WO2022032179A1 - Pin1 inhibitors and uses thereof - Google Patents

Pin1 inhibitors and uses thereof Download PDF

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Publication number
WO2022032179A1
WO2022032179A1 PCT/US2021/045081 US2021045081W WO2022032179A1 WO 2022032179 A1 WO2022032179 A1 WO 2022032179A1 US 2021045081 W US2021045081 W US 2021045081W WO 2022032179 A1 WO2022032179 A1 WO 2022032179A1
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substituted
unsubstituted
alkyl
membered
heteroalkyl
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PCT/US2021/045081
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French (fr)
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Daniel M.C. SCHWARZ
Jason E. GESTWISKI
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The Regents Of The University Of California
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Publication of WO2022032179A1 publication Critical patent/WO2022032179A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • This prodrug caging group leverages the consecutive action of esterase activity on the O-carboxy ester, followed by spontaneous liberation of the phospho-ester by intramolecular nucleophilic attack, and then hydrolysis of the N-linked amino ester by a phosphoramidase enzyme, often the histidine triad nucleotide binding protein 1 (HINT1) (Maize KM et al., Mol Pharm.2017; 14(11):3987–97). Together, these enzymatic activities and structural rearrangements release the ProTide in the cytosol, where the active molecule is retained. ProTides have proven especially successful in enhancing the cellular delivery of nucleotide-based anti-viral drugs, including blockbuster drugs (i.e.
  • sofosbuvir (Sofia MJ et al., J Med Chem.2010; 53(19):7202–18.), clinical candidates, i.e. NUC-1031 (Blagden SP et al., Br J Cancer [Internet].2018; 119(7):815–22. Available from: http://dx.doi.org/10.1038/s41416-018-0244-1), and tool molecules (i.e.4Ei-10 (Ahmad Z. et al., Cancer Chemother Pharmacol [Internet].2020; 85(2):425–32. Available from: https://doi.org/10.1007/s00280-020-04029-9)).
  • PIN1 Peptidyl-prolyl isomerase
  • PIN1 activates at least 19 oncogenes/growth enhancers, including ⁇ -catenin, cyclin D1, NF- ⁇ B, c-Jun, c-fos, AKT, A1B1, HER2/Neu, MCI-1, Notch, Raf-1, Stat3, c-Myb, Hbx, Tax, and v-rel, and also inactivates at least 12 tumor suppressors/growth inhibitors, including PML, SMRT, FOXOs, RAR ⁇ , and Smad.
  • PIN1 knockdown inhibits cancer cell growth in cell cultures and mice.
  • PIN1-null mice are highly resistant to tumorigenesis induced either by oncogenes such as activated Ras or HER2/Neu, or tumor suppressors such as p53.
  • PIN1 catalyzes the cis-trans isomerization of proline residues that are adjacent to phosphorylated Ser/Thr (e.g. the pS/T-Pro motif), a motif that is generated by proline-directed kinases (Lu KP et al., Trends Cell Biol [Internet].2002; 12(4):164–72. Available from: http://dx.doi.org/10.1016/S0962-8924(02)02253-5).
  • R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl
  • R 21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 22a and R 22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; wherein R 22a and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl;R 22b and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R 22a and R 22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstit
  • R 2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • X is oxygen or unsubstituted C 1 -C 5 alkylene.
  • -L 1 -R 24 is a fragment of a drug, wherein said drug has the formula HO-P(O) 2 -X-L 1 - R 24 , HO-S(O) 2 -X-L 1 -R 24 or HOOC-X- L 1 -R 24 , wherein -L 1 -R 24 does not comprise a ribose.
  • L 1 is independently a bond, 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.
  • A is –S-, -S(O)2, -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O) 2 , or a bond.
  • R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is hydroxyl, -NH(R 5 ), -N(R 5 )2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R 5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; or R 5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; 3 bstituted or unsubstituted heterocy 1 cloalkyl; Z is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z 2 , wherein Z 2 is –O-, -S-, -NH-, -N(CH
  • Q, Q 1 , Q 2 , and Q 3 are independently -N, -CH 2 - or –CH, and wherein not more than two Q are N.
  • T is –CH or –N; T 1 is –O-, -HN, or –NCH 3 .
  • R and V are independently hydrogen, halogen, hydroxyl, -NH 3 , nitrile, or substituted or unsubstituted alkyl.
  • R 7 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or L-R 7A , wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and R 7A is substituted or unsubstituted aryl; wherein A 1 is hydrogen or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R 18 R 19 ;
  • R 13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR 36 R 37 ;
  • R 14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl;
  • R 15 is –S(O) 2 NR 38 R 39 or –CONR 38 R 39 ;
  • R 16 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyl or substituted or unsubstituted
  • R 26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR 2 , -C(O)R 2 , or –C(O)NR 2 R 4 ;
  • R 2 and R 4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubsti
  • R 31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 32 and R 33 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroc cloalk l substituted or unsubstituted ar l or substituted or unsubstituted heteroaryl.
  • the compound is of formula (VII): pharmaceutically acceptable salt thereof, wherein R 34 and R 35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • Ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.
  • n3 is 0, 1, or 2.
  • a pharmaceutical composition comprising a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.
  • a method of treating a disease or disorder mediated by PIN1 activity comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • a therapeutically effective amount of the compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • a method of treating a disease or disorder mediated by PIN1 activity comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), and a kinase inhibitor or a chemotherapy agent.
  • a therapeutically effective amount of the compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), and a kinase inhibitor or a chemotherapy agent.
  • a method of inhibiting of tumor colony formation comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • a therapeutically effective amount of the compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • a method of delivering the compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a cell, said method comprising a step of contacting the cell with the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), thereby releasing the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) in the cytosol.
  • embodiments e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof
  • FIG.1 depicts schematic of phosphoramidate liberation in a cell.
  • FIGS.2A-2C In vitro binding confirms Pin1 binding by 1(R)-phosphate.
  • FIG.2A While a shortened construct of Pin1 lacking the WW domain is required for the FP competition experiment, full length WT Pin1 can be used for ITC experiments.
  • FIG.2C ITC experiment demonstrated that in the context of FL Pin1, the 1(R)-phosphate binds with 1:1 stoichiometry confirming that Pin1 catalytic domain is the only target of these molecules.
  • FIG.3 depicts cellular liberation of 1-(R).
  • FIGS.4A and 4B depict target engagement by SETSA. Fig.4A.
  • FIGS.5A-5C demonstrate cellular effect of Pin1 inhibition by 1-(R)-phosphoramidate.
  • FIG.5A Treatment of MDA-MB-231 cells with 1(R) for 72 hours resulted in a dose-responsive increase in Pin1 abundance.
  • FIG.5C PC3 cells were treated with 1(R) or (S) at the indicated concentrations and colony number was plotted.1-(R) but not (S) was potently anti-colonogenic in PC3 cells.
  • FIGS.6A-6E Docking experiments in support of the 1(R)- and 1(S)-phosphoramidate metabolites bind to the HINT1 catalytic site in catalytically viable poses.
  • FIG.6A
  • HINT1:Lys- AMS cocrystal structure (4EQE) highlights the tractability of designing non-nucleotide HINT1 substrates. While the polar catalytic pocket is defined and must bind phosphoramidates in a catalytically viable conformation, the distal nucleobase contacts are largely hydrophobic and appear tolerant to structural diversity.
  • FIG.6B The syn diastereomer of 1(R)-phosphoramidate de-esterified metabolite (solid) docked pose in the HINT1 catalytic site largely overlays with the co-crystallized Lys-AMS ligand (transparent) [left].
  • FIG.6C The active diastereomer of sofosbuvir-alanine metabolite which is known to be cleaved by HINT1 was submitted for an identical docking experiment and the lowest energy catalytic site pose is shown overlayed again with the cocrystalized Lys-AMS ligand [left] and is similarly well posed in the catalytic site to 1(R)-Gly [right].
  • FIG.6D The active diastereomer of sofosbuvir-alanine metabolite which is known to be cleaved by HINT1 was submitted for an identical docking experiment and the lowest energy catalytic site pose is shown overlayed again with the cocrystalized Lys-AMS ligand [left] and is similarly well posed in the catalytic site to 1(R)-Gly [right].
  • FIG.6D The active diastereomer of sofosbuvir-alanine metabolite which is known to be cleaved by HINT1 was submitted for an
  • FIGS.7A-7D Summary energy scores for all four possible 1(R)- phosphoramidate glycine metabolites’ docked poses in the catalytic site are similar to sofosbuvir- alanine positive control. Sofosbuvir and 1(R)-phosphoramidate syn diastereomer, which are structurally represented in 6A-6D respectively.
  • FIG.6E Measurements from key catalytic residues H114, H112, and S107 the highest scoring catalytic poses of the syn diastereomer of 1(R)-Gly metabolite and sofosbuvir-Ala metabolite position their phosphoramidates similarly in the HINT1 active site. [0028] FIGS.7A-7D.
  • FIG.7A.1R-phosphate binds potently to the Pin1 catalytic domain and adopts a pose wherein the phenyl group binds the proline pocket and benzothiophene packs on the hydrophobic shelf setting the phosphate in the cationic groove to be coordinated by K63, R68, and R69.
  • FIGS.7B-7D show that
  • FIG.7B depicted PC3 cell colony formation assay full plate.
  • FIG.9 Viability of PC3 cells following a 72 hour MTT assay is unaffected by 1(R)- or 1(S)-phosphoramidate. Pin1 inhibition has shown no significant effect on bulk proliferation/viability on short moderate-confluence growth assays. Points represent individual replicates of this experiment while mean and standard deviation are represented by the bar plot. DETAILED DESCRIPTION I. Definitions [0031] 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.
  • 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).
  • 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., O, 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 to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • 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 an 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.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • the cycloalkyl is fully saturated.
  • the cycloalkyl is monounsaturated.
  • the cycloalkyl is polyunsaturated.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is monounsaturated.
  • the heterocycloalkyl is polyunsaturated.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • 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.
  • 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.
  • a cycloalkyl is a cycloalkenyl.
  • the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • 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.
  • heterocycloalkyl means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system.
  • 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.
  • 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.
  • halo(C1- C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring 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.
  • 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).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazo
  • Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
  • a fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.
  • Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.
  • 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).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • alkylsulfonyl means a moiety having the formula -S(O 2 )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).
  • 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 fo l or .
  • An alkylarylene moiety may be substituted (e.g.
  • the alkylarylene is unsubstituted.
  • 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.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , - C(O)CH2OCH3, and the like.
  • each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
  • Substituents for rings e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O) 2 -, -S(O)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.
  • 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'-.
  • R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OC
  • 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 C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is
  • 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 C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or un
  • 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.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 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
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
  • 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 C 3 -C 8 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
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 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 C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted 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
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
  • 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 alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • 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.
  • substituent groups size-limited substituent groups, and lower substituent groups
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • Certain compounds of the present disclosure possess asymmetric carbon and phosphorous 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 “regioisomers” refers to compounds having the basic carbon skeleton unchanged but their functional groups or substituents change their position on a parent structure.
  • 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.
  • 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.
  • 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 C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 1 substituents are present, each R 1 substituent may be distinguished as R 1A , R 1B , R 1C , R 1D , etc., wherein each of R 1A , R 1B , R 1C , R 1D , etc.
  • variable e.g., moiety or linker
  • a compound or of a compound genus e.g., a genus described herein
  • the unfilled valence(s) of the variable will be dictated by the context in which the variable is used.
  • variable of a compound as described herein when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named “methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or –CH3).
  • variable is the divalent form of a standalone compound (e.g., if the variable is assigned to “PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • bind and bound as used herein is used in accordance with its plain and ordinary meaning and refers to the association between atoms or molecules. The association can be direct or indirect. For example, bound atoms or molecules may be direct, e.g., by covalent bond or linker (e.g.
  • a first linker or 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).
  • non-covalent bond e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g. dipole- dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like.
  • a target e.g., a NF- ⁇ B, a Toll-like receptor protein
  • a moiety is capable of binding a target
  • the moiety is capable of binding with a Kd of less than about 10 ⁇ M, 5 ⁇ M, 1 ⁇ M, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.
  • the terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease may be a cancer.
  • the disease may be an autoimmune disease.
  • the disease may be an inflammatory disease.
  • the disease may be an infectious disease.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc. including solid and lymphoid cancers, kidney, breast, lung, bladder, colon,
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemias, lymphomas, carcinomas and sarcomas.
  • exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, Medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's Disease, and Non-Hodgkin's Lymphomas.
  • Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus.
  • Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non- small cell lung carcinoma, mesothelioma, 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, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract
  • 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, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
  • the term "sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemo
  • 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.
  • 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).
  • 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.
  • treating refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term "treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing.
  • Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • treatment includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.
  • Treating and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is no prophylactic treatment. [0098] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient.
  • the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
  • “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.
  • a “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g.
  • an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0101] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted independently to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, parenteral, 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.
  • the administering does not include administration of any active agent other than the recited active agent.
  • 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 provided herein can be administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the compounds independently 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).
  • the compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • control or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • Cancer model organism as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above.
  • cancer model organisms include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans).
  • cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.
  • the terms “selective” or “selectivity” or the like of a compound refers to the compound’s ability to discriminate between molecular targets .
  • the terms “specific”, “specifically”, “specificity”, or the like of a compound refers to the compound’s ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.
  • the term “Peptidyl-prolyl cis/trans isomerase, or PIN1” refers to an enzyme that isomerases only phospho-Serine/Threonine-Proline motifs in prokaryotic and eukaryotic cells.
  • the term “phosphoramidate” or “ ProTide” refers to a strategy aimed to mask an anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho- ester, such that a release of an active drug requires consecutive enzymatic liberation in the cytosol by an esterase and then by an phosphoramidase.
  • the phosphoramidase is Hint1.
  • Hint1 refers to a histidine triad nucleotide-binding protein 1 that can act as a tumot suppressor.
  • phosphate caging groups refers to a chemical group capable of proteting a phosphate group by masking it as a neutral residue.
  • membrane permeability refers to a passive diffusion rate of permeated molecules across the biomembrane, which depends on charge number, polarity, size, and the molar mass of the molecule.
  • permeable membrane refers to a biomembrane that allows solvents and solutes, i.e., ions and molecules, to pass through them.
  • the term “selectively permeable membrane” refers to a biomembrane that allows certain solutes pass through while blocking others.
  • R 21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 22a and R 22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl
  • R 22a and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl
  • R 22b and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl
  • R 22a and R 22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl
  • R 23 is optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl
  • R 23 is hydrogen, substituted or un
  • R 2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • X is oxygen or unsubstituted C1-C5 alkylene.
  • -L 1 -R 24 is a fragment of a drug, wherein said drug has the formula HO-P(O)2-X-L 1 - R 24 , HO-S(O) 2 -X-L 1 -R 24 or HOOC-X- L 1 -R 24 , wherein -L 1 -R 24 does not comprise a ribose.
  • L 1 is independently a bond, 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.
  • X is oxygen or unsubstituted C1-C5 alkylene. In embodiments, X is oxygen. In embodiments, X is unsubstituted C1-C5 alkylene. In embodiments, X is unsubstituted C1- C 4 alkylene.
  • X is unsubstituted C 1 -C 3 alkylene. In embodiments, X is unsubstituted C1-C2 alkylene. In embodiments, X is unsubstituted C1 alkylene.
  • -L 1 -R 24 is a fragment of a drug, wherein said drug has the formula HO- P(O) 2 -X-L 1 -R 24 , HO-S(O) 2 -X-L 1 -R 24 or HOOC-X- L 1 -R 24 . In embodiments, said drug has the formula HO-P(O) 2 -X-L 1 -R 24 .
  • said drug has the formula HO-S(O) 2 -X-L 1 -R 24 . In embodiments, said drug has the formula HOOC-X- L 1 -R 24 . [0120] In embodiments, -L 1 -R 24 does not comprise a ribose. In embodiments, -L 1 -R 24 inhibits a target protein, when a phosphate, sulfate, phosphonate, sulfonate, or carboxylate group is attached by a linker, wherein the linker is L 1 .
  • -L 1 -R 24 inhibits a target in a biological system when a phosphate, sulfate, phosphonate, sulfonate, or carboxylate group is attached by a linker, wherein the linker is L 1 .
  • -L 1 -R 24 inhibits a target in a biological system when a prodrug is attached by a linker, wherein the linker is L 1 .
  • R 24 is a fragment of a drug, which is defined by formulae (IIa)-(VII).
  • the drug is less permeable to a cell membrane than the compound of formula (I).
  • the drug does not have significant affinity for a known nucleotide binding site.
  • the molecular weight of the compound of formula (I) is about 0.1 - 10.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 0.1 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 0.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 1.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 1.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 2.0 kDa.
  • the molecular weight of the compound of formula (I) is less than 2.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 3.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 3.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 4.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 4.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 5.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 5.5 kDa.
  • the molecular weight of the compound of formula (I) is less than 6.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 6.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 7.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 7.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 8.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 8.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 9.0 kDa.
  • the molecular weight of the compound of formula (I) is less than 9.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 10.0 kDa.
  • L 1 is a bond, 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. In embodiments, L 1 is a bond.
  • L 1 is a 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 1 is a substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene), a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), a substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), a substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), a substituted or unsubstituted arylene (e.g.,
  • L 1 is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, wherein each substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, or substituted heteroarylene is substituted with at least one substituent group (i.e., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, or substituted heteroarylene).
  • L 1 is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, wherein each alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is unsubstituted (i.e., unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, or unsubstituted heteroarylene).
  • L 1 is a substituted or unsubstituted alkylene.
  • L 1 is (CH 2 ) n4 , and n4 is an integer from 0 to 4.
  • L 1 is methylene or ethylene.
  • R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In embodiments, R 20 is hydrogen.
  • R 20 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • R 20 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstitute
  • R 20 is unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or unsubstituted aryl (e.g., C6-C10, C6, or phenyl).
  • alkyl e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4
  • unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • unsubstituted cycloalkyl e.g., C3-C8, C3-C6, or C5-C
  • R 20 is R 40 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 40 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 40 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), or R 40 - substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • alkyl e.g., C 1 -C 8 alkyl, C 1
  • R 20 is R 40 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 20 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 20 is R 40 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 20 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 20 is R 40 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 20 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 20 is R 40 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 20 is unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 40 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, R 41 -substituted or unsubstituted
  • R 40 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 40 is R 41 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 41 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 41 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 41 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R
  • R 41 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 42 -substituted or un
  • R 41 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 41 is R 42 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), R 42 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 42 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 42 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 42 -
  • R 42 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (
  • R 42 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 42 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., 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 pheny
  • R 21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R 21 is hydrogen. [0141] In embodiments, R 21 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ) or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • R 21 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -
  • R 21 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • R 21 is R 43 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) or R 43 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 21 is R 43 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 21 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
  • R 21 is R 43 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 21 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 43 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 44 -substituted or
  • R 43 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 43 is R 44 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 44 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 44 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 44 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R
  • R 44 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, R 45 -substituted or unsubstituted
  • R 44 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 44 is R 45 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 45 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 45 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 45 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • alkyl
  • R 45 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (
  • R 45 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 45 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or pheny
  • R 22a and R 22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • R 22a and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl.
  • R 22b and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl.
