, -OR2D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. 49. The compound of claim 36, wherein R2 is independently –Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3. 50. The compound of claim 36, wherein z2 is 0. 51. The compound of claim 36, wherein z2 is 1. 52. The compound of claim 36, wherein z2 is 2. 53. The compound of claim 36, wherein R3 and R4 are independently unsubstituted C1-C4 alkyl. 54. The compound of claim 36, wherein R3 and R4 are unsubstituted methyl.
55. The compound of claim 36, wherein R3 and R4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. 56. The compound of claim 36, wherein R3 and R4 combine to form a substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl. 57. The compound of claim 36, wherein R3 and R4 combine to form: NH2 . 59. The compound of claim 36, wherein L2 is a bond. 60. The compound of claim 36, wherein R1 is -C(NR1C)NR1AR1B or -C(O)NR1AR1B. 61. The compound of claim 36, wherein R1 is -C(NH)NH2, -C(NH)NHOH, or –C(O)NH2. 62. The compound of claim 36, wherein R1 is -C(NH)NH2. 63. A pharmaceutical composition comprising the compound of one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 64. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of claims 1 to 62, or a pharmaceutically acceptable salt thereof. 65. The method of claim 64, wherein the cancer is an estrogen receptor positive cancer.
66. The method of claim 64, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. 67. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a subject, said method comprising administering to said subject a compound, or a pharmaceutically acceptable salt thereof, having the formula: cycloalkylene or substituted or unsubstituted heterocycloalkylene; W is O or NH; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; z6 is an integer from 0 to 2; each R10, R20, R30, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, - -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2. 68. A method of increasing the level of a 14-3-3 protein–ERα protein complex in a cell, said method comprising contacting the cell with a compound, or a salt thereof, having the formula:
or ; ituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; L1 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20-, -S(O)2-, -NR20S(O)2-, -S(O)2NR 20-, 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; L3 is -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR30-, -C(O)NR30-, -NR30C(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L4 is –NR40- or -O-; L5 is –NR90- or substituted or unsubstituted heteroalkylene; L6 is a bond or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R2 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; z2 is an integer from 0 to 5; R3 and R4 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 and R4 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R5 and R6 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5; z6 is an integer from 0 to 2; each R10, R20, R30, R40, and R90 is independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R50, R60, R70, and R80 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 and X2 is independently –F, -Cl, -Br, or –I; n1 and n2 are independently an integer from 0 to 4; and m1, m2, v1, and v2 are independently 1 or 2.
69. The method of one of claims 67 to 68, wherein Ring A is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. 70. The method of one of claims 67 to 68, wherein Ring B is a substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted 3 to 8 membered heterocycloalkylene. 71. The method of one of claims 67 to 68, wherein is , R4 combine to form a substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl. 73. The method of one of claims 67 to 68, wherein R3 and R4 combine to form a substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl. 74. The method of one of claims 67 to 68, wherein R3 and R4 combine to form: NH2 , 75. The method of one of claims 67 to 68, wherein W is O.
76. The method of one of claims 67 to 68, wherein W is NH. 77. The method of one of claims 67 to 68, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted C1-C4 alkyl. 78. The method of one of claims 67 to 68, wherein R50, R60, R70, and R80 are independently hydrogen or unsubstituted methyl. 79. The method of one of claims 67 to 68, wherein R2 is independently halogen, -CX2 3, -C(O)R2C, -C(O)OR2C, -OR2D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. 80. The method of one of claims 67 to 68, wherein R2 is independently -Cl, -Br, -CF3, -C(O)CH3, -C(O)OH, or –OCH3. 81. The method of one of claims 67 to 68, wherein z2 is 0. 82. The method of one of claims 67 to 68, wherein z2 is 1. 83. The method of one of claims 67 to 68, wherein z2 is 2. 84. The method of one of claims 67 to 68, wherein L1 is a bond or unsubstituted C1-C4 alkylene. 85. The method of one of claims 67 to 68, wherein L1 is a bond or unsubstituted methylene. 86. The method of one of claims 67 to 68, wherein L2 is a bond. 87. The method of one of claims 67 to 68, wherein R1 is E. 88. The method of claim 87, wherein E is
O R11 N R12 , -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X11, X12, and X13 are independently –F, -Cl, -Br, or –I. 89. The method of claim 88, wherein R11, R12, R13, and R14 are hydrogen. 90. The method of one of claims 67 to 68, wherein R1 is O Cl . 91. The method of one of claims 67 to 68, wherein R1 is -C(NR1C)NR1AR1B or -C(O)NR1AR1B. 92. The method of one of claims 67 to 68, wherein R1 is -C(NH)NH2, -C(NH)NHOH, or –C(O)NH2.
93. The method of one of claims 67 to 68, wherein R1 is -C(NH)NH2. 94. The method of one of claims 67 to 68, wherein the compound has the formula: O Cl O ,
, , ,
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