  • R 22a and R 22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.
  • R 22a and R 22b are independently hydrogen.
  • R 22a and R 22b are substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C 1 -C 4 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C 6 -C 10 , C 6 , or phenyl).
  • aryl e.g., C 6 -C 10 , C 6 , or phenyl
  • R 22a and R 22b are unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), or unsubstituted aryl (e.g., C 6 -C 10 , C 6 , or phenyl).
  • alkyl e.g., C1-C8, C1-C6, or C1-C4
  • cycloalkyl e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6
  • aryl e.g., C 6 -C 10 , C 6 , or phenyl
  • R 22a and R 22b are R 46 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 46 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), or R 60 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • alkyl e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl
  • R 46 -substituted or unsubstituted cycloalkyl e.g., C3-C8 cycloalky
  • R 22a and R 22b are R 46 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 22a and R 22b are unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 22a and R 22b are R 46 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 22a and R 22b are R 46 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl).
  • R 46 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 22a and R 22b are R 46 - substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 22a and R 22b are unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • R 46 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 47 -substituted or un
  • R 46 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 46 is R 47 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), R 47 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 47 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 47 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 47 -
  • R 47 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 48 - substituted or unsubsti
  • R 47 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 47 is R 48 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 48 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 48 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 48 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 48 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, unsubstituted alkyl (e.g.,
  • R 48 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 48 is independently 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., C 3 -C 8 cycloalkyl, C 3 - C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or pheny
  • R 23 is hydrogen, -C(O)OR 2 , -C(O)R 2 , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 23 is hydrogen.
  • R 23 is halogen.
  • R 23 is –F, -Cl, -Br, or –I.
  • R 23 is -C(O)OR 2 or -C(O)R 2 .
  • R 2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 2 is hydrogen.
  • R 2 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl.
  • R 2 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 2 is phenyl or naphthalenyl.
  • R 23 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted (e.g., substituted with a substituent group, a size-limited substituent
  • R 23 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0173] In embodiments, R 23 is R 49 -substituted alkyl (e
  • R 23 is R 49 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 23 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 23 is R 49 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 23 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 23 is R 49 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 23 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 23 is R 49 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R 23 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R 23 is R 49 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 23 is unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 23 is R 49 -substituted heteroaryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 23 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered).
  • R 49 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, R 50 -substituted or unsubstituted
  • R 49 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br,
  • R 49 is R 50 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), R 50 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 50 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 50 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
  • alkyl e
  • R 50 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I,
  • R 50 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 50 is R 51 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 51 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 51 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 51 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R
  • R 51 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (e
  • R 51 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 51 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • aryl e
  • the drug is a PIN1 inhibitor.
  • the compound is of formula (IIa): pharmaceutically acceptable salt thereof, wherein X, R 20 , R 21 , R 22a , R 22b , and R 23 are as defined above, including embodiments thereof.
  • n is 0, 1, or 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.
  • A is –S-, -S(O) 2 , -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O)2, or a bond.
  • A is –S-, -S(O)2, -O-Y-, -Y-S-, or -S-Y, wherein Y is C(O), C(S), S(O), S(O)2, or a bond.
  • A is –S-.
  • A is -S(O) 2 .
  • A is -O-Y-, wherein Y is C(O), C(S), S(O), S(O) 2 , or a bond.
  • A is -Y-S-, wherein Y is C(O), C(S), S(O), S(O) 2 , or a bond.
  • Y is C(O).
  • Y is C(S).
  • Y is S(O).
  • Y is S(O)2.
  • Y is a bond.
  • A is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, A is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, A is a substituted or unsubstituted alkyl, wherein alkyl is unsubstituted (i.e., unsubstituted alkyl).
  • A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl.
  • R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5- C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e
  • R 1 is unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0192] In embodiments, R 1 is R 52 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 52 -substituted or unsubstituted hetero
  • R 1 is R 52 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 1 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 1 is R 52 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 1 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 1 is R 52 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 1 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • R 1 is R 52 -substituted heteroaryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 1 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered).
  • R 52 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2
  • R 52 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 52 is R 53 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 53 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 53 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 53 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 53 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 54 - substituted or unsubstit
  • R 53 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 53 is R 54 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 54 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 54 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 54 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • alkyl
  • R 54 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, unsubstituted alkyl (e.
  • R 54 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 54 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or pheny
  • R 3 is hydroxyl, -NH(R 5 ), -N(R 5 )2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is hydroxyl.
  • R 3 is -NH(R 5 ) or -N(R 5 ) 2.
  • R 5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
  • R 5 is hydrogen.
  • R 5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl.
  • R 5 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1- C 4 alkyl) or a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. In embodiments, R 5 is phenyl or naphthalenyl. [0207] In embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group), substituted (e.
  • R 3 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0210] In embodiments, R 3 is R 55 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl,
  • R 3 is R 55 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 3 is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 3 is R 55 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl.
  • R 3 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 3 is R 52 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 3 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 3 is R 55 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 3 is unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 3 is R 55 -substituted heteroaryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 3 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered).
  • aryl e.g., C6-C10 aryl, C10 aryl, or phenyl
  • R 3 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or
  • R 55 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, R 56 -substituted or unsubstituted
  • R 55 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 55 is R 56 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 56 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 56 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 56 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 56 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I,
  • R 56 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br,
  • R 56 is R 57 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), R 57 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 57 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 57 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 57 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, unsubstituted alkyl (e.g.,
  • R 57 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 57 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., 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
  • aryl e
  • Ring B is a 5-6 membered substituted or unsubstituted heterocycloalkyl.
  • Z 1 is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z 2 , wherein Z 2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-.
  • R 6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
  • Ring B is a substituted or unsubstituted heterocycloalkyl.
  • Ring B is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • Ring B is a substituted or unsubstituted heterocycloalkyl, wherein each substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl).
  • Ring B is a substituted or unsubstituted heterocycloalkyl, wherein each heterocycloalkyl is unsubstituted (i.e., unsubstituted heterocycloalkyl).
  • ring B is morpholinyl, pyrazinyl, or piperazinyl.
  • Z 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.
  • Z 1 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • a substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Z 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, wherein each substituted heterocycloalkyl or each substituted heteroaryl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl or substituted heteroaryl).
  • Z 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, wherein each heterocycloalkyl or heteroaryl is unsubstituted (i.e., unsubstituted heterocycloalkyl or unsubstituted heteroaryl).
  • Z 1 is morpholinyl, pyrazinyl, or piperazinyl. In embodiments, Z 1 is thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazoyl, izoxazolyl, thaizolyl, isothiazolyl, benzimidazolyl, pyrimidinyl, pyridinyl, triazolyl, or tetrazolyl. [0224] In embodiments, Z 1 is C(O)Z 2 . In embodiments, Z 2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH 2 -.
  • Z 2 is –O-. In embodiments, Z 2 is -S-. In embodiments, Z 2 is -NH-. In embodiments, Z 2 is -N(CH 3 )-. In embodiments, Z 2 is -C(O) 2 -. In embodiments, Z 2 is –CH 2 -.
  • R 6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In embodiments, R 6 is hydrogen. [0226] In embodiments, R 6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl.
  • R 6 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • R 6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl.
  • R 6 is phenyl or naphthalenyl.
  • the compound is of formula (III): pharmaceutically acceptable salt thereof, wherein X, R 20 , R 21 , R 22a , R 22b , and R 23 are as defined above, including embodiments thereof.
  • the symbol is a single bond or double bond.
  • n1 is 0 or 1.
  • Q, Q 1 , Q 2 , and Q 3 are independently -N, -CH2- or –CH, wherein not more than two Q are N.
  • T is –CH or –N.
  • T 1 is –O-, -HN, or –NCH 3 .
  • X 1 is –NH.
  • X 1 is -O-.
  • X 1 is -NR’.
  • R’ is a substituted or unsubstituted alkyl.
  • R ’ is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
  • R ’ is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl).
  • R ’ is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl).
  • R’ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl.
  • Y 1 is –C(O)-, -CH2-, -NH-, or -C(O)N(R 9 )-. In embodiments, Y 1 is –C(O)-. In embodiments, Y 1 is -CH 2 -. In embodiments, Y 1 is -NH-. In embodiments, Y 1 is -C(O)N(R 9 )-. In embodiments, R 9 is hydrogen. In embodiments, R 9 is a substituted or unsubstituted alkyl.
  • R 9 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 9 is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, R 9 is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl).
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl.
  • Z 3 is hydrogen.
  • Z 3 is a substituted or unsubstituted alkyl.
  • Z 3 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • Z 3 is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, Z 3 is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, Z 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl.
  • X 1 , Y 1 , and Z 3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. In embodiments, X 1 , Y 1 , and Z 3 are optionally joined together to form a substituted or unsubstituted morpholinyl, pyrazinyl, or piperazinyl. In embodiments, X 1 and Y 1 together form a substituted or unsubstituted heterocycloalkyl. In embodiments, X 1 and Y 1 together form a substituted or unsubstituted morpholinyl, pyrazinyl, or piperazinyl.
  • R and V are independently hydrogen, halogen, hydroxyl, -NH 3 , nitrile, or substituted or unsubstituted alkyl. In embodiments, R and V are independently hydrogen. In embodiments, R and V are independently –F, -Cl, -Br, or –I. In embodiments, R and V are independently hydroxyl. In embodiments, R and V are independently -NH 3 . In embodiments, R and V are independently nitrile. [0237] In embodiments, R and V are independently substituted or unsubstituted alkyl.
  • R and V are independently a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 - C6 alkyl, or C1-C4 alkyl). In embodiments, R and V are independently a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, R and V are independently a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl).
  • R and V are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl.
  • R 7 is L-R 7A , wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and R 7A is substituted or unsubstituted aryl.
  • R 7 is L-R 7A , wherein L is –O- or -S-. In embodiments, L is –O-. In embodiments, L is -S-.
  • R 7 is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • R 7 is a substituted or unsubstituted alkylene (e.g., C1-C8 alkylene,C1-C6 alkylene, or C 1 -C 4 alkylene) or a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • R 7 is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each substituted alkylene or a substituted or unsubstituted heteroalkylene is substituted with at least one substituent group (i.e., substituted alkylene or substituted alkylene).
  • R 7 is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each alkylene or heteroalkylene is unsubstituted (i.e., unsubstituted alkylene or unsubstituted heteroalkylene).
  • L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene.
  • L is a substituted or unsubstituted alkylene (e.g., C1- C 8 alkylene, C 1 -C 6 alkylene, or C 1 -C 4 alkylene) or a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each substituted alkylene or a substituted heteroalkylene is substituted with at least one substituent group (i.e., substituted alkylene or substituted alkylene).
  • L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each alkylene or heteroalkylene is unsubstituted (i.e., unsubstituted alkylene or unsubstituted heteroalkylene).
  • R 7A is substituted or unsubstituted aryl.
  • R 7A is a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 7A is a substituted or unsubstituted aryl, wherein each substituted aryl is substituted with at least one substituent group (i.e., substituted aryl). In embodiments, R 7A is a substituted or unsubstituted aryl, wherein each aryl is unsubstituted (i.e., unsubstituted aryl). In embodiments, R 7A is phenyl or naphthalenyl.
  • R 7 is or , wherein A 1 is hydrogen or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, A 1 is hydrogen. [0243] In embodiments, A 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.
  • a 1 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein each substituted aryl or substituted heteroaryl is substituted with at least one substituent group (i.e., substituted aryl or substituted heteroaryl).
  • a 1 is a substituted or unsubstituted aryl or substituted or unsubstituted heteroarylaryl, wherein each aryl or heteroaryl is unsubstituted (i.e., unsubstituted aryl or unsubstituted heteroaryl).
  • a 1 is phenyl or naphthalenyl.
  • a 1 is thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazoyl, izoxazolyl, thaizolyl, isothiazolyl, benzimidazolyl, pyrimidinyl, pyridinyl, triazolyl, or tetrazolyl.
  • the compound is of formula (IV): p , , , , , , s defined above, including embodiments thereof.
  • the symbol is a single bond or double bond.
  • n2 is 0 or 1.
  • R 12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R 18 R 19 .
  • R 13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR 36 R 37 .
  • R 14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl.
  • R 15 is –S(O)2NR 38 R 39 or –CONR 38 R 39 .
  • R 16 and R 17 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 18 , R 19, R 36 , R 37, R 38 , and R 39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 12 is –C(O)R 18 R 19 , a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl.
  • R 12 is –C(O)R 18 R 19 .
  • R 12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 12 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 12 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 12 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0248] In embodiments, R 18 and R 19 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R 18 and R 19 are independently hydrogen.
  • R 18 and R 19 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 18 and R 19 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 18 and R 19 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 18 and R 19 are independently a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 18 and R 19 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 18 and R 19 are independently phenyl or naphthalenyl. [0250] In embodiments, R 13 is –CONR 36 R 37 , a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl. In embodiments, R 13 is –CONR 36 R 37 .
  • R 13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 13 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 13 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0252] In embodiments, R 36 and R 37 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R 36 and R 37 are independently hydrogen.
  • R 36 and R 37 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 36 and R 37 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • R 36 and R 37 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 36 and R 37 are independently a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 36 and R 37 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 36 and R 37 are independently phenyl or naphthalenyl. [0254] In embodiments, R 14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl.
  • R 14 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or substituted (e.g., substituted with a substituent group, a size-
  • R 14 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or unsubstituted aryl (e.g., C 6 -C 10 , C 6 , or phenyl).
  • alkyl e.g., C1-C8, C1-C6, or C1-C4
  • unsubstituted cycloalkyl e.g., C3-C8, C3-C6, or C5-C6
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • aryl
  • R 14 is R 58 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 58 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 58 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl), or R 58 - substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • alkyl e.g., C1-C8 alkyl, C1
  • R 14 is R 58 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 14 is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 14 is R 58 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 58 -substituted alkyl e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl.
  • R 14 is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6
  • R 14 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 14 is R 58 -substituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl).
  • R 14 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl).
  • R 14 is R 58 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 14 is unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 58 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 59 -substituted
  • R 58 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 58 is R 59 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 59 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 59 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 59 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 member
  • R 59 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2
  • R 59 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 59 is R 60 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), R 60 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 60 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 60 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • alkyl e
  • R 60 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, unsubstituted alkyl (e.g., C
  • R 60 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 60 is independently 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl (e.g.,
  • R 15 is –S(O)2NR 38 R 39 or –CONR 38 R 39 . In embodiments, R 15 is –S(O) 2 NR 38 R 39 . In embodiments, R 15 is–CONR 38 R 39 . In embodiments, R 38 and R 39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R 38 and R 39 are independently hydrogen. [0269] In embodiments, R 38 and R 39 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 38 and R 39 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 38 and R 39 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 38 and R 39 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 38 and R 39 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl.
  • R 38 and R 39 are independently phenyl or naphthalenyl.
  • R 16 and R 17 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R 16 and R 17 are independently hydrogen. [0271] In embodiments, R 16 and R 17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 16 and R 17 are independently a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 16 and R 17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 16 and R 17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 16 and R 17 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 16 and R 17 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • the compound is of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein X, R 20 , R 21 , R 22a , R 22b , and R 23 are as defined above, including embodiments thereof.
  • R 26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR 2 , -C(O)R 2 , or –C(O)NR 2 R 4 .
  • R 2 and R 4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • ring C is a 5-6 membered substituted or unsubstituted heterocycloalkyl.
  • R 26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 26 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.
  • alkyl e
  • R 26 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • alkyl e.g., C1-C8, C1-C6, or C1-C4
  • unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • unsubstituted aryl e.g., C6-C10, C6, or phenyl
  • R 26 is R 61 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 61 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 61 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or R 61 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 al
  • R 26 is R 61 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 26 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 26 is R 461 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 26 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 26 is R 61 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 26 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
  • R 26 is R 61 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 26 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 61 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, R 62 -substituted or unsubstit
  • R 61 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 61 is R 62 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 62 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 62 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 62 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 member
  • R 62 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I
  • R 62 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 62 is R 63 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 63 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 63 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 63 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocyclo
  • R 63 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, unsubstituted alkyl (e.g.,
  • R 63 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I.
  • R 63 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or pheny
  • R 27 , R 28 , and R 29 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R 27 , R 28 , and R 29 are independently hydrogen. [0289] In embodiments, R 27 , R 28 , and R 29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 27 , R 28 , and R 29 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • alkyl e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl
  • a substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • R 27 , R 28 , and R 29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 27 , R 28 , and R 29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 27 , R 28 , and R 29 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 27 , R 28 , and R 29 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • R 30 is hydrogen, -C(O)OR 2 , -C(O)R 2 , or –C(O)NR 2 R 4 , substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 30 is hydrogen.
  • R 30 is -C(O)OR 2 .
  • R 30 is -C(O)R 2 .
  • R 30 is –C(O)NR 2 R 4 .
  • R 30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 30 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • alkyl e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl
  • a substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • R 30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 30 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 30 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0292] In embodiments, R 2 and R 4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R 2 and R 4 are independently hydrogen.
  • R 2 and R 4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl.
  • R 2 and R 4 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 2 and R 4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl).
  • R 2 and R 4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl).
  • R 2 and R 4 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 2 and R 4 are independently phenyl or naphthalenyl.
  • ring C is a substituted or unsubstituted heterocycloalkyl. In embodiments, ring C is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • ring C is a substituted or unsubstituted heterocycloalkyl, wherein each substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl).
  • ring C is a substituted or unsubstituted heterocycloalkyl, wherein each heterocycloalkyl is unsubstituted (i.e., unsubstituted heterocycloalkyl).
  • ring C is pyrazolyl, morpholinyl, or pyrazinyl.
  • the compound is of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein X, R 20 , R 21 , R 22a , R 22b , and R 23 are as defined above, including embodiments thereof.
  • R 31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 32 and R 33 are independently hydrogen, 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.
  • T 2 is –O-, -NH-, or –N(CH3).
  • R 31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 31 is hydrogen. In embodiments, R 31 is hydroxyl. In embodiments, R 31 is amine. [0298] In embodiments, R 31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R 31 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 31 is hydrogen. In embodiments, R 31 is hydroxyl. In embodiments, R 31 is amine.
  • R 31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R 31 is a substituted
  • R 31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 31 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 31 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • R 32 and R 33 are independently hydrogen, 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. In embodiments, R 32 and R 33 are independently hydrogen.
  • R 32 and R 33 are independently a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 - C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited
  • R 32 and R 33 are independently an unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0302] In embodiments, R 32 and R 33
  • R 32 and R 33 are independently R 64 -substituted alkyl (e.g., C 1 -C 8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 32 and R 33 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 32 and R 33 are independently R 64 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 64 -substituted alkyl e.g., C 1 -C 8 alkyl, C1-C6 alkyl, or C1-C4 alkyl.
  • R 32 and R 33 are independently R 64 -substituted heteroalkyl (e.g., 2 to 8 membere
  • R 32 and R 33 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 32 and R 33 are independently R 64 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 32 and R 33 are independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 32 and R 33 are independently R 64 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 32 and R 33 are independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • R 32 and R 33 are independently R 64 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R 32 and R 33 are independently unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 32 and R 33 are independently R 64 -substituted heteroaryl (e.g., C 6 - C10 aryl, C10 aryl, or phenyl).
  • R 32 and R 33 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered).
  • R 64 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2
  • R 64 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 64 is R 65 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 65 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 65 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 65 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 65 - substitute
  • R 65 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R 66 - substituted or unsubsti
  • R 65 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr 2 , -OCHI 2, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F , -OCH 2 Cl, -OCH 2 Br, or -OCH 2 I.
  • R 65 is R 66 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), R 66 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 66 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), R 66 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membere
  • R 66 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCCl 3 , -OCBr 3 , OCI 3 , -OCHF 2 , -OCHCl 2 , -OCHBr 2 , -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I
  • R 66 is independently halogen, -CF 3 , -CCl 3 , -CBr 3 , -CI 3, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -N 3 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,-NHC(O)NHNH 2 , -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -
  • R 66 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phen
  • R 34 and R 35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.
  • R 34 and R 35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 34 and R 35 are independently hydrogen.
  • R 34 and R 35 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl.
  • R 34 and R 35 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • alkyl e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl
  • a substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
  • R 34 and R 35 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl).
  • R 31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl).
  • R 34 and R 35 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R 34 and R 35 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0318] In embodiments, ring D is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.
  • ring D is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) or a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • a substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered.
  • ring D is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl, wherein each substituted cycloalkyl or substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted cycloalkyl or substituted heterocycloalkyl).
  • ring D is a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is unsubstituted (i.e., unsubstituted cycloalkyl or unsubstituted heterocycloalkyl).
  • ring D is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • ring D is pyrazolyl, morpholinyl, or pyrazinyl.
  • n is an integer from 0 to 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. [0320] n1 is an integer from 0 to 1. In embodiments, n1 is 0. In embodiments, n1 is 1. [0321] n2 is an integer from 0 to 1. In embodiments, n2 is 0. In embodiments, n2 is 1. [0322] n3 is an integer from 0 to 2. In embodiments, n3 is 0. In embodiments, n3 is 1. In embodiments, n3 is 2. [0323] n4 is an integer from 0 to 4. In embodiments, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2.
  • n4 is 3. In embodiments, n4 is 4. [0324] X 1 is halogen. In embodiments, halogen is –F, -Cl, -Br, -I. In embodiments, X 1 is –F. In embodiments, X 1 is –Cl. In embodiments, X 1 is –Br. In embodiments, X 1 is –I.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • 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.
  • the compound has the formula as described elsewhere herein, for example within a table, claim or example.
  • the compound is of the formula: .
  • the compound is of the formula:
  • compositions including a compound as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), and a pharmaceutically acceptable excipient.
  • the compounds as described herein of the present disclosure may be in the form of compositions suitable for administration to a subject.
  • compositions are “pharmaceutical compositions” comprising a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII)), and one or more pharmaceutically acceptable or physiologically acceptable excipients (e.g., acceptable diluents or carriers).
  • the compounds are present in a therapeutically effective amount.
  • the pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.
  • compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • the pharmaceutical compositions containing the active ingredient e.g., an inhibitor of Peptidyl-prolyl isomerase, PIN1, or a compound described herein
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture thereof.
  • excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.
  • Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene- vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition.
  • a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene- vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition.
  • the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system.
  • Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polyoxy-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate).
  • dispersing or wetting agents for
  • the aqueous suspensions may also contain one or more preservatives.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
  • the pharmaceutical compositions of the present disclosure may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the pharmaceutical compositions typically comprise a therapeutically effective amount of a compound described herein contemplated by the present disclosure and one or more pharmaceutically and physiologically acceptable formulation agents.
  • Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable buffering agents include, for example, a Tris buffer; N-(2- Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N- Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyl]methyl-3- aminopropanesulfonic acid (TAPS).
  • Tris buffer N-(2- Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)
  • MES 2-(N-Morpholino)ethanesulfonic acid
  • MES 2-(N-Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3-(N- Morpholino)propanesulfonic acid
  • TAPS N
  • a pharmaceutical composition After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
  • the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi- use vial) is provided in other embodiments.
  • a single-use container e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
  • a multi-use container e.g., a multi- use vial
  • Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed
  • Any drug delivery apparatus may be used to deliver a PIN1 inhibitor, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to release a compound disclosed herein over a defined period of time. Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • Acceptable diluents, solvents and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ® EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, find use in the preparation of injectables.
  • Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
  • an agent that delays absorption e.g., aluminum monostearate or gelatin.
  • the present disclosure contemplates the administration of the compounds described herein in the form of suppositories for rectal administration.
  • the suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter and polyethylene glycols.
  • the compounds described herein contemplated by the present disclosure may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use) currently known or developed in the future.
  • IV. Methods of use [0350]
  • a method of treating a disease or disorder mediated by PIN1 activity including administering an effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a patient in need of such treatment.
  • said method further comprising administering to a patient in need thereof a kinase inhibitor or a chemotherapy agent.
  • a method of inhibiting of tumor colony formation comprising administering an effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a patient in need of such treatment.
  • the tumor is a neuroendocrine prostate tumor.
  • a method of delivering a compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), to a cell, said method comprising a step of contacting the cell with the compound described herein, thereby releasing the compound described herein in the cytosol.
  • the cell is a leukemia cell, breast cancer cell, or prostate tumor cell.
  • the cell is a leukemia cell.
  • the cell is a breast cancer cell.
  • the cell is a prostate tumor cell.
  • a compound described herein can be used to treat or prevent a proliferative condition or disorder, including a cancer.
  • the cancer is brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, leukemia, Hodgkin's Disease, or Non-Hodgkin's Lymphoma.
  • cancers that may be treated with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus.
  • structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII) include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus.
  • cancers that may be treated with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), or method provided herein include hematological malignancies.
  • a hematological malignancy is leukemia, lymphoma, or multiple myeloma.
  • additional examples include thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, 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, thyroid cancer, neuroblastoma, esophageal cancer,
  • the present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis.
  • immunogenic tumors e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • virus-induced cancers e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • the disclosure contemplates reducing tolerance to a tumor cell or cancer cell antigen, e.g., by modulating activity of a regulatory T-cell and/or a CD8+ T-cell (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J. Med.349:1501-09).
  • the tumor or cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neutoendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, and lymphoma.
  • cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia.
  • the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neutoendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, and lymphoma.
  • a cancer can be metastatic or at risk of becoming metastatic, or may occur in a diffuse tissue, including cancers of the blood or bone marrow (e.g., leukemia or lymphoma).
  • the compound as described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) can be used to overcome T-cell tolerance.
  • the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein , including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional kinase inhibitor or a chemotherapy agent.
  • the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional kinase inhibitor.
  • the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein , including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional chemotherapy agent.
  • the present disclosure provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder or condition with a compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • a compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof).
  • the hematological malignancy is leukemia.
  • leukemia is acute leukemia.
  • acute leukemia is acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, or acute erythroleukemia.
  • leukemia is chronic leukemia.
  • chronic leukemia is chronic myelocytic leukemia or chronic lymphocytic leukemia.
  • acute leukemia is acute lymphocytic leukemia.
  • acute leukemia is acute myelocytic leukemia.
  • acute leukemia is acute myeloblastic leukemia.
  • acute leukemia is acute promyelocytic leukemia.
  • acute leukemia is acute myelomonocytic leukemia.
  • acute leukemia is acute monocytic leukemia.
  • acute leukemia is acute erythroleukemia.
  • chronic leukemia is chronic myelocytic leukemia.
  • chronic leukemia is chronic lymphocytic leukemia.
  • the hematological malignancy is lymphoma.
  • lymphoma is Hodgkin's lymphoma or Non-Hodgkin's lymphoma.
  • the Non-Hodgkin's lymphoma is a B-cell lymphoma. In embodiments, the Non-Hodgkin's lymphoma is indolent lymphoma. In embodiments, the Non-Hodgkin's lymphoma is aggressive lymphoma.
  • B-cell lymphoma is diffuse B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Burkitt lymphoma, lymphoplasmacytuc lymphoma, or marginal zone lymphoma. In embodiments, B-cell lymphoma is diffuse B-cell lymphoma.
  • B-cell lymphoma is follicular lymphoma. In embodiments, B-cell lymphoma is small lymphocytic lymphoma (SLL). In embodiments, B-cell lymphoma is mantle cell lymphoma (MCL. In embodiments, B-cell lymphoma is Burkitt lymphoma. In embodiments, B-cell lymphoma is lymphoplasmacytuc lymphoma. In embodiments, B-cell lymphoma is marginal zone lymphoma. [0360] In embodiments, the Non-Hodgkin's lymphoma is a T-cell lymphoma.
  • T- cell lymphoma is cutaneous T-cell lymphoma (CTCL), periferal T-cell lymphoma (PTCL), mycosis fungoides, angioimmunoblastic lymphoma, or anaplastic large cell lymphoma.
  • T- cell lymphoma is cutaneous T-cell lymphoma (CTCL).
  • T-cell lymphoma is periferal T-cell lymphoma (PTCL).
  • T-cell lymphoma is mycosis fungoides.
  • T-cell lymphoma is angioimmunoblastic lymphoma.
  • T-cell lymphoma is anaplastic large cell lymphoma.
  • Hodgkin's lymphoma is a classic Hodgkin's lymphoma or nodular lymphocyte-predominant Hodgkin's lymphoma.
  • classic Hodgkin's lymphoma is nodular sclerosis Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte-rich Hodgkin's lymphoma, or lymphocyte-depleted Hodgkin's lymphoma.
  • classic Hodgkin's lymphoma is nodular sclerosis Hodgkin's lymphoma.
  • classic Hodgkin's lymphoma is mixed cellularity Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is lymphocyte-rich Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is lymphocyte-depleted Hodgkin's lymphoma.
  • the cancer is breast cancer. In embodiments, the breast cancer is a metastatic breast cancer. In embodiments, the metastatic breast cancer is a triple negative metastatic breast cancer.
  • a therapeutically effective amount of a compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) results in a cancer survival rate greater than the cancer survival rate observed by not administering a therapeutically effective amount of the compound.
  • the administration of a therapeutically effective amount of a compound described herein results in a reduction of tumor size or a slowing of tumor growth greater than reduction of tumor size or tumor growth observed following lack of administration of a therapeutically effective amount of the compound.
  • Embodiments of the present disclosure contemplate the administration of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of PIN1 modulation.
  • diseases, disorders and conditions may include, for example, human immunodeficiency virus (HIV), hepatitis, herpes, or a neuropsychiatric disorder.
  • the disease or disorder is a human immunodeficiency virus (HIV).
  • the disease or disorder is a hepatitis.
  • the disease or disorder is a hepatitis A, hepatitis B, or hepatitis C. In embodiments, the disease or disorder is a hepatitis A. In embodiments, the disease or disorder is a hepatitis B. In embodiments, the disease or disorder is a hepatitis C. [0367] In embodiments, the disease or disorder is a herpes virus. In embodiments, the herpes virus is HSV-1, HSV-2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, or Kaposi’s sarcoma- associated herpes virus. In embodiments, the herpes virus is HSV-1 virus.
  • the herpes virus is HSV-2 virus. In embodiments, the herpes virus is varicella zoster virus. In embodiments, the herpes virus is Epstein-Barr virus. In embodiments, the herpes virus is cytomegalovirus. In embodiments, the herpes virus is Kaposi’s sarcoma-associated herpes virus.
  • the disease or disorder is a neuropsychiatric disorder. In embodiments, a neuropsychiatric disorder is a brain disease, an anxiety, a mood disorder, an eating disorder, or a learning diability.
  • the neuropsychiatric disorder is an Alzheimer’s disease (AD), Parkinson’s desease (PD), epilepsy, multiple sclerosis, autism, stroke, amnesia, alcoholism, altitude sickness, or attention deficit disorder.
  • the disease or disorder is an Alzheimer’s disease.
  • the disease or disorder is Parkinson’s desease.
  • the disease or disorder is epilepsy.
  • the disease or disorder is multiple sclerosis.
  • the disease or disorder is autism.
  • the disease or disorder is stroke.
  • the disease or disorder is amnesia.
  • the disease or disorder is alcoholism.
  • the disease or disorder is altitude sickness.
  • the disease or disorder is attention deficit disorder.
  • compositions e.g., pharmaceutical salts, pharmaceutical composition
  • Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds disclosed herein over a defined period of time.
  • the administration is oral administration.
  • the administration is parenteral administration.
  • the compounds as described herein, including embodiments may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof.
  • the dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.
  • Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
  • dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject.
  • MTD maximum tolerated dose
  • Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
  • An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it.
  • the “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered.
  • the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors.
  • the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED 50 .
  • an effective dose of the compounds as described herein, including embodiments may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject.
  • an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
  • the compounds as described herein, including embodiments may be administered (e.g., intravenously) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one, two, three, four or more times a day, to obtain the desired therapeutic effect.
  • compositions can be provided in the form of tablets, capsules and the like containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient.
  • a pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g.
  • the dosage of the compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) is contained in a “unit dosage form”.
  • unit dosage form refers to physically discrete units, each unit including a predetermined amount of a compound (e.g., a compound described herein), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved. V.
  • kits including a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) or pharmaceutical compositions thereof.
  • the kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described above.
  • a kit may include one or more of the compounds described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compounds described herein can be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration.
  • the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with, or separately from, the compound.
  • diluents e.g., sterile water
  • buffers e.g., glycerol
  • pharmaceutically acceptable excipients e.g., EDTA
  • kits of the present disclosure may be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • the label or packaging insert may be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial).
  • Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD- ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • a computer readable medium such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD- ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided.
  • NUMBERED EMBODIMENTS [0380] Embodiment 1.
  • R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl
  • R 21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 22a and R 22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, wherein: R 22a and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; R 22b and R 21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R 22a and R 22b are optionally joined together to form a substituted or unsubstituted cycloalkyl;
  • Embodiment 2 The compound of embodiment 1, wherein -L 1 -R 24 does not comprise a ribose.
  • Embodiment 3. The compound of embodiment 1 or 2, wherein said drug is less permeable to a cell membrane than the compound of formula (I).
  • Embodiment 4. The compound of any one of embodiments 1 to 3, wherein the molecular weight of the compound of formula (I) is less than 2 kDa.
  • Embodiment 5. The compound of any one of embodiments 1 to 4, wherein said drug does not have significant affinity for a known nucleotide binding site.
  • Embodiment 6. The compound of any one of embodiments 1 to 5, wherein L 1 is a bond.
  • Embodiment 7 The compound of any one of embodiments 1 to 5, wherein L 1 is a 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.
  • Embodiment 8 The compound of any one of embodiments 1 to 7, wherein said drug is a PIN1 inhibitor.
  • n 0, 1, or 2
  • A is –S-, -S(O) 2 , -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O) 2 , or a bond
  • R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 3 is hydroxyl, -NH(R 5 ), -N(R 5 ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • Embodiment 11 The compound of any one of embodiments 1 to 8, wherein the c m nd i f f rm l IV , pharmaceutically acceptable salt thereof, wherein: the symbol is a single bond or double bond; n2 is 0 or 1; R 12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R 18 R 19 ; R 13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR 36 R 37 ; R 14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl; R 15 is –S(O) 2 NR 38 R 39 or –CONR 38 R 39 ; R 16 is hydrogen, substituted
  • Embodiment 12 The compound of any one of embodiments 1 to 8, wherein the compound is of formula (V): , pharmaceutically acceptable salt thereof, wherein: R 26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR 2 , -C(O)R 2 , or –C(O
  • Embodiment 14 The compound of any one of embodiments 1 to 8, wherein the compound is of formula (VII): pharmaceutically acceptable salt thereof, whe R 34 and R 35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; and n3 is 0, 1, or 2. [0394] Embodiment 15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier. [0395] Embodiment 16.
  • a method of treating a disease or disorder mediated by PIN1 activity comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I).
  • Embodiment 17 The method of embodiment 16, further comprising administering to a patient in need thereof a kinase inhibitor or a chemotherapy agent.
  • Embodiment 18 The method of embodiment 16 or 17, wherein the disease or disorder is a human immunodeficiency virus.
  • Embodiment 19 The method of embodiment 16 or 17, wherein the disease or disorder is a hepatitis virus.
  • Embodiment 20 The method of embodiment 16 or 17, wherein the disease or disorder is a herpes virus.
  • Embodiment 21 The method of embodiment 16 or 17, wherein the disease or disorder is a herpes virus.
  • Embodiment 22 The method of embodiment 16 or 17, wherein the disease or disorder is a neuropsychiatric disorder.
  • Embodiment 22 The method of embodiment 16 or 17, wherein the disease or disorder is cancer.
  • Embodiment 23 The method of embodiment 22, wherein the cancer is leukemia.
  • Embodiment 24 The method of embodiment 22, wherein the cancer is breast cancer.
  • Embodiment 25 The method of embodiment 24, wherein the breast cancer is a metastatic breast cancer.
  • Embodiment 26 The method of embodiment 25, wherein the metastatic breast cancer is triple negative metastatic breast cancer.
  • Embodiment 27 Embodiment 27.
  • Embodiment 28 A method of inhibiting of tumor colony formation, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I).
  • Embodiment 28 The method of embodiment 27, wherein the tumor is a neuroendocrine prostate tumor.
  • Embodiment 29 A method of delivering the compound of formula (I) to a cell, said method comprising a step of contacting the cell with the compound of formula (I), thereby releasing the compound of formula (I) in the cytosol.
  • Embodiment 30 The method of embodiment 29, wherein the cell is a leukemia cell, breast cancer cell, or prostate tumor cell.
  • Embodiment 31 Embodiment 31.
  • the leukemia is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia.
  • the cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile
  • HINT1 is a selective enzyme that is not considered likely to accept non-nucleosides that are structurally distinct from its natural substrates.
  • Pin1-FL Full length Pin1
  • Pin1-FL also contains a WW domain, which has been shown to bind some phosphorylated substrates (Rippmann JF et al., Cell Growth Differ [Internet].2000;11(7):409–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10939594).1(R)-phosphate is potentially selective for the active site.1(R)-phosphate mimics the twisted-amide transition state that is recognized by the catalytic domain, which is known to prefer trans-proline. (Guo et al., supra).
  • the reaction mixture was cooled to -78 ⁇ C and anhydrous triethylamine (1.5 eq) was added dropwise.
  • the mixture was stirred at -78 ⁇ C for 30 minutes and then allowed to slowly warm to ambient temperature. After stirring at ambient temperature for 2 hours, the mixture was concentrated by rotary evaporation with drying column adapter and resuspended in anhydrous diethyl ether. White precipitate was filtered under a blanket of Ar gas. Flow-through was once again concentrated by rotary evaporation under a drying column and resuspended in anhydrous dichloromethane.
  • HINT1 docking experiments The HINT1 co-crystal structure with 5'-O-[(L- lysylamino)sulfonyl]adenosine (Accession: 4EQE) was submitted for docking experiments in SwissDock (6) with all four diastereomers of compound 1-phosphoramidate as well as a sofosbuvir- alanine positive control: Mol2 models of each compound were prepared at a simulated pH 7.0 in Open Bable (7) and were each submitted to identical docking experiments with default settings in SwissDock.
  • HINT1:Lys-AMS cocrystal structure (4EQE) highlighted the tractability of designing non-nucleotide HINT1 substrates. While the polar catalytic pocket is defined and must bind phosphoramidates in a catalytically viable conformation, the distal nucleobase contacts are largely hydrophobic and appeared tolerant to structural diversity.
  • MDA-MB-231 cells were obtained by ATCC and cultured in DMEM supplemented with 10% fetal bovine serum and 100 ⁇ g/mL penicillin/streptomycin.
  • K562 and PC3 cells were obtained by ATCC and cultured in RPMI supplemented with 10% fetal bovine serum and 100 ⁇ g/mL penicillin/streptomycin. All cells were maintained at 37 ⁇ C and 5% CO2 in a humidified incubator.
  • Pin1-cat competition fluorescence polarization Binding and competition binding experiments were conducted as previously described .
  • Isothermal titration calorimetry Affinity and stoicheometry of binding to the full length Pin1 were measured in a microCal ITC200 (General Electric).50 ⁇ M ligand in 0.5% DMSO 50 mM Tris, 50 mM NaCl, pH 7.5 was loaded into syringe. Cell was loaded with 5 ⁇ M Pin1 in 0.5% DMSO, 50 mM Tris, 50 mM NaCl, pH 7.5. Isotherms measured during the titration were converted to their corresponding Wiseman plots using PEAQ-ITC analysis software (Malvern Panalytical).
  • MDA-MB-231 cells were treated under standard growth conditions with 25 ⁇ L 1(R) phosphoramidate or matching concentration of DMSO for 5 hours. Cells were lifted by mechanical scraping, pelleted, and resuspended to a density of 2 million per mL. Cell slurry was portioned to 50 ⁇ L aliquots and were heated to 48 ⁇ C for 4 minutes. Slurry was then cooled to ambient temperature for 4 minutes and snap frozen in liquid nitrogen. Samples were processed and analyzed as K562 samples were. [0439] Pin1 induction assay: MDA-MB-231 cells were treated with 1(R)-phosphoramidate or DMSO for 72 hours and were subsequently lysed in 4% SDS in TBS and boiled.
  • MTT viability assay PC3 cells were plated in a poly-d-lysine-coatedclear 96-well plate at 5,000 cells/well and treated with 1 ⁇ M 1(R)-phosphoramidate, 1(S)-phosphoramidate, or a matched concentration of DMSO. Cells were allowed to proliferate for 72 hours in their given conditions.

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Abstract

Disclosed herein are, inter alia, compounds modulating activity and methods of use thereof for treating PIN1 -mediated disorders.

Description

PIN1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Application No.63/063,175 filed August 7, 2020, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This invention was made with government support under grant no. U54 CA209891 awarded by The National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] Phosphate groups are important in molecular recognition throughout biology. However, inhibitors that incorporate phosphates or phospho-mimetics often become too anionic to be passively permeable to membranes (Lipinski CA, J Pharmacol Toxicol Methods 2000; 44(1):235– 49; Palte MJ et al., J Am Chem Soc.2012; 134(14):6218–23). While removing these features often restores permeability, this improvement comes at the cost of reduced selectivity and weakened potency (Leeson PD, Springthorpe B., Nat Rev Drug Discov.2007; 6(11):881–90). Accordingly, many prodrug strategies have been developed to mask phosphate (Gross DM et al., J Pharmacol Exp Ther.1981;216(3):552–7; Tsien RY, Nature, 1981; 290(5806):527–8; McGuigan C. et al., Antiviral Res.1991; 15(3):255–63), allowing better balance between potency and permeability. One of the most successful are the phosphoramidate “ProTides” (Curley D. et al., Antiviral Res.1990; 14(6):345–56). This prodrug caging group leverages the consecutive action of esterase activity on the O-carboxy ester, followed by spontaneous liberation of the phospho-ester by intramolecular nucleophilic attack, and then hydrolysis of the N-linked amino ester by a phosphoramidase enzyme, often the histidine triad nucleotide binding protein 1 (HINT1) (Maize KM et al., Mol Pharm.2017; 14(11):3987–97). Together, these enzymatic activities and structural rearrangements release the ProTide in the cytosol, where the active molecule is retained. ProTides have proven especially successful in enhancing the cellular delivery of nucleotide-based anti-viral drugs, including blockbuster drugs (i.e. sofosbuvir (Sofia MJ et al., J Med Chem.2010; 53(19):7202–18.), clinical candidates, i.e. NUC-1031 (Blagden SP et al., Br J Cancer [Internet].2018; 119(7):815–22. Available from: http://dx.doi.org/10.1038/s41416-018-0244-1), and tool molecules (i.e.4Ei-10 (Ahmad Z. et al., Cancer Chemother Pharmacol [Internet].2020; 85(2):425–32. Available from: https://doi.org/10.1007/s00280-020-04029-9)). [0004] However, the applicability of this strategy to non-nucleotides is nascent; while ProTides have been shown to improve the plasma lifetime and clogP values for select non-nucleotides, it has not yet clear whether they can be enzymatically liberated in cells (.Serpi M, et al., J Med Chem. 2012; 55(10):4629–39; Lentini NA et al., J Med Chem.2018; 61(19):8658–69; Davey MS et al., J Med Chem.2018; 61(5):2111–7; Miccoli A. et al., Medchemcomm [Internet].2019; 10(2):200–8. Available from: http://dx.doi.org/10.1039/C8MD00244D). [0005] Peptidyl-prolyl isomerase, PIN1, is an attractive cancer target, owing to its high expression in numerous tumors and the strong anti-tumor effects of PIN1 knockdown (Shen M. et al., Genes Dev.1998; 12(5):706–20). That high PIN1 marker levels correlate with poor clinical outcome in many cancers. In contrast, the PIN1 polymorphism that reduces PIN1 expression is associated with reduced cancer risk in humans. Significantly, PIN1 activates at least 19 oncogenes/growth enhancers, including β-catenin, cyclin D1, NF-κB, c-Jun, c-fos, AKT, A1B1, HER2/Neu, MCI-1, Notch, Raf-1, Stat3, c-Myb, Hbx, Tax, and v-rel, and also inactivates at least 12 tumor suppressors/growth inhibitors, including PML, SMRT, FOXOs, RARα, and Smad. Whereas PIN1 overexpression causes cell transformation and tumorigenesis, PIN1 knockdown inhibits cancer cell growth in cell cultures and mice. PIN1-null mice are highly resistant to tumorigenesis induced either by oncogenes such as activated Ras or HER2/Neu, or tumor suppressors such as p53. [0006] PIN1 catalyzes the cis-trans isomerization of proline residues that are adjacent to phosphorylated Ser/Thr (e.g. the pS/T-Pro motif), a motif that is generated by proline-directed kinases (Lu KP et al., Trends Cell Biol [Internet].2002; 12(4):164–72. Available from: http://dx.doi.org/10.1016/S0962-8924(02)02253-5). Potent phosphate-based inhibitors of Pin1, such as 1(R)-phosphate, were described by Pfizer (WO 2004/087720, WO 2006/040646), but these were found to be too polar to be membrane permeable (Guo C. et al., Bioorganic Med Chem Lett [Internet].2009; 19:5613–6. Available from: http://dx.doi.org/10.1016/j.bmcl.2009.08.034). Attempts to improve the clogP of these compounds focused on replacing the phosphate (Guo, supra; Dong L. et al., Bioorganic Med Chem Lett.2010; 20:2210–4; Guo C. et al., Bioorganic Med Chem Lett [Internet].2014; 24(17):4187–91; Available from: http://dx.doi.org/10.1016/j.bmcl.2014.07.044; Potter AJ. et al., Bioorganic Med Chem Lett [Internet].2010;20(2):586–90. Available from: http://dx.doi.org/10.1016/j.bmcl.2009.11.090; Potter A. et al., Bioorganic Med Chem Lett [Internet].2010;20(22):6483–8. Available from: http://dx.doi.org/10.1016/j.bmcl.2010.09.063). Likewise, cyclic peptides (Liu T. et al., J Med Chem [Internet].2010 Mar 25 [cited 2017 Mar 12];53(6):2494–501. Available from: http://pubs.acs.org/doi/abs/10.1021/jm901778v) and covalent inhibitors (Ieda N. et al., Bioorganic Med Chem Lett.2019 Feb 1;29(3):353–6; Dubiella C. et al., bioRxiv.2020) all lacking the phosphate, have been explored. The resulting molecules have relatively limited permeability. [0007] The membrane permeability of nucleotide-based drugs requires installation of phosphate- caging groups. There is an unmet need for non-nucleotide-based phosphate-containing inhibitors of PIN1. The proposed compounds have the potential to deliver potent small molecule inhibitors of PIN1 to address this need. BRIEF SUMMARY [0008] Provided herein, inter alia, are small molecule non-nucleotide-based phosphate-containing inhibitors of PIN1, pharmaceutical compositions comprising these compounds, and the use of these compounds for the treatment of a disease or disorder mediated by PIN1 activity. [0009] In one aspect, provided is a compound of formula (I):
Figure imgf000005_0001
pharmaceutically acceptable salt thereof. R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; R21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R22a and R22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; wherein R22a and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl;R22b and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R22a and R22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)OR2, -C(O)R2, or halogen. R2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. X is oxygen or unsubstituted C1-C5 alkylene. -L1-R24 is a fragment of a drug, wherein said drug has the formula HO-P(O)2-X-L1- R24, HO-S(O)2-X-L1-R24 or HOOC-X- L1-R24, wherein -L1-R24 does not comprise a ribose. L1 is independently a bond, 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. [001 (IIa):
Figure imgf000006_0001
(IIa), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. A is –S-, -S(O)2, -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O)2, or a bond. R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydroxyl, -NH(R5), -N(R5)2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; or R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; 3 bstituted or unsubstituted heterocy 1
Figure imgf000006_0002
cloalkyl; Z is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z2, wherein Z2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-; and R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [
Figure imgf000007_0001
23 R22b R (III), or a pharmaceutically acceptable salt thereof, wherein the symbol is a single bond or double bond, n1 is 0 or 1. Q, Q1, Q2, and Q3 are independently -N, -CH2- or –CH, and wherein not more than two Q are N. T is –CH or –N; T1 is –O-, -HN, or –NCH3. X1 is –NH, -O-, -CH=, or -NR’, wherein R’ is a substituted or unsubstituted alkyl; Y1 is –C(O)-, -CH2-, -NH-, or -C(O)N(R9)-, wherein R9 is hydrogen or a substituted or unsubstituted alkyl; Z3 is hydrogen or a substituted or unsubstituted alkyl; wherein X1, Y1, and Z3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or X and Y1 together form a substituted or unsubstituted heterocycloalkyl. R and V are independently hydrogen, halogen, hydroxyl, -NH3, nitrile, or substituted or unsubstituted alkyl. R7 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or L-R7A, wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and R7A is substituted or unsubstituted aryl; wherein A1 is hydrogen or substituted or unsubstituted aryl,
Figure imgf000007_0002
or substituted or unsubstituted heteroaryl. [0012] Provided herein is the compound of formula (IV): (IV), or
Figure imgf000007_0003
apharmaceutically acceptable salt thereof, wherein the symbol is a single bond or double bond, and n2 is 0 or 1. R12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R18R19; R13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR36R37; R14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl; R15 is –S(O)2NR38R39 or –CONR38R39; R16 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R17 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R18 and R19 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R36 and R37 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R38 and R39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. [0013] Provided herein is the compound of formula (V):
Figure imgf000008_0001
pharmaceutically acceptable salt thereof, wherein R26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR2, -C(O)R2, or –C(O)NR2R4; R2 and R4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. Ring C is a 5-6 membered substituted or unsubstituted heterocycloalkyl. [0014] Provided herein is the compound of formula (VI):
Figure imgf000009_0001
(VI), or a pharmaceutically acceptable salt thereof, wherein R31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R32 and R33 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroc cloalk l substituted or unsubstituted ar l or substituted or unsubstituted
Figure imgf000009_0002
heteroaryl. T2 is –O-, -NH-, or –N(CH3); and T3 is –CH= or –N=. [0015] Provided herein is the compound is of formula (VII): pharmaceutically acceptable salt thereof,
Figure imgf000009_0003
wherein R34 and R35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. Ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. n3 is 0, 1, or 2. [0016] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier. [0017] In another aspect, provided herein is a method of treating a disease or disorder mediated by PIN1 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof). [0018] Further provided herein is a method of treating a disease or disorder mediated by PIN1 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), and a kinase inhibitor or a chemotherapy agent. [0019] Further provided is a method of inhibiting of tumor colony formation, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof). [0020] Further provided is a method of delivering the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a cell, said method comprising a step of contacting the cell with the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), thereby releasing the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) in the cytosol. [0021] In another aspect, provided herein is a kit including a compound described, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), or pharmaceutical compositions thereof. DETAILD DESCRIPTION OF THE DRAWINGS [0022] FIG.1 depicts schematic of phosphoramidate liberation in a cell. [0023] FIGS.2A-2C. In vitro binding confirms Pin1 binding by 1(R)-phosphate. FIG.2A. While a shortened construct of Pin1 lacking the WW domain is required for the FP competition experiment, full length WT Pin1 can be used for ITC experiments. FIG.2B. WFYpSPFLE-FAM was competed off of Pin1 by 1(R)-phosphate more potently than 1(S)-phosphate. Neither 1-(R) or 1-(S) phosphoramidates bind Pin1. FIG.2C. ITC experiment demonstrated that in the context of FL Pin1, the 1(R)-phosphate binds with 1:1 stoichiometry confirming that Pin1 catalytic domain is the only target of these molecules. [0024] FIG.3 depicts cellular liberation of 1-(R). [0025] FIGS.4A and 4B depict target engagement by SETSA. Fig.4A. K562 cells were treated with 1(R)-phosphoramidate or mock-treated and heated along a temperature gradient from 3 –56˚C. Following the thermocycle, cells were lysed under non-denaturing conditions and the lysate was clarified. The soluble fraction was assayed for Pin1 abundance by western blot. FIG.4B. The above experiment was repeated in MDA-MB-231 cells at a fixed temperature (48 ˚C) in biological quadruplicate. [0026] FIGS.5A-5C demonstrate cellular effect of Pin1 inhibition by 1-(R)-phosphoramidate. FIG.5A. Treatment of MDA-MB-231 cells with 1(R) for 72 hours resulted in a dose-responsive increase in Pin1 abundance. FIG.5B. Using Pin1 increase as a biomarker for compound activity, the dependence of 1-(R) on Hint1 activity was tested. When treated with the Hint1 inhibitor TrpGc, Pin1 increase is muted. FIG.5C. PC3 cells were treated with 1(R) or (S) at the indicated concentrations and colony number was plotted.1-(R) but not (S) was potently anti-colonogenic in PC3 cells. [0027] FIGS.6A-6E. Docking experiments in support of the 1(R)- and 1(S)-phosphoramidate metabolites bind to the HINT1 catalytic site in catalytically viable poses. FIG.6A. HINT1:Lys- AMS cocrystal structure (4EQE) highlights the tractability of designing non-nucleotide HINT1 substrates. While the polar catalytic pocket is defined and must bind phosphoramidates in a catalytically viable conformation, the distal nucleobase contacts are largely hydrophobic and appear tolerant to structural diversity. FIG.6B. The syn diastereomer of 1(R)-phosphoramidate de-esterified metabolite (solid) docked pose in the HINT1 catalytic site largely overlays with the co-crystallized Lys-AMS ligand (transparent) [left]. Closer analysis of the catalytic site shows the orientation of the docked phosphoramidate in relation to the catalytic residues [right]. FIG.6C. The active diastereomer of sofosbuvir-alanine metabolite which is known to be cleaved by HINT1 was submitted for an identical docking experiment and the lowest energy catalytic site pose is shown overlayed again with the cocrystalized Lys-AMS ligand [left] and is similarly well posed in the catalytic site to 1(R)-Gly [right]. FIG.6D. Summary energy scores for all four possible 1(R)- phosphoramidate glycine metabolites’ docked poses in the catalytic site are similar to sofosbuvir- alanine positive control. Sofosbuvir and 1(R)-phosphoramidate syn diastereomer, which are structurally represented in 6A-6D respectively. FIG.6E. Measurements from key catalytic residues H114, H112, and S107 the highest scoring catalytic poses of the syn diastereomer of 1(R)-Gly metabolite and sofosbuvir-Ala metabolite position their phosphoramidates similarly in the HINT1 active site. [0028] FIGS.7A-7D. Pin1-cat: 1R-phosphate co-crystal structure (3IKD) binding mode appears disrupted by in silico inversion of the stereocenter to 1S-phosphate. FIG.7A.1R-phosphate binds potently to the Pin1 catalytic domain and adopts a pose wherein the phenyl group binds the proline pocket and benzothiophene packs on the hydrophobic shelf setting the phosphate in the cationic groove to be coordinated by K63, R68, and R69. FIGS.7B-7D. The PDB file 3IKD was manipulated in PyMol to invert the stereochemistry of the chiral carbon in 1R-phosphate to approximate 1S-phosphate binding to Pin1 catalytic domain while maintaining as many contacts as possible. When cationic groove and hydrophobic shelf contacts are maintained (FIG.7B), the phenyl group sterically clashes with the contour of the proline pocket. If proline pocket and hydrophobic shelf packing are maintained (FIG.7C), the phosphate is displaced from the cationic groove. If cationic groove and proline pocket are maintained (FIG.7D), the hydrophobic benzothiophene is left solvated. [0029] FIG.8 depicted PC3 cell colony formation assay full plate. Data in Figure 5C is a quantification of the above experiments. [0030] FIG.9. Viability of PC3 cells following a 72 hour MTT assay is unaffected by 1(R)- or 1(S)-phosphoramidate. Pin1 inhibition has shown no significant effect on bulk proliferation/viability on short moderate-confluence growth assays. Points represent individual replicates of this experiment while mean and standard deviation are represented by the bar plot. DETAILED DESCRIPTION I. Definitions [0031] 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. [0032] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equially encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to –OCH2-. [0033] 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. [0034] 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. [0035] 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., O, 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, -CH2-S-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. [0036] 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 to, -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 an 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. [0037] 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. [0038] 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. [0039] 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. [0040] 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. [0041] 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. [0042] 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. [0043] 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. [0044] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein. [0045] 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. [0046] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0047] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0048] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”). [0049] 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 fo l
Figure imgf000018_0001
or . [0050] 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. [0051] 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. [0052] 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', -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, -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). [0053] 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. [0054] 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. [0055] 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. [0056] 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. [0057] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0058] 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, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4 H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCH F2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, - CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, 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). [0059] 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. [0060] 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 C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0061] 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. [0062] 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. [0063] 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. [0064] 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). [0065] 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. [0066] 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. [0067] 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. [0068] 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. [0069] Certain compounds of the present disclosure possess asymmetric carbon and phosphorous 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. [0070] 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. As used herein, the term “regioisomers” refers to compounds having the basic carbon skeleton unchanged but their functional groups or substituents change their position on a parent structure. [0071] 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. [0072] 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. [0073] 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. [0074] 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. [0075] 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. [0076] 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. [0077] “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0078] 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. [0079] 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 R1 substituents are present, each R1 substituent may be distinguished as R1A, R1B, R1C, R1D, etc., wherein each of R1A, R1B, R1C, R1D, etc. is defined within the scope of the definition of R1 and optionally differently. [0080] 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. [0081] A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named “methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or –CH3). Likewise, for a linker variable (e.g., L1, L2, or L3 as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to “PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG). [0082] As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. [0083] The terms “bind” and “bound” as used herein is used in accordance with its plain and ordinary meaning and refers to the association between atoms or molecules. The association can be direct or indirect. For example, bound atoms or molecules may be direct, e.g., by covalent bond or linker (e.g. a first linker or 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). [0084] The term “capable of binding” as used herein refers to a moiety (e.g. a compound as described herein) that is able to measurably bind to a target (e.g., a NF-κB, a Toll-like receptor protein). In embodiments, where a moiety is capable of binding a target, the moiety is capable of binding with a Kd of less than about 10 µM, 5 µM, 1 µM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM. [0085] The terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease. In some further instances, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma. [0086] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, Medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's Disease, and Non-Hodgkin's Lymphomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non- small cell lung carcinoma, mesothelioma, 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, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. [0087] 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. [0088] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma. [0089] 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. [0090] 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. [0091] 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. [0092] 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. [0093] 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. [0094] 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. [0095] The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. [0096] “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. [0097] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is no prophylactic treatment. [0098] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. [0099] “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. [0100] A “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0101] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0102] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. [0103] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. [0104] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted independently to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0105] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, 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. In embodiments, the administering does not include administration of any active agent other than the recited active agent. [0106] As used herein, the term "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 provided herein can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds independently 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 disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0107] As used herein, the term “control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples). [0108] Cancer model organism, as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans. [0109] As used herein, the terms “selective” or “selectivity” or the like of a compound refers to the compound’s ability to discriminate between molecular targets . [0110] As used herein, the terms “specific”, “specifically”, “specificity”, or the like of a compound refers to the compound’s ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell. [0111] As used herein, the term “Peptidyl-prolyl cis/trans isomerase, or PIN1”, refers to an enzyme that isomerases only phospho-Serine/Threonine-Proline motifs in prokaryotic and eukaryotic cells. [0112] As used herein, the term “phosphoramidate” or “ ProTide” refers to a strategy aimed to mask an anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho- ester, such that a release of an active drug requires consecutive enzymatic liberation in the cytosol by an esterase and then by an phosphoramidase. In embodiments, the phosphoramidase is Hint1. [0113] As used herein “Hint1” refers to a histidine triad nucleotide-binding protein 1 that can act as a tumot suppressor. [0114] As used herein, the term “phosphate caging groups” refers to a chemical group capable of proteting a phosphate group by masking it as a neutral residue. [0115] As used herein, the term “membrane permeability” refers to a passive diffusion rate of permeated molecules across the biomembrane, which depends on charge number, polarity, size, and the molar mass of the molecule. As used herein, the term “permeable membrane” refers to a biomembrane that allows solvents and solutes, i.e., ions and molecules, to pass through them. As used herein, the term “selectively permeable membrane” refers to a biomembrane that allows certain solutes pass through while blocking others. II. Compounds [0116] In an aspect, provided herein is a compound of formula (I): pharmaceutically acceptable salt thereof. [
Figure imgf000038_0001
stituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; R21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R22a and R22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; wherein R22a and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl;R22b and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R22a and R22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)OR2, -C(O)R2, or halogen. R2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. X is oxygen or unsubstituted C1-C5 alkylene. -L1-R24 is a fragment of a drug, wherein said drug has the formula HO-P(O)2-X-L1- R24, HO-S(O)2-X-L1-R24 or HOOC-X- L1-R24, wherein -L1-R24 does not comprise a ribose. L1 is independently a bond, 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. [0118] In embodiments, X is oxygen or unsubstituted C1-C5 alkylene. In embodiments, X is oxygen. In embodiments, X is unsubstituted C1-C5 alkylene. In embodiments, X is unsubstituted C1- C4 alkylene. In embodiments, X is unsubstituted C1-C3 alkylene. In embodiments, X is unsubstituted C1-C2 alkylene. In embodiments, X is unsubstituted C1 alkylene. [0119] In embodiments, -L1-R24 is a fragment of a drug, wherein said drug has the formula HO- P(O)2-X-L1-R24, HO-S(O)2-X-L1-R24 or HOOC-X- L1-R24. In embodiments, said drug has the formula HO-P(O)2-X-L1-R24. In embodiments, said drug has the formula HO-S(O)2-X-L1-R24. In embodiments, said drug has the formula HOOC-X- L1-R24. [0120] In embodiments, -L1-R24 does not comprise a ribose. In embodiments, -L1-R24 inhibits a target protein, when a phosphate, sulfate, phosphonate, sulfonate, or carboxylate group is attached by a linker, wherein the linker is L1. In embodiments, -L1-R24 inhibits a target in a biological system when a phosphate, sulfate, phosphonate, sulfonate, or carboxylate group is attached by a linker, wherein the linker is L1. In embodiments, -L1-R24 inhibits a target in a biological system when a prodrug is attached by a linker, wherein the linker is L1. [0121] In embodiments, R24 is a fragment of a drug, which is defined by formulae (IIa)-(VII). [0122] In embodiments, the drug is less permeable to a cell membrane than the compound of formula (I). In embodiments, the drug does not have significant affinity for a known nucleotide binding site. [0123] In embodiments, the molecular weight of the compound of formula (I) is about 0.1 - 10.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 0.1 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 0.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 1.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 1.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 2.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 2.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 3.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 3.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 4.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 4.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 5.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 5.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 6.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 6.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 7.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 7.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 8.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 8.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 9.0 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 9.5 kDa. In embodiments, the molecular weight of the compound of formula (I) is less than 10.0 kDa. [0124] In embodiments, L1 is a bond, 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. In embodiments, L1 is a bond. [0125] In embodiments, L1 is a 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. In embodiments, L1 is a substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), a substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), a substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), a substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L1 is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, wherein each substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, or substituted heteroarylene is substituted with at least one substituent group (i.e., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, or substituted heteroarylene). In embodiments, L1 is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, wherein each alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is unsubstituted (i.e., unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, or unsubstituted heteroarylene). L1 is a substituted or unsubstituted alkylene. In embodiments, L1 is (CH2)n4, and n4 is an integer from 0 to 4. In embodiments, L1 is methylene or ethylene. [0126] In embodiments, R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In embodiments, R20 is hydrogen. [0127] In embodiments, R20 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In embodiments, R20 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0128] In embodiments, R20 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0129] In embodiments, R20 is R40-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R40-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R40-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or R40- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0130] In embodiments, R20 is R40-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is R40-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R20 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R20 is R40-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is R40-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R20 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0131] R40 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R41-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R41-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R41-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R41-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R41-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R41-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0132] In embodiments, R40 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0133] In embodiments, R40 is R41-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R41-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R41-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R41- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R41-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R41-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0134] R41 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R42-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R42-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R42-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R42-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R42-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R42-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0135] In embodiments, R41 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0136] In embodiments, R41 is R42-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R42-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R42-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R42- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R42-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R42-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0137] R42 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0138] In embodiments, R42 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0139] In embodiments, R42 is independently 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). [0140] In embodiments, R21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R21 is hydrogen. [0141] In embodiments, R21 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4) or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). [0142] In embodiments, R21 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). [0143] In embodiments, R21 is R43-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or R43-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0144] In embodiments, R21 is R43-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is R43-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R21 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0145] R43 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R44-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R44-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R44-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R44-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R44-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R44-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0146] In embodiments, R43 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0147] In embodiments, R43 is R44-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R44-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R44-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R44- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R44-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R44-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0148] R44 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R45-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R45-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R45-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R45-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R45-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R45-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0149] In embodiments, R44 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0150] In embodiments, R44 is R45-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R45-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R45-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R45- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R45-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R45-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0151] R45 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0152] In embodiments, R45 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0153] In embodiments, R45 is independently 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). [0154] In embodiments, R22a and R22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In embodiments, R22a and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R22b and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R22a and R22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. In embodiments, R22a and R22b are independently hydrogen. [0155] In embodiments, R22a and R22b are substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0156] In embodiments, R22a and R22b are unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0157] In embodiments, R22a and R22b are R46-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R46-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0158] In embodiments, R22a and R22b are R46-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R22a and R22b are unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R22a and R22b are R46-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R46 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R22a and R22b are R46- substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R22a and R22b are unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0159] R46 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R47-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R47-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R47-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R47-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R47-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R47-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0160] In embodiments, R46 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0161] In embodiments, R46 is R47-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R47-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R47-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R47- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R47-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R47-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0162] R47 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R48- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R48-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R48-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R48-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R48-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R48-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0163] In embodiments, R47 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0164] In embodiments, R47 is R48-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R48-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R48-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R48- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R48-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R48-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0165] R48 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0166] In embodiments, R48 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0167] In embodiments, R48 is independently 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). [0168] In embodiments, R23 is hydrogen, -C(O)OR2, -C(O)R2, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0169] In embodiments, R23 is hydrogen. In embodiments, R23 is halogen. In embodiments, R23 is –F, -Cl, -Br, or –I. [0170] In embodiments, R23 is -C(O)OR2 or -C(O)R2. In embodiments, R2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R2 is hydrogen. In embodiments, R2 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). Im embodiments, R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. In embodiments, R2 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 is phenyl or naphthalenyl. [0171] In embodiments, R23 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0172] In embodiments, R23 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0173] In embodiments, R23 is R49-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R49-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R49-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R49- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R49-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R49- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0174] In embodiments, R23 is R49-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is R49-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R23 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R23 is R49-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is R49-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R23 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R23 is R49-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is R49-substituted heteroaryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0175] R49 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R50-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R50-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R50-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R50-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R50-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R50-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0176] In embodiments, R49 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0177] In embodiments, R49 is R50-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R50-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R50-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R50- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R50-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R50-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0178] R50 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R51-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R51-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R51-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R51-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R51-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R51-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0179] In embodiments, R50 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0180] In embodiments, R50 is R51-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R51-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R51-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R51- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R51-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R51-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0181] R51 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0182] In embodiments, R51 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0183] In embodiments, R51 is independently 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). [0184] In embodiments, the drug is a PIN1 inhibitor. [0185] In embodiments, the compound is of formula (IIa):
Figure imgf000054_0001
pharmaceutically acceptable salt thereof, wherein X, R20, R21, R22a, R22b, and R23 are as defined above, including embodiments thereof. [0186] In embodiments, n is 0, 1, or 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. [0187] In embodiments, A is –S-, -S(O)2, -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O)2, or a bond. In embodiments, A is –S-, -S(O)2, -O-Y-, -Y-S-, or -S-Y, wherein Y is C(O), C(S), S(O), S(O)2, or a bond. In embodiments, A is –S-. In embodiments, A is -S(O)2. A is -O-Y-, wherein Y is C(O), C(S), S(O), S(O)2, or a bond. In embodiments, A is -Y-S-,, wherein Y is C(O), C(S), S(O), S(O)2, or a bond. In embodiments, Y is C(O). In embodiments, Y is C(S). In embodiments, Y is S(O). In embodiments, Y is S(O)2. In embodiments, Y is a bond. [0188] In embodiments, A is a substituted or unsubstituted alkyl. In embodiments, A is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, A is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, A is a substituted or unsubstituted alkyl, wherein alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. [0189] In embodiments, R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0190] In embodiments, R1 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5- C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0191] In embodiments, R1 is unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0192] In embodiments, R1 is R52-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R52-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R52-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R52-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0193] In embodiments, R1 is R52-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is R52-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R1 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R1 is R52-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is R52-substituted heteroaryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0194] R52 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R53-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R53-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R53-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R53-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R53-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R53-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0195] In embodiments, R52 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0196] In embodiments, R52 is R53-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R53-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R53-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R53- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R53-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R53-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0197] R53 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R54- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R54-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R54-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R54-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R54-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R54-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0198] In embodiments, R53 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0199] In embodiments, R53 is R54-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R54-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R54-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R54- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R54-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R54-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0200] R54 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0201] In embodiments, R54 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0202] In embodiments, R54 is independently 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). [0203] In embodiments, R3 is hydroxyl, -NH(R5), -N(R5)2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3 is hydroxyl. In embodiments, R3 is -NH(R5) or -N(R5)2. [0204] In embodiments, R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [0205] In embodiments, R5 is hydrogen. [0206] In embodiments, R5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. In embodiments, R5 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1- C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R5 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. In embodiments, R5 is phenyl or naphthalenyl. [0207] In embodiments, R3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0208] In embodiments, R3 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0209] In embodiments, R3 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0210] In embodiments, R3 is R55-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R55-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R55-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R55-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R55-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0211] In embodiments, R3 is R55-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is R55-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is R52-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R3 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R3 is R55-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is R55-substituted heteroaryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0212] R55 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R56-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R56-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R56-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R56-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R56-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R56-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0213] In embodiments, R55 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0214] In embodiments, R55 is R56-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R56-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R56-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R56- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R56-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R56-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0215] R56 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R57-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R57-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R57-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R57-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R57-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R57-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0216] In embodiments, R56 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0217] In embodiments, R56 is R57-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R57-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R57-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R57- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R57-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R57-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0218] R57 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0219] In embodiments, R57 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0220] In embodiments, R57 is independently 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). [ , -A-R3 is:
Figure imgf000062_0001
(IIb). In embodiments, Ring B is a 5-6 membered substituted or unsubstituted heterocycloalkyl. In embodiments, Z1 is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z2, wherein Z2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-. In embodiments, R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [0222] In embodiments, Ring B is a substituted or unsubstituted heterocycloalkyl. In embodiments, Ring B is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, Ring B is a substituted or unsubstituted heterocycloalkyl, wherein each substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl). In embodiments, Ring B is a substituted or unsubstituted heterocycloalkyl, wherein each heterocycloalkyl is unsubstituted (i.e., unsubstituted heterocycloalkyl). In embodiments, ring B is morpholinyl, pyrazinyl, or piperazinyl. [0223] In embodiments, Z1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, Z1 is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, Z1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, wherein each substituted heterocycloalkyl or each substituted heteroaryl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl or substituted heteroaryl). In embodiments, Z1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, wherein each heterocycloalkyl or heteroaryl is unsubstituted (i.e., unsubstituted heterocycloalkyl or unsubstituted heteroaryl). In embodiments, Z1 is morpholinyl, pyrazinyl, or piperazinyl. In embodiments, Z1 is thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazoyl, izoxazolyl, thaizolyl, isothiazolyl, benzimidazolyl, pyrimidinyl, pyridinyl, triazolyl, or tetrazolyl. [0224] In embodiments, Z1 is C(O)Z2. In embodiments, Z2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-. In embodiments, Z2 is –O-. In embodiments, Z2 is -S-. In embodiments, Z2 is -NH-. In embodiments, Z2 is -N(CH3)-. In embodiments, Z2 is -C(O)2-. In embodiments, Z2 is –CH2-. [0225] In embodiments, R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In embodiments, R6 is hydrogen. [0226] In embodiments, R6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. In embodiments, R6 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R6 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R6 is phenyl or naphthalenyl. [0227] In embodiments, the compound is of formula (III): pharmaceutically
Figure imgf000063_0001
acceptable salt thereof, wherein X, R20, R21, R22a, R22b, and R23 are as defined above, including embodiments thereof. [0228] In embodiments, the symbol is a single bond or double bond. In embodiments, n1 is 0 or 1. In embodiments Q, Q1, Q2, and Q3 are independently -N, -CH2- or –CH, wherein not more than two Q are N. In embodiments, T is –CH or –N. In embodiments T1 is –O-, -HN, or –NCH3. [0229] In embodiments, X1 is –NH, -O-, -CH=, or -NR’, wherein R’ is a substituted or unsubstituted alkyl. In embodiments, X1 is –NH. In embodiments, X1 is -O-. In embodiments, X1 is - CH=. In embodiments, X1 is -NR’. [0230] In embodiments, R’ is a substituted or unsubstituted alkyl. In embodiments, R’ is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R’ is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, R’ is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, R’ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. [0231] In embodiments, Y1 is –C(O)-, -CH2-, -NH-, or -C(O)N(R9)-. In embodiments, Y1 is –C(O)-. In embodiments, Y1 is -CH2-. In embodiments, Y1 is -NH-. In embodiments, Y1 is -C(O)N(R9)-. In embodiments, R9 is hydrogen. In embodiments, R9 is a substituted or unsubstituted alkyl. [0232] In embodiments, R9 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, R9 is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, R9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. [0233] In embodiments, Z3 is hydrogen. In embodiments, Z3 is a substituted or unsubstituted alkyl. [0234] In embodiments, Z3 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, Z3 is a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, Z3 is a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, Z3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, peptyl, sexyl, heptyl, or octyl. [0235] In embodiments, X1, Y1, and Z3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. In embodiments, X1, Y1, and Z3 are optionally joined together to form a substituted or unsubstituted morpholinyl, pyrazinyl, or piperazinyl. In embodiments, X1 and Y1 together form a substituted or unsubstituted heterocycloalkyl. In embodiments, X1 and Y1 together form a substituted or unsubstituted morpholinyl, pyrazinyl, or piperazinyl. [0236] In embodiments, R and V are independently hydrogen, halogen, hydroxyl, -NH3, nitrile, or substituted or unsubstituted alkyl. In embodiments, R and V are independently hydrogen. In embodiments, R and V are independently –F, -Cl, -Br, or –I. In embodiments, R and V are independently hydroxyl. In embodiments, R and V are independently -NH3. In embodiments, R and V are independently nitrile. [0237] In embodiments, R and V are independently substituted or unsubstituted alkyl. In embodiments, R and V are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1- C6 alkyl, or C1-C4 alkyl). In embodiments, R and V are independently a substituted or unsubstituted alkyl, wherein each substituted alkyl is substituted with at least one substituent group (i.e., substituted alkyl). In embodiments, R and V are independently a substituted or unsubstituted alkyl, wherein each alkyl is unsubstituted (i.e., unsubstituted alkyl). In embodiments, R and V are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. [0238] In embodiments, R7 is L-R7A, wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and R7A is substituted or unsubstituted aryl. In embodiments, R7 is L-R7A, wherein L is –O- or -S-. In embodiments, L is –O-. In embodiments, L is -S-. In embodiments, R7 is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. [0239] In embodiments, R7 is a substituted or unsubstituted alkylene (e.g., C1-C8 alkylene,C1-C6 alkylene, or C1-C4 alkylene) or a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, R7 is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each substituted alkylene or a substituted or unsubstituted heteroalkylene is substituted with at least one substituent group (i.e., substituted alkylene or substituted alkylene). In embodiments, R7 is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each alkylene or heteroalkylene is unsubstituted (i.e., unsubstituted alkylene or unsubstituted heteroalkylene). [0240] In embodiments, L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene. In embodiments, L is a substituted or unsubstituted alkylene (e.g., C1- C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene) or a substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each substituted alkylene or a substituted heteroalkylene is substituted with at least one substituent group (i.e., substituted alkylene or substituted alkylene). In embodiments, L is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, wherein each alkylene or heteroalkylene is unsubstituted (i.e., unsubstituted alkylene or unsubstituted heteroalkylene). [0241] In embodiments, R7A is substituted or unsubstituted aryl. In embodiments, R7A is a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R7A is a substituted or unsubstituted aryl, wherein each substituted aryl is substituted with at least one substituent group (i.e., substituted aryl). In embodiments, R7A is a substituted or unsubstituted aryl, wherein each aryl is unsubstituted (i.e., unsubstituted aryl). In embodiments, R7A is phenyl or naphthalenyl.
Figure imgf000066_0001
[0242] In embodiements, R7 is or , wherein A1 is hydrogen or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, A1 is hydrogen. [0243] In embodiments, A1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In embodiments, A1 is a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, A1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein each substituted aryl or substituted heteroaryl is substituted with at least one substituent group (i.e., substituted aryl or substituted heteroaryl). In embodiments, A1 is a substituted or unsubstituted aryl or substituted or unsubstituted heteroarylaryl, wherein each aryl or heteroaryl is unsubstituted (i.e., unsubstituted aryl or unsubstituted heteroaryl). In embodiments, A1 is phenyl or naphthalenyl. In embodiments, A1 is thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazoyl, izoxazolyl, thaizolyl, isothiazolyl, benzimidazolyl, pyrimidinyl, pyridinyl, triazolyl, or tetrazolyl. [0244] In embodiments, the compound is of formula (IV): p
Figure imgf000066_0002
, , , , , , s defined above, including embodiments thereof. [0245] In embodiments, the symbol is a single bond or double bond. In embodiments, n2 is 0 or 1. In embodiments, R12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R18R19. In embodiments, R13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR36R37. In embodiments, R14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl. In embodiments, R15 is –S(O)2NR38R39 or –CONR38R39. In embodiments, R16 and R17 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R18, R19, R36, R37, R38, and R39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. [0246] In embodiments, R12 is –C(O)R18R19, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl. In embodiments, R12 is –C(O)R18R19. [0247] In embodiments, R12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R12 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R12 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R12 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R12 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0248] In embodiments, R18 and R19 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R18 and R19 are independently hydrogen. [0249] In embodiments, R18 and R19 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R18 and R19 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18 and R19 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R18 and R19 are independently a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R18 and R19 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R18 and R19 are independently phenyl or naphthalenyl. [0250] In embodiments, R13 is –CONR36R37, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl. In embodiments, R13 is –CONR36R37. [0251] In embodiments, R13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R13 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R13 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R13 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0252] In embodiments, R36 and R37 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R36 and R37 are independently hydrogen. [0253] In embodiments, R36 and R37 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R36 and R37 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R36 and R37 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R36 and R37 are independently a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R36 and R37 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R36 and R37 are independently phenyl or naphthalenyl. [0254] In embodiments, R14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl. [0255] In embodiments, R14 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0256] In embodiments, R14 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or unsubstituted aryl (e.g., C6-C10, C6, or phenyl). [0257] In embodiments, R14 is R58-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R58-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R58-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl), or R58- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0258] In embodiments, R14 is R58-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is R58-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is R58-substituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl). In embodiments, R14 is unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heteroalkyl, 3 to 6 membered heteroalkyl, or 5 to 6 membered heteroalkyl). In embodiments, R14 is R58-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R14 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0259] R58 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R59-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R59-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R59-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R59-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R59-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R59-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0260] In embodiments, R58 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0261] In embodiments, R58 is R59-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R59-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R59-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R59- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R59-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R59-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0262] R59 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R60-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R60-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R60-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R60-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R60-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0263] In embodiments, R59 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0264] In embodiments, R59 is R60-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R60-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R60-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R60- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R60-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R60-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0265] R60 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0266] In embodiments, R60 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0267] In embodiments, R60 is independently 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). [0268] In embodiments, R15 is –S(O)2NR38R39 or –CONR38R39. In embodiments, R15 is –S(O)2NR38R39. In embodiments, R15 is–CONR38R39. In embodiments, R38 and R39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R38 and R39 are independently hydrogen. [0269] In embodiments, R38 and R39 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R38 and R39 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R38 and R39 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R38 and R39 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R38 and R39 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R38 and R39 are independently phenyl or naphthalenyl. [0270] In embodiments, R16 and R17 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R16 and R17 are independently hydrogen. [0271] In embodiments, R16 and R17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R16 and R17 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R16 and R17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R16 and R17 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R16 and R17 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R16 and R17 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl.
Figure imgf000073_0001
[0272] In embodiments, the compound is of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein X, R20, R21, R22a, R22b, and R23 are as defined above, including embodiments thereof. [0273] In embodiments, R26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR2, -C(O)R2, or –C(O)NR2R4. In embodiments, R2 and R4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, ring C is a 5-6 membered substituted or unsubstituted heterocycloalkyl. [0274] In embodiments, R26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0275] In embodiments, R26 is substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0276] In embodiments, R26 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0277] In embodiments, R26 is R61-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R61-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R61-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R61-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0278] In embodiments, R26 is R61-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is R461-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R26 is unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R26 is R61-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is R61-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R26 is unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0279] R61 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R62-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R62-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R62-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R62-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R62-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R62-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0280] In embodiments, R61 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0281] In embodiments, R61 is R62-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R62-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R62-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R62- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R62-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R62-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0282] R62 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R63-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R63-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R63-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl), R63-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R63-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R63-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0283] In embodiments, R62 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0284] In embodiments, R62 is R63-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R63-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R63-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R63- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R63-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R63-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0285] R63 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0286] In embodiments, R63 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0287] In embodiments, R63 is independently 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). [0288] In embodiments, R27, R28, and R29 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R27, R28, and R29 are independently hydrogen. [0289] In embodiments, R27, R28, and R29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R27, R28, and R29 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R27, R28, and R29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R27, R28, and R29 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R27, R28, and R29 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R27, R28, and R29 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0290] In embodiments, R30 is hydrogen, -C(O)OR2, -C(O)R2, or –C(O)NR2R4, substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R30 is hydrogen. In embodiments, R30 is -C(O)OR2. In embodiments, R30 is -C(O)R2. In embodiments, R30 is –C(O)NR2R4. [0291] In embodiments, R30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R30 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R30 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R30 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R30 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0292] In embodiments, R2 and R4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In embodiments, R2 and R4 are independently hydrogen. [0293] In embodiments, R2 and R4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. In embodiments, R2 and R4 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 and R4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each substituted alkyl or substituted aryl is substituted with at least one substituent group (i.e., substituted alkyl or substituted aryl). In embodiments, R2 and R4 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein each alkyl or aryl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted aryl). In embodiments, R2 and R4 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R2 and R4 are independently phenyl or naphthalenyl. [0294] In embodiments, ring C is a substituted or unsubstituted heterocycloalkyl. In embodiments, ring C is a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, ring C is a substituted or unsubstituted heterocycloalkyl, wherein each substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted heterocycloalkyl). In embodiments, ring C is a substituted or unsubstituted heterocycloalkyl, wherein each heterocycloalkyl is unsubstituted (i.e., unsubstituted heterocycloalkyl). In embodiments, ring C is pyrazolyl, morpholinyl, or pyrazinyl. [0295] In embodiments, the compound is of formula (VI):
Figure imgf000078_0001
(VI), or a pharmaceutically acceptable salt thereof, wherein X, R20, R21, R22a, R22b, and R23 are as defined above, including embodiments thereof. [0296] In embodiments, R31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R32 and R33 are independently hydrogen, 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. In embodiments, T2 is –O-, -NH-, or –N(CH3). In embodiments, T3 is –CH= or –N=. [0297] In embodiments, R31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R31 is hydrogen. In embodiments, R31 is hydroxyl. In embodiments, R31 is amine. [0298] In embodiments, R31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R31 is a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R31 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R31 is a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0299] In embodiments, R32 and R33 are independently hydrogen, 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. In embodiments, R32 and R33 are independently hydrogen. [0300] In embodiments, R32 and R33 are independently a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0301] In embodiments, R32 and R33 are independently an unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered) [0302] In embodiments, R32 and R33 are independently R64-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R64-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R64- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R64-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R64-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R64-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0303] In embodiments, R32 and R33 are independently R64-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 and R33 are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 and R33 are independently R64-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R32 and R33 are independently unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R32 and R33 are independently R64-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 and R33 are independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 and R33 are independently R64-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R32 and R33 are independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R32 and R33 are independently R64-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R32 and R33 are independently unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R32 and R33 are independently R64-substituted heteroaryl (e.g., C6- C10 aryl, C10 aryl, or phenyl). In embodiments, R32 and R33 are independently unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered). [0304] R64 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R65-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R65-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R65-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R65-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R65-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R65-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0305] In embodiments, R64 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0306] In embodiments, R64 is R65-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R65-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R65-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R65- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R65-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R65-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0307] R65 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, R66- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R66-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R66-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R66-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R66-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R66-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0308] In embodiments, R65 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0309] In embodiments, R65 is R66-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R66-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R66-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R66- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R66-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R66-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0310] R66 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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). [0311] In embodiments, R66 is independently halogen, -CF3, -CCl3, -CBr3, -CI3, -OH, -NH2, -COOH, -CONH2, -NO2, -N3, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NHNH2, -NHSO2H, -NHC(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCCl3, -OCBr3, OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -OCH2Cl, -OCH2Br, or -OCH2I. [0312] In embodiments, R66 is independently 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). [0313] In embodiments, T2 is –O-, -NH-, or –N(CH3). In embodiments, T2 is –O-. In embodiments, T2 is -NH-. In embodiments, T2 is –N(CH3). In embodiments, T3 is –CH= or –N=. In embodiments, T3 is –CH=. In embodiments, T3 is –N=. [ d is of formula (VII):
Figure imgf000083_0001
(VII), or a pharmaceutically acceptable salt thereof, wherein X, R20, R21, R22a, R22b, and R23 are as defined above, including embodiments thereof. [0315] In embodiments, n3 is 0, 1, or 2. In embodiments, R34 and R35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. [0316] In embodiments, R34 and R35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R34 and R35 are independently hydrogen. [0317] In embodiments, R34 and R35 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In embodiments, R34 and R35 are independently a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) or a substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R34 and R35 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each substituted alkyl or substituted heteroalkyl is substituted with at least one substituent group (i.e., substituted alkyl or substituted heteroalkyl). In embodiments, R31 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, wherein each alkyl or heteroalkyl is unsubstituted (i.e., unsubstituted alkyl or unsubstituted heteroalkyl). In embodiments, R34 and R35 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. In embodiments, R34 and R35 are independently a 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl. [0318] In embodiments, ring D is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. In embodiments, ring D is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) or a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, ring D is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl, wherein each substituted cycloalkyl or substituted heterocycloalkyl is substituted with at least one substituent group (i.e., substituted cycloalkyl or substituted heterocycloalkyl). In embodiments, ring D is a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is unsubstituted (i.e., unsubstituted cycloalkyl or unsubstituted heterocycloalkyl). In embodiments, ring D is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In embodiments, ring D is pyrazolyl, morpholinyl, or pyrazinyl. [0319] n is an integer from 0 to 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. [0320] n1 is an integer from 0 to 1. In embodiments, n1 is 0. In embodiments, n1 is 1. [0321] n2 is an integer from 0 to 1. In embodiments, n2 is 0. In embodiments, n2 is 1. [0322] n3 is an integer from 0 to 2. In embodiments, n3 is 0. In embodiments, n3 is 1. In embodiments, n3 is 2. [0323] n4 is an integer from 0 to 4. In embodiments, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4. [0324] X1 is halogen. In embodiments, halogen is –F, -Cl, -Br, -I. In embodiments, X1 is –F. In embodiments, X1 is –Cl. In embodiments, X1 is –Br. In embodiments, X1 is –I. [0325] 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). [0326] 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. [0327] 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. [0328] 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. [0329] 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. [0330] In embodiments, the compound has the formula as described elsewhere herein, for example within a table, claim or example. [0331] In embodiments, the compound is of the formula: .
Figure imgf000086_0001
[0332] In embodiments, the compound is of the formula:
Figure imgf000087_0001
. III. Pharmaceutical compositions [0333] In an aspect, there is provided a pharmaceutical composition, including a compound as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), and a pharmaceutically acceptable excipient. [0334] The compounds as described herein of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are “pharmaceutical compositions” comprising a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII)), and one or more pharmaceutically acceptable or physiologically acceptable excipients (e.g., acceptable diluents or carriers). In certain embodiments, the compounds are present in a therapeutically effective amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein. [0335] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. [0336] The pharmaceutical compositions containing the active ingredient (e.g., an inhibitor of Peptidyl-prolyl isomerase, PIN1, or a compound described herein) may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture thereof. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. [0337] The tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene- vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art. [0338] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [0339] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polyoxy-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives. [0340] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. [0341] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein. [0342] The pharmaceutical compositions of the present disclosure may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. [0343] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound described herein contemplated by the present disclosure and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer; N-(2- Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N- Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyl]methyl-3- aminopropanesulfonic acid (TAPS). [0344] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi- use vial) is provided in other embodiments. [0345] Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed. Any drug delivery apparatus may be used to deliver a PIN1 inhibitor, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan. [0346] Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release a compound disclosed herein over a defined period of time. Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections. [0347] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor® EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin). [0348] The present disclosure contemplates the administration of the compounds described herein in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols. [0349] The compounds described herein contemplated by the present disclosure may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use) currently known or developed in the future. IV. Methods of use [0350] In another aspect, there is provided a method of treating a disease or disorder mediated by PIN1 activity, said method including administering an effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a patient in need of such treatment. In embodiments, said method further comprising administering to a patient in need thereof a kinase inhibitor or a chemotherapy agent. [0351] In another aspect, there is provided a method of inhibiting of tumor colony formation, said method comprising administering an effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a patient in need of such treatment. In embodiments, the tumor is a neuroendocrine prostate tumor. [0352] In yet another aspect, there is provided a method of delivering a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), to a cell, said method comprising a step of contacting the cell with the compound described herein, thereby releasing the compound described herein in the cytosol. In embodiments, the cell is a leukemia cell, breast cancer cell, or prostate tumor cell. In embodiments, the cell is a leukemia cell. In embodiments, the cell is a breast cancer cell. In embodiments, the cell is a prostate tumor cell. [0353] In accordance with the present disclosure, a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), can be used to treat or prevent a proliferative condition or disorder, including a cancer. In embodiments, the cancer is brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, leukemia, Hodgkin's Disease, or Non-Hodgkin's Lymphoma. In embodiments, cancers that may be treated with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. In embodiments, cancers that may be treated with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof), or method provided herein include hematological malignancies. In embodiments, a hematological malignancy is leukemia, lymphoma, or multiple myeloma. [0354] In embodiments, additional examples include thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, 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, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis. The disclosure contemplates reducing tolerance to a tumor cell or cancer cell antigen, e.g., by modulating activity of a regulatory T-cell and/or a CD8+ T-cell (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J. Med.349:1501-09). In some embodiments, the tumor or cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neutoendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, and lymphoma. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia. In embodiments, the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neutoendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, and lymphoma. [0355] In embodiments, a cancer can be metastatic or at risk of becoming metastatic, or may occur in a diffuse tissue, including cancers of the blood or bone marrow (e.g., leukemia or lymphoma). In some further embodiments, the compound as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) can be used to overcome T-cell tolerance. [0356] In some embodiments, the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein , including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional kinase inhibitor or a chemotherapy agent. In some embodiments, the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional kinase inhibitor. In some embodiments, the present disclosure provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein , including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and at least one additional chemotherapy agent. [0357] The present disclosure provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder or condition with a compound described herein including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof). [0358] In embodiments, the hematological malignancy is leukemia. In embodiments, leukemia is acute leukemia. In embodiments, acute leukemia is acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, or acute erythroleukemia. In embodiments, leukemia is chronic leukemia. In embodiments, chronic leukemia is chronic myelocytic leukemia or chronic lymphocytic leukemia. In embodiments, acute leukemia is acute lymphocytic leukemia. In embodiments, acute leukemia is acute myelocytic leukemia. In embodiments, acute leukemia is acute myeloblastic leukemia. In embodiments, acute leukemia is acute promyelocytic leukemia. In embodiments, acute leukemia is acute myelomonocytic leukemia. In embodiments, acute leukemia is acute monocytic leukemia. In embodiments, acute leukemia is acute erythroleukemia. In embodiments, chronic leukemia is chronic myelocytic leukemia. In embodiments, chronic leukemia is chronic lymphocytic leukemia. [0359] In embodiments, the hematological malignancy is lymphoma. In embodiments, lymphoma is Hodgkin's lymphoma or Non-Hodgkin's lymphoma. In embodiments, the Non-Hodgkin's lymphoma is a B-cell lymphoma. In embodiments, the Non-Hodgkin's lymphoma is indolent lymphoma. In embodiments, the Non-Hodgkin's lymphoma is aggressive lymphoma. In embodiments, B-cell lymphoma is diffuse B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Burkitt lymphoma, lymphoplasmacytuc lymphoma, or marginal zone lymphoma. In embodiments, B-cell lymphoma is diffuse B-cell lymphoma. In embodiments, B-cell lymphoma is follicular lymphoma. In embodiments, B-cell lymphoma is small lymphocytic lymphoma (SLL). In embodiments, B-cell lymphoma is mantle cell lymphoma (MCL. In embodiments, B-cell lymphoma is Burkitt lymphoma. In embodiments, B-cell lymphoma is lymphoplasmacytuc lymphoma. In embodiments, B-cell lymphoma is marginal zone lymphoma. [0360] In embodiments, the Non-Hodgkin's lymphoma is a T-cell lymphoma. In embodiments, T- cell lymphoma is cutaneous T-cell lymphoma (CTCL), periferal T-cell lymphoma (PTCL), mycosis fungoides, angioimmunoblastic lymphoma, or anaplastic large cell lymphoma. In embodiments, T- cell lymphoma is cutaneous T-cell lymphoma (CTCL). In embodiments, T-cell lymphoma is periferal T-cell lymphoma (PTCL). In embodiments, T-cell lymphoma is mycosis fungoides. In embodiments, T-cell lymphoma is angioimmunoblastic lymphoma. In embodiments, T-cell lymphoma is anaplastic large cell lymphoma. [0361] In embodiments, Hodgkin's lymphoma is a classic Hodgkin's lymphoma or nodular lymphocyte-predominant Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is nodular sclerosis Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte-rich Hodgkin's lymphoma, or lymphocyte-depleted Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is nodular sclerosis Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is mixed cellularity Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is lymphocyte-rich Hodgkin's lymphoma. In embodiments, classic Hodgkin's lymphoma is lymphocyte-depleted Hodgkin's lymphoma. [0362] In embodiments, the cancer is breast cancer. In embodiments, the breast cancer is a metastatic breast cancer. In embodiments, the metastatic breast cancer is a triple negative metastatic breast cancer. [0363] In embodiments drawn to methods of treating cancer, the administration of a therapeutically effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) results in a cancer survival rate greater than the cancer survival rate observed by not administering a therapeutically effective amount of the compound. In further embodiments drawn to methods of treating cancer, the administration of a therapeutically effective amount of a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) results in a reduction of tumor size or a slowing of tumor growth greater than reduction of tumor size or tumor growth observed following lack of administration of a therapeutically effective amount of the compound. [0364] Embodiments of the present disclosure contemplate the administration of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of PIN1 modulation. Such diseases, disorders and conditions may include, for example, human immunodeficiency virus (HIV), hepatitis, herpes, or a neuropsychiatric disorder. [0365] In embodiments, the disease or disorder is a human immunodeficiency virus (HIV). [0366] In embodiments, the disease or disorder is a hepatitis. In embodiments, the disease or disorder is a hepatitis A, hepatitis B, or hepatitis C. In embodiments, the disease or disorder is a hepatitis A. In embodiments, the disease or disorder is a hepatitis B. In embodiments, the disease or disorder is a hepatitis C. [0367] In embodiments, the disease or disorder is a herpes virus. In embodiments, the herpes virus is HSV-1, HSV-2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, or Kaposi’s sarcoma- associated herpes virus. In embodiments, the herpes virus is HSV-1 virus. In embodiments, the herpes virus is HSV-2 virus. In embodiments, the herpes virus is varicella zoster virus. In embodiments, the herpes virus is Epstein-Barr virus. In embodiments, the herpes virus is cytomegalovirus. In embodiments, the herpes virus is Kaposi’s sarcoma-associated herpes virus. [0368] In embodiments, the disease or disorder is a neuropsychiatric disorder. In embodiments, a neuropsychiatric disorder is a brain disease, an anxiety, a mood disorder, an eating disorder, or a learning diability. In embodiments, the neuropsychiatric disorder is an Alzheimer’s disease (AD), Parkinson’s desease (PD), epilepsy, multiple sclerosis, autism, stroke, amnesia, alcoholism, altitude sickness, or attention deficit disorder. In embodiments, the disease or disorder is an Alzheimer’s disease. In embodiments, the disease or disorder is Parkinson’s desease. In embodiments, the disease or disorder is epilepsy. In embodiments, the disease or disorder is multiple sclerosis. In embodiments, the disease or disorder is autism. In embodiments, the disease or disorder is stroke. In embodiments, the disease or disorder is amnesia. In embodiments, the disease or disorder is alcoholism. In embodiments, the disease or disorder is altitude sickness. In embodiments, the disease or disorder is attention deficit disorder. [0369] The present disclosure contemplates the administration of the compounds described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) and compositions (e.g., pharmaceutical salts, pharmaceutical composition) thereof, in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds disclosed herein over a defined period of time. In embodiments, the administration is oral administration. In embodiments, the administration is parenteral administration. [0370] The compounds as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan. [0371] In general, dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors. [0372] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50. [0373] In addition, an effective dose of the compounds as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject. [0374] In embodiments, the compounds as described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) may be administered (e.g., intravenously) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one, two, three, four or more times a day, to obtain the desired therapeutic effect. For administration of an oral agent, the compositions can be provided in the form of tablets, capsules and the like containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient. A pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g. [0375] In embodiments, the dosage of the compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) is contained in a “unit dosage form”. The phrase “unit dosage form” refers to physically discrete units, each unit including a predetermined amount of a compound (e.g., a compound described herein), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved. V. KITS [0376] In another aspect, provided herein is a kit including a compound described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) or pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described above. [0377] A kit may include one or more of the compounds described herein, including embodiments (e.g., structural Formulae (I), (IIa), (III), (IV), (V), (VI), and (VII), or a pharmaceutically acceptable salt thereof) (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration. When the compound is in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with, or separately from, the compound. Each component of the kit may be enclosed within an individual container, and all of the various containers may be within a single package. A kit of the present disclosure may be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). [0378] A kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or inserts can include manufacturer information such as lot numbers and expiration dates. The label or packaging insert may be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial). [0379] Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD- ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided. NUMBERED EMBODIMENTS [0380] Embodiment 1. A compound having formula (I):
Figure imgf000099_0001
wherein: R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; R21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R22a and R22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, wherein: R22a and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; R22b and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R22a and R22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)OR2, -C(O)R2, or halogen; R2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; X is oxygen or unsubstituted C1-C5 alkylene; -L1-R24 is a fragment of a drug, wherein said drug has the formula HO-P(O)2-X-L1-R24, HO-S(O)2-X-L1-R24 or HOOC-X- L1-R24; and L1 is independently a bond, 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. [0381] Embodiment 2. The compound of embodiment 1, wherein -L1-R24 does not comprise a ribose. [0382] Embodiment 3. The compound of embodiment 1 or 2, wherein said drug is less permeable to a cell membrane than the compound of formula (I). [0383] Embodiment 4. The compound of any one of embodiments 1 to 3, wherein the molecular weight of the compound of formula (I) is less than 2 kDa. [0384] Embodiment 5. The compound of any one of embodiments 1 to 4, wherein said drug does not have significant affinity for a known nucleotide binding site. [0385] Embodiment 6. The compound of any one of embodiments 1 to 5, wherein L1 is a bond. [0386] Embodiment 7. The compound of any one of embodiments 1 to 5, wherein L1 is a 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. [0387] Embodiment 8. The compound of any one of embodiments 1 to 7, wherein said drug is a PIN1 inhibitor. [0388] Embodiment 9. The compound of any one of embodiments 1 to 8, wherein the com i f f l II
Figure imgf000101_0001
(IIa) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; A is –S-, -S(O)2, -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O)2, or a bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydroxyl, -NH(R5), -N(R5)2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; or -A-R3 is : wherein:
Figure imgf000101_0002
Ring B is a 5-6 membered substituted or unsubstituted heterocycloalkyl; Z1 is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z2, wherein Z2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-; and R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [0389] Embodiment 10. The compound of any one of embodiments 1 to 8, wherein the c
Figure imgf000102_0001
(III), or a pharmaceutically acceptable salt thereof,wherein: the symbol is a single bond or double bond; n1 is 0 or 1; Q, Q1, Q2, and Q3 are independently -N, -CH2- or –CH, and wherein not more than two Q are N; T is –CH or –N; T1 is –O-, -HN, or –NCH3; X1 is –NH, -O-, -CH=, or -NR’, wherein R’ is a substituted or unsubstituted alkyl; Y1 is –C(O)-, -CH2-, -NH-, or -C(O)N(R9)-, wherein R9 is hydrogen or a substituted or unsubstituted alkyl; Z3 is hydrogen or a substituted or unsubstituted alkyl; wherein X1, Y1, and Z3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or X and Y1 together form a substituted or unsubstituted heterocycloalkyl; R and V are independently hydrogen, halogen, hydroxyl, -NH3, nitrile, or substituted or unsubstituted alkyl; and R7 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or L-R7A, wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted unsubstituted aryl;
Figure imgf000103_0001
, or , wherein A1 is hydrogen or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0390] Embodiment 11. The compound of any one of embodiments 1 to 8, wherein the c m nd i f f rm l IV
Figure imgf000103_0002
, pharmaceutically acceptable salt thereof, wherein: the symbol is a single bond or double bond; n2 is 0 or 1; R12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R18R19; R13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR36R37; R14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl; R15 is –S(O)2NR38R39 or –CONR38R39; R16 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R17 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; and R18 and R19 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R36 and R37 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R38 and R39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. [0391] Embodiment 12. The compound of any one of embodiments 1 to 8, wherein the compound is of formula (V):
Figure imgf000104_0001
, pharmaceutically acceptable salt thereof, wherein: R26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR2, -C(O)R2, or –C(O)NR2R4; R2 and R4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and ring C is a 5-6 membered substituted or unsubstituted heterocycloalkyl. [0392] Embodiment 13. wherein the
Figure imgf000105_0001
compound is of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein: R31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R32 and R33 are independently hydrogen, 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; T2 is –O-, -NH-, or –N(CH3); and T3 is –CH= or –N=. [0393] Embodiment 14. The compound of any one of embodiments 1 to 8, wherein the compound is of formula (VII): pharmaceutically acceptable salt thereof, whe
Figure imgf000105_0002
R34 and R35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; and n3 is 0, 1, or 2. [0394] Embodiment 15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier. [0395] Embodiment 16. A method of treating a disease or disorder mediated by PIN1 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I). [0396] Embodiment 17. The method of embodiment 16, further comprising administering to a patient in need thereof a kinase inhibitor or a chemotherapy agent. [0397] Embodiment 18. The method of embodiment 16 or 17, wherein the disease or disorder is a human immunodeficiency virus. [0398] Embodiment 19. The method of embodiment 16 or 17, wherein the disease or disorder is a hepatitis virus. [0399] Embodiment 20. The method of embodiment 16 or 17, wherein the disease or disorder is a herpes virus. [0400] Embodiment 21. The method of embodiment 16 or 17, wherein the disease or disorder is a neuropsychiatric disorder. [0401] Embodiment 22. The method of embodiment 16 or 17, wherein the disease or disorder is cancer. [0402] Embodiment 23. The method of embodiment 22, wherein the cancer is leukemia. [0403] Embodiment 24. The method of embodiment 22, wherein the cancer is breast cancer. [0404] Embodiment 25. The method of embodiment 24, wherein the breast cancer is a metastatic breast cancer. [0405] Embodiment 26. The method of embodiment 25, wherein the metastatic breast cancer is triple negative metastatic breast cancer. [0406] Embodiment 27. A method of inhibiting of tumor colony formation, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I). [0407] Embodiment 28. The method of embodiment 27, wherein the tumor is a neuroendocrine prostate tumor. [0408] Embodiment 29. A method of delivering the compound of formula (I) to a cell, said method comprising a step of contacting the cell with the compound of formula (I), thereby releasing the compound of formula (I) in the cytosol. [0409] Embodiment 30. The method of embodiment 29, wherein the cell is a leukemia cell, breast cancer cell, or prostate tumor cell. [0410] Embodiment 31. The method of embodiment 23, wherein the leukemia is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia. [0411] Embodiment 32. The method of embodiment 22, wherein the cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. EXAMPLES [0412] The membrane permeability of nucleotide-based drugs, such as sofosabuvir (Sovaldi), requires installation of phosphate-caging groups. The phosphoramidate or “ProTide” strategy masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation in the cytosol by an esterase and then a phosphoramidase, such as Hint1. As Hint1 is known to be selective for nucleotides, it was not clear if ProTides could be used on non-nucleotides. We demonstrated that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 dramatically increased its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 activity in cells. Thus, Hint1 recognizes a broader set of substrates than previously appreciated. It is possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach. Example 1. A Phosphoramidate Strategy Enables Membrane Permeability of a Non Nucleotide Inhibitor of Pin1 [0413] HINT1 is a selective enzyme that is not considered likely to accept non-nucleosides that are structurally distinct from its natural substrates. Crystal structures of substrate-bound HINT1 revealed a restrictive substrate envelope that is dominated by polar interactions around the phosphate (FIG.1) (Maize KM et al., Mol Pharm.2017; 14(11):3987–97). However, a modest hydrophobic pocket opposite this contact and surrounding the nucleobase was larger and potentially more accommodating (FIG.6). It was suggested that this pocket might be tolerant of non- nucleotides of moderate size, providing that they fit within the substrate envelope. [0414] We synthesized 1(R)-phosphate and its (S) enantiomer (Scheme 1) as both the phosphoramidate and the corresponding phosphate (Guo, supra; Domon K. et al., ACS Cent Sci.2020;6:283–92; Serpi M. et al., Curr Protoc Nucleic Acid Chem. 2013;(SUPPL.53):1–15). Based on co-crystal structures, 1(R)-phosphate would bind Pin1, while 1(S)-phosphate would be inactive (FIG.7). In these experiments, competitive binding was measured using a fluorescent peptide tracer WFYpSPFLE-FAM (Pintide) by fluorescence polarization (FP). Based on measuring the binding to the purified catalytic domain of Pin1 (Pin1-Cat; residues 45 – 163), we showed that the 1(R)-phosphate (Ki <300 nM), but not 1(S)-phosphate (Ki >10,000 nM), bound to Pin1-Cat (Fig 2B). Based on structural information, installation of the ProTide would sterically preclude binding. We showed that neither 1(R)-phosphoramidate nor 1(S)-phosphoramidate bound Pin1-Cat (Ki >> 10,000 nM). Full length Pin1 (Pin1-FL) also contains a WW domain, which has been shown to bind some phosphorylated substrates (Rippmann JF et al., Cell Growth Differ [Internet].2000;11(7):409–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10939594).1(R)-phosphate is potentially selective for the active site.1(R)-phosphate mimics the twisted-amide transition state that is recognized by the catalytic domain, which is known to prefer trans-proline. (Guo et al., supra). We measured binding to Pin1-FL by isothermal calorimetry (ITC) to determine the stoichiometry of the interaction.1(R)- phosphate bound with an apparent Kd of 72 ±37 nM, consistent with the improved affinity of Pin1- FL over Pin1-Cat for substrates in the literature (Eichner T. et al., J Mol Biol [Internet]. 2016;428(9):1760–75. Available from: http://dx.doi.org/10.1016/j.jmb.2016.03.009). The observed stoichiometry (N = 0.94±0.03) suggested that the compound indeed bound the catalytic site (Fig 2C). ITC experiment demonstrated that in the context of FL Pin1, the 1(R)-phosphate binds with 1:1 stoichiometry confirming that Pin1 catalytic domain is the only target of these molecules. [0415] Having determined that 1(R)-phosphate binds Pin1 with the expected affinity in vitro, we explored whether 1(R)-phosphoramidate might be liberated to this molecule in cells. Specifically, K562 leukemia cells were treated with 1(R)-phosphoramidate for five hours under serum-free conditions, followed by extensive washing, centrifugation, ethyl acetate extraction and measurement of the reaction products by UPLC-MS. K562 cells treated with 1-(R) were pelleted and extracted with EtOAc. Once solvent swapped into methanol, the lysate was analyzed by UPLC-MS to yield the base peak chromatogram. Phosphoramidate mass (553 m/z; purple chromatogram), phosphate mass (393 m/z; green chromatogram) and the mass of the dephosphorylated byproduct (312 m/z; gray chromatogram) were searched and these peaks were compared to the elution window of the standards (overlay chromatogram). Both the intermediate product of esterase activity and the 1(R)- phosphate product were detected (FIG.3). A small amount of dephosphorylated metabolite was also present and its identity confirmed with an authentic standard. To ensure that 1(R)-phosphate was being processed by intracellular enzymatic activities, we repeated the experiments in media without cells. No intermediate or 1(R)-phosphate was identified in these control experiments, confirming that enzymes were required. Together, these results suggest that 1(R)-phosphoramidate is permeable and that it is converted to the active form in cells. Thus, phosphoramidates like the nucleotide analog sobosbuvir or the non-nucleotide prodrug 1 are enzymatically liberated by a carboxylesterase saponification (i.e. CES1) and subseguest phosphoramidase sctivity (i.e. Hint1). [0416] To test whether the liberated 1(R)-phosphate might engage Pin1, we performed a cellular thermal shift assay (CETSA). Specifically, K562 cells were treated with 1(R)-phosphoramidate (25 µM) or solvent alone (0.25% DMSO) for 5 hours to allow for liberation of the active inhibitor. Following this incubation, cells were heat-denatured on a temperature gradient, lysed, and the soluble fraction assayed for Pin1 abundance by western blot (FIG.4A). Pin1 was strongly protected by the compound treatment, consistent with an interaction. This result was also repeated in MDA- MB-231 cells. In these experiments, the CETSA was performed near the half-maximal temperature (48 ˚C). As in the K562 cells, Pin1 was stabilized (Fig 4B). Together, these results suggest that released 1(R)-phosphate binds Pin1 in cells. [0417] An inhibitor of Hint1, TrpGc was employed to explore whether 1(R)-phosphoramidate was converted by the known, enzyme-based mechanism (Bardaweel SK. et al., Bioorganic Med Chem Lett [Internet].2012;22(1):558–60. Available from: http://dx.doi.org/10.1016/j.bmcl.2011.10.082); Shah RM. et al., ACS Chem Neurosci.2019;10(10):4385–93; Okon A. et al., ACS Med Chem Lett. 2017;8(9):958–62). Treatment of MDA-MB-231 cells with 1(R)-phosphoramidate at timepoints longer than 24 hours led to a dose-responsive increase in Pin1 levels (FIG. 5A). Co-treatment with TrpGc (100 µM) blocked the cellular activity of 1(R)-phosphoramidate (FIG.5B), strongly supporting an essential role for Hint1. [0418] Because Pin1 has both catalytic and WW domains, it was not entirely clear which physiological responses were mediated by prolyl isomerase functions. One of the best characterized biological roles for Pin1 is in tumor colony formation as Pin1 knockdown is reported to strongly inhibit clonogenic potential (Ryo A. et al., , Clin Cancer Res.2005;11(20):7523–31). Using PC3 neuroendocrine prostate cancer cells, we tested the ability of 1(R)-phosphoramidate or 1(S)- phosphoramidate to reduce colony formation. Strong inhibitory effect was found for 1(R)- phosphoramidate, but not for 1(S)-phosphoramidate (FIG.5C). Treatment with 1(R)- phosphoramidate did not reduce proliferation of PC3 cells after 72-hours based on either ATP-Glo or MTT assays (FIG.9). Knockdown of Pin1has been shown to have a similarly preferential effect at low cell density and long timeframes (Ryo, supra). [0419] We provided evidence that the “ProTide” approach is more broadly applicable than previously appreciated.1(R)-phosphoramidate is a powerful new tool for exploring Pin1 biology. This approach re-balances the interplay between permeability and potency, creating a chemical probe for this promising target. EXPERIMENTAL Chemical Synthesis [0420] Synthesis of intermediate b: In a flask equipped with a drying column and argon balloon, phosphorous(V)oxychloride (1.0 eq) and phenol (1.0 eq) were dissolved in anhydrous dichloromethane and sparged with Ar gas for 5 minutes while stirring at ambient temperature. The reaction mixture was cooled to -78˚C and anhydrous triethylamine (1.5 eq) was added dropwise. The mixture was stirred at -78˚C for 30 minutes and then allowed to slowly warm to ambient temperature. After stirring at ambient temperature for 2 hours, the mixture was concentrated by rotary evaporation with drying column adapter and resuspended in anhydrous diethyl ether. White precipitate was filtered under a blanket of Ar gas. Flow-through was once again concentrated by rotary evaporation under a drying column and resuspended in anhydrous dichloromethane. To the solution was added ethyl glycine hydrochloride (1.0 eq) and the solution was sparged with Ar gas for 5 minutes at ambient temperature. The reaction mixture was cooled to -78˚C and triethyl amine (3.0 eq) was added dropwise. Resultant mixture was stirred at -78˚C for 30 minutes and allowed to slowly warm to ambient temperature. Following a 2-hour incubation, the mixture was concentrated to dryness on a rotary evaporator under a drying column. The residue was resuspended in diethyl ether and white solids were filtered under a blanket of argon. Flowthrough was concentrated to dryness and resuspended in anhydrous tetrahydrofuran. Crude was carried forward or stored sealed under argon at 4˚C (1). [0421] General synthesis of intermediate d: To a flask charged with D- or L-phenylglycinol (1.0 eq) and benzo[b]thiophene-2-carbonyl chloride (1.2 eq) was added anhydrous tetrahydrofuran and diisopropylethyl amine (2.5 eq). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted in ethyl acetate and washed with 2 X 0.5M HCl (aqueous) then 3 X brine. The organic layer was dried with sodium sulfate and concentrated to dryness. The resultant residue was purified by flash column chromatography (silica gel 0-20% methanol in dichloromethane). [0422] General synthesis of compound 1-phosphoramidate: intermediate d (1.0 eq) was dissolved in anhydrous tetrahydrofuran and sparged with Ar gas. To the solution was added 1.0 M tert-butyl magnesium chloride dropwise (1.2 eq) and the resultant mixture was stirred at room temperature for 30 min. Intermediate b (crude, excess) was added to the slurry dropwise and the resultant reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated to residue and purified by reverse-phase flash chromatography to a 60:40 mixture of diastereomers (C185 - 95% acetonitrile in water). [0423] General synthesis of compound 1-phosphate: Intermediate d (1.0 eq), phosphoenolpyruvic acid mono potassium salt (10.0 eq), and tetrabutylammonium hydrogen were dissolved in anhydrous dimethylformamide and sparged with Ar gas. The mixture was heated to 100 ˚C and stirred under Ar gas for 5 hours. The mixture was purified by semi-preparative HPLC (C185 - 95% acetonitrile in water). [0424] These compounds are depicted in Scheme 1. [0425] Scheme 1:
Figure imgf000112_0001
[0426] Intermediate d-(R): 1H-NMR (d6-DMSO, 400 MHz) d: 8.53 (d, J=0.02, 1H), 8.13 (s, 1H), 8.04 – 7.90 (m, 2H), 7.50 – 7.39 (m, 2H), 7.32 – 7.20 (m, 4H), 7.20 – 7.11 (m, 1H), 4.96 – 4.88 (m, 1H), 4.21 – 4.09 (m, 1H), 3.59 – 3.42 (m, 2H), 3.01 – 2.75 (m, 2H).13C-NMR (d6-DMSO, 400 MHz) δ:161.57, 140.77, 140.56, 139.74, 139.62, 129.55, 128.63, 126.55, 126.40, 125.58, 125.32, 124.98, 123.22, 63.25, 54.00, 36.92. ESI-MS [M+H]+: [0427] Intermediate d-(S): 1H-NMR (d6-DMSO, 400 MHz) d: 8.53 (d, J=0.02, 1H), 8.13 (s, 1H), 8.03 – 7.90 (m, 2H), 7.49 – 7.38 (m, 2H), 7.33 – 7.21 (m, 4H), 7.20 – 7.12 (m, 1H), 4.92 (t, J= 0.02, 1H), 4.21 – 4.08 (m, 1H), 3.57 – 3.42 (m, 2H), 3.01 – 2.75 (m, 2H).13C-NMR (d6-DMSO, 400 MHz) δ:161.57, 140.75, 140.55, 139.72, 139.63, 129.54, 128.61, 126.53, 126.40, 125.56, 125.32, 124.98, 123.22, 63.25, 54.00, 36.92.
Figure imgf000113_0001
. d-(R) d-(S) [0428] Compound 1(R)-phosphoramidate: 1H-NMR (d6-DMSO, 400 MHz) d: 8.73 (d, J=0.02, 1H), 8.10 (d, J=0.01, 1H), 7.99 (dd, Jba=0.05, Jbc=0.02, 2H), 7.46 (m, 2H), 7.25 (m, 10H), 5.94 (q, J=0.18, 1H), 4.39 (m, 1H), 4.10 (m, 2H), 4.01 (m, 2H), 3.66 (q, J=0.02), 2.90 (m, 2H), 1.12 (m, 3H). 13C-NMR (d6-DMSO, 400 MHz) δ:171.22, 161.76, 161.70, 151.14, 140.60, 140.24, 139.50, 138.62, 130.05, 129.97, 129.54, 128.73, 126.74, 126.68, 125.58, 125.39, 125.23, 125.03, 124.96, 123.26, 120.75, 120.70, 60.91, 42.83, 14.43. [0429] Compound 1(S)-phosphoramidate: 1H-NMR (d6-DMSO, 400 MHz) d: 8.74 (d, J=0.02, 1H), 8.10 (d, J=0.01, 1H), 7.99 (dd, Jba=0.05, Jbc=0.02, 2H), 7.46 (m, 2H), 7.25 (m, 10H), 5.94 (q, J=0.18, 1H), 4.39 (m, 1H), 4.10 (m, 2H), 4.01 (m, 2H), 3.66 (q, J=0.02), 2.90 (m, 2H), 1.12 (m, 3H). 13C-NMR (d6-DMSO, 400 MHz) δ:171.21, 161.76, 161.70, 140.64, 140.24, 139.54, 138.67, 130.05, 129.98, 129.54, 128.72, 126.71, 126.66, 125.61, 125.39, 125.23, 125.03, 124.97, 123.27, 120.74, 120.69, 60.92, 42.93, 14.42.
Figure imgf000113_0002
( )-p osp oram date (S)-p osp oram date [0430] Compound 1(R)-phosphate: 1H-NMR (MeOD, 400 MHz) d: 7.98 (s, 1H), 7.90 – 7.87 (m, 2H), 7.48 – 7.40 (m, 2H), 7.37-7.18 (m, 5H), 4.55 – 4.42 (m, 1H), 4.18 – 4.02 (m, 2H), 3.14 – 2.95 (m, 2H).13C-NMR (MeOD, 400 MHz) δ: 141.01, 139.33, 138.62, 137.83, 128.98, 128.11, 126.20, 126.05, 125.15, 124.82, 124.57, 122.15, 66.34, 51.98, 36.27. [0431] Compound 1(S)-phosphate: 1H-NMR (MeOD, 400 MHz) d:7.97 (s, 1H), 7.95 – 7.86 (m, 2H), 7.49 – 7.38 (m, 2H), 7.37 -7.15 (m, 5H), 4.56 – 4.31 (m, 1H), 4.18 – 3.99 (m, 2H), 3.14 – 2.96 (m, 2H).13C-NMR (MeOD, 400 MHz) δ: 141.05, 139.36, 138.59, 137.83, 128.97, 128.11, 126.18, 125.99, 1
Figure imgf000114_0001
and . 1(R)-phosphate 1(S)-phosphate [0432] HINT1 docking experiments: The HINT1 co-crystal structure with 5'-O-[(L- lysylamino)sulfonyl]adenosine (Accession: 4EQE) was submitted for docking experiments in SwissDock (6) with all four diastereomers of compound 1-phosphoramidate as well as a sofosbuvir- alanine positive control:
Figure imgf000114_0002
Mol2 models of each compound were prepared at a simulated pH 7.0 in Open Bable (7) and were each submitted to identical docking experiments with default settings in SwissDock. Resultant poses were manually curated for approximately proper pose in the catalytic pocket for hydrolysis and energy scores and DGbinding were plotted in Prism 8 (Graphpad). Structures were overlayed with the co-crystal structure to evaluate the orientation of the lowest energy poses. HINT1:Lys-AMS cocrystal structure (4EQE) highlighted the tractability of designing non-nucleotide HINT1 substrates. While the polar catalytic pocket is defined and must bind phosphoramidates in a catalytically viable conformation, the distal nucleobase contacts are largely hydrophobic and appeared tolerant to structural diversity. The syn diastereomer of 1(R)-phosphoramidate de- esterified metabolite docked pose in the HINT1 catalytic site largely overlays with the co- crystallized Lys-AMS ligand. Closer analysis of the catalytic site has shown the orientation of the docked phosphoramidate in relation to the catalytic residues. The active diastereomer of sofosbuvir- alanine metabolite which is known to be cleaved by HINT1 was submitted for an identical docking experiment and the lowest energy catalytic site pose was shown overlayed again with the cocrystalized Lys-AMS ligand and is similarly well posed in the catalytic site to 1(R)-Gly. Summary energy scores for all four possible 1(R)-phosphoramidate glycine metabolites’ docked poses in the catalytic site are similar to sofosbuvir-alanine positive control. Measurements from key catalytic residues (H114, H112, and S107), the highest scoring catalytic poses of the syn diastereomer of 1(R)-Gly metabolite and sofosbuvir-Ala metabolite position their phosphoramidates similarly in the HINT1 active site. Biological Assays [0433] Protein expression and purification: The full length and catalytic constructs of Pin1 were expressed and purified as previously described (Leeson, supra). [0434] Cell culture: MDA-MB-231 cells were obtained by ATCC and cultured in DMEM supplemented with 10% fetal bovine serum and 100 μg/mL penicillin/streptomycin. K562 and PC3 cells were obtained by ATCC and cultured in RPMI supplemented with 10% fetal bovine serum and 100 μg/mL penicillin/streptomycin. All cells were maintained at 37˚C and 5% CO2 in a humidified incubator. [0435] Pin1-cat competition fluorescence polarization: Binding and competition binding experiments were conducted as previously described . Briefly, in a M5 plate reader (SpectroMax), saturation was determined for increasing concentrations of Pin1-cat titrated against a fixed 25 nM concentration of FITC-WFYpSPFLE fluorescent tracer peptide. Competition experiments were conducted at a fixed concentration of Pin1-cat (500 nM) and tracer (25 nM) and varying competitor competition. Ki,app was calculated using the following equation (Gross, supra): ^^i,app = ^^50/ ^^50/ ^^d + ^^0/ ^^d + 1, where I50 is the concentration of free inhibitor at 50% inhibition, L50 is the concentration of free tracer at 50% inhibition, P0 is the total receptor concentration, and Kd is the dissociation constant of receptor and tracer (3.53 μM for Pin1-cat: FITC-WFYpSPFLE) . [0436] Isothermal titration calorimetry: Affinity and stoicheometry of binding to the full length Pin1 were measured in a microCal ITC200 (General Electric).50 μM ligand in 0.5% DMSO 50 mM Tris, 50 mM NaCl, pH 7.5 was loaded into syringe. Cell was loaded with 5 μM Pin1 in 0.5% DMSO, 50 mM Tris, 50 mM NaCl, pH 7.5. Isotherms measured during the titration were converted to their corresponding Wiseman plots using PEAQ-ITC analysis software (Malvern Panalytical). [0437] Cellular liberation of phosphate by LC-MS: K562 cells at a density of 3.9 million cells per milliliter were treated with 1(R)-phosphoramidate in serum free conditions for 5 hours. Following incubation, 1 mL of cell suspension was pelleted at 300 relative centrifugal force. The media was removed and pellets were then resuspended in 1 mL ethyl acetate and incubated at -30˚C for 24 hours. Following extraction, the mixture was concentrated by rotary evaporation and the residue was resuspended in LC-MS grade methanol (100 μL). The resultant solution was filtered and analyzed on a Acquity H-Class/TQD UPLC-MS/MS (Model #: B10UPB541M; Waters). Standards of 1(R)-phosphoramidate, 1(R)-phosphate, and intermediate d elution times and m/z were compared to the LC-MS trace of cell extract and appreciable 1(R)-phosphate and 1(R)-phosphoramidate were detected with trace intermediate d detected. [0438] Cellular thermal shift assay (CETSA): K562 cells were treated with 1(R)- phosphoramidate (25 μM) or concentration of DMSO for 5 hours and incubated under standard growth conditions (37 ˚C, 5% CO2). Following incubation, cells were pelleted and resuspended in compound- or mock-treated media at a density of 2 million per mL.50 μL aliquots were transferred to PCR tubes and were heated to a set temperature from 38 – 60˚C (at 2˚C increments) for 4 minutes. Tubes were then returned to ambient temperature for 4 minutes and then snap-frozen in liquid nitrogen. Cells were lysed by freeze-thaw cycles (3) and the insoluble fraction was pelleted by high-speed centrifugation. Soluble fractions were assayed by western blot for Pin1 and tubulin. MDA-MB-231 cells were treated under standard growth conditions with 25 μL 1(R) phosphoramidate or matching concentration of DMSO for 5 hours. Cells were lifted by mechanical scraping, pelleted, and resuspended to a density of 2 million per mL. Cell slurry was portioned to 50 μL aliquots and were heated to 48˚C for 4 minutes. Slurry was then cooled to ambient temperature for 4 minutes and snap frozen in liquid nitrogen. Samples were processed and analyzed as K562 samples were. [0439] Pin1 induction assay: MDA-MB-231 cells were treated with 1(R)-phosphoramidate or DMSO for 72 hours and were subsequently lysed in 4% SDS in TBS and boiled. Clarified lysate was assayed by western blot for Pin1 and tubulin. Subsequently, MDA-MB-231 cells were treated with 5 μM 1(R)- or 1(S)-phosphoramidate, 5μM 1(R)-phosphoramidate with 100 μM TrpGc, or 100 μM TrpGc alone for 48 hours. Cells were subsequently lysed, lysate was clarified and assayed by western blot for Pin1 and tubulin as before. [0440] Colony Formation Assay: PC3 cells were plated on poly-d-lysine-coated 12-well plates (250 cells per well) with the indicated compound treatment. Cells were allowed to proliferate until untreated wells reached colonies of > 50 cells each (~2.5 weeks). Media was removed, cells were stained with Crystal Violet stain (5), and plate was imaged using a document scanner. Colonies were manually counted. [0441] MTT viability assay: PC3 cells were plated in a poly-d-lysine-coatedclear 96-well plate at 5,000 cells/well and treated with 1μM 1(R)-phosphoramidate, 1(S)-phosphoramidate, or a matched concentration of DMSO. Cells were allowed to proliferate for 72 hours in their given conditions. Following the out-growth, media was replaced with 50 μL untreated serum free media supplemented with 1 mg/mL MTT reagent and cells were incubated in normal growth conditions for three hours. An additional row of the plate which lacked cells was treated with MTT-media as a negative control. Media was then aspirated carefully and replaced with 50 μL DMSO and nutated for 10 minutes. Plate was analyzed by measuring A590 on a M5 plate reader (Spectromax).Viability was determined by the following equation:
Figure imgf000117_0001
[0442] It is understood that the examples described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS: 1. A h i f l I
Figure imgf000118_0001
(I), wherein: R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; R21 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R22a and R22b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, wherein: R22a and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; R22b and R21 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or R22a and R22b are optionally joined together to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)OR2, -C(O)R2, or halogen; R2 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; X is oxygen or unsubstituted C1-C5 alkylene; -L1-R24 is a fragment of a drug, wherein said drug has the formula HO-P(O)2-X-L1-R24, HO-S(O)2-X-L1-R24 or HOOC-X- L1-R24; and L1 is independently a bond, 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.
2. The compound of claim 1, wherein -L1-R24 does not comprise a ribose.
3. The compound of claim 1, wherein said drug is less permeable to a cell membrane than the compound of formula (I).
4. The compound of claim 1, wherein the molecular weight of the compound of formula (I) is less than 2 kDa.
5. The compound of claim 1, wherein said drug does not have significant affinity for a known nucleotide binding site.
6. The compound of claim 1, wherein L1 is a bond.
7. The compound of claim 1, wherein L1 is a 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.
8. The compound of claim 1, wherein said drug is a PIN1 inhibitor.
9. The compound of claim 8, wherein the compound is of formula (IIa): phar
Figure imgf000119_0001
wherein: n is 0, 1, or 2; A is –S-, -S(O)2, -O-Y-, -Y-S-, -S-Y, or a substituted or unsubstituted alkyl, wherein Y is C(O), C(S), S(O), S(O)2, or a bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydroxyl, -NH(R5), -N(R5)2, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; or A R3 i
Figure imgf000120_0001
(IIb), wherein: ring B is a 5-6 membered substituted or unsubstituted heterocycloalkyl; Z1 is a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or C(O)Z2, wherein Z2 is –O-, -S-, -NH-, -N(CH3)-, -C(O)2-, or –CH2-; and R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
10. The compound of claim 8, wherein the compound is of formula (III): or a ph
Figure imgf000120_0002
wherein: the symbol is a single bond or double bond; n1 is 0 or 1; Q, Q1, Q2, and Q3 are independently -N, -CH2- or –CH, and wherein not more than two Q are N; T is –CH or –N; T1 is –O-, -HN, or –NCH3; X1 is –NH, -O-, -CH=, or -NR’, wherein R’ is a substituted or unsubstituted alkyl; Y1 is –C(O)-, -CH2-, -NH-, or -C(O)N(R9)-, wherein R9 is hydrogen or a substituted or unsubstituted alkyl; Z3 is hydrogen or a substituted or unsubstituted alkyl; wherein X1, Y1, and Z3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; or X and Y1 together form a substituted or unsubstituted heterocycloalkyl; R and V are independently hydrogen, halogen, hydroxyl, -NH3, nitrile, or substituted or unsubstituted alkyl; and R7 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or L-R7A, wherein L is –O-, -S-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and R7A is substituted or unsubstituted aryl;
Figure imgf000121_0001
wherein A1 is hydrogen or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
11. The compound of claim 8, wherein the compound is of formula (IV):
Figure imgf000122_0001
(IV), or a pharmaceutically acceptable salt thereof, wherein: the symbol is a single bond or double bond; n2 is 0 or 1; R12 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –C(O)R18R19; R13 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or –CONR36R37; R14 is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl; R15 is –S(O)2NR38R39 or –CONR38R39; R16 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R17 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R18 and R19 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R36 and R37 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R38 and R39 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
12. compound is of formula (V):
Figure imgf000123_0001
(V), or a pharmaceutically acceptable salt thereof, wherein: R26 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R27 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R28 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R29 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R30 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, -C(O)OR2, -C(O)R2, or –C(O)NR2R4; R2 and R4 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and ring C is a 5-6 membered substituted or unsubstituted heterocycloalkyl.
13. The compound of claim 8, wherein the compound is of formula (VI):
Figure imgf000124_0001
(VI), or a pharmaceutically acceptable salt thereof, wherein: R31 is hydrogen, hydroxyl, amine, or a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R32 and R33 are independently hydrogen, 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; T2 is –O-, -NH-, or –N(CH3); and T3 is –CH= or –N=.
14. The compound of claim 8, wherein the compound is of formula (VII): pharmaceutically acceptable salt thereof, wh
Figure imgf000124_0002
R34 and R35 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; ring D is a 5-6 membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; and n3 is 0, 1, or 2.
15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.
16. A method of treating a disease or disorder mediated by PIN1 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I).
17. The method of claim 16 further comprising administering to a patient in need thereof a kinase inhibitor or a chemotherapy agent.
18. The method of claim 16 or 17, wherein the disease or disorder is a human immunodeficiency virus.
19. The method of claim 16 or 17, wherein the disease or disorder is a hepatitis virus.
20. The method of claim 16 or 17, wherein the disease or disorder is a herpes virus.
21. The method of claim 16 or 17, wherein the disease or disorder is a neuropsychiatric disorder.
22. The method of claim 16 or 17, wherein the disease or disorder is cancer.
23. The method of claim 22, wherein the cancer is leukemia.
24. The method of claim 22, wherein the cancer is breast cancer.
25. The method of claim 24, wherein the breast cancer is a metastatic breast cancer.
26. The method of claim 25, wherein the metastatic breast cancer is triple negative metastatic breast cancer.
27. A method of inhibiting of tumor colony formation, said method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I).
28. The method of claim 27, wherein the tumor is a neuroendocrine prostate tumor.
29. A method of delivering the compound of formula (I) to a cell, said method comprising a step of contacting the cell with the compound of formula (I), thereby releasing the compound of formula (I) in the cytosol.
30. The method of claim 29, wherein the cell is a leukemia cell, breast cancer cell, or prostate tumor cell.
31. The method of claim 23, wherein the leukemia is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia.
32. The method of claim 22, wherein the cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
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