WO2018112435A1 - Compounds for the inhibition of a prolyl isomerase and methods of use thereof - Google Patents

Compounds for the inhibition of a prolyl isomerase and methods of use thereof Download PDF

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WO2018112435A1
WO2018112435A1 PCT/US2017/066862 US2017066862W WO2018112435A1 WO 2018112435 A1 WO2018112435 A1 WO 2018112435A1 US 2017066862 W US2017066862 W US 2017066862W WO 2018112435 A1 WO2018112435 A1 WO 2018112435A1
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substituted
unsubstituted
group
compound
membered
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PCT/US2017/066862
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French (fr)
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Jason E. Gestwicki
Bryan M. DUNYAK
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The Regents Of The University Of California
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • PPIases Peptidyl-prolyl isomerases
  • FKBPs FK506-binding proteins
  • cyclophilins The macrocyclic natural products FK506 and rapamycin inhibit the FKBP class of PPIases and the cyclophilins are inhibited by the macrocyclic natural product, cyclosporin.
  • NEVIA-interacting 1 Pinl
  • PPIases have emerged as important targets in cancer, neurodegeneration, mental illnesses and neuropathic pain.
  • Targeting the peptidyl-prolyl isomerases has been a challenge as most inhibitors have overlapping specificity for multiple family members and are lacking cellular activity.
  • Disclosed herein are novel, selective inhibitors for the peptidyl-prolyl isomerase Pinl to overcome this challenge.
  • a peptidyl-prolyl cis-trans isomerase NFMA-interacting 1 (Pin 1) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
  • an FK506 binding protein (FKBP) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
  • a macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506, or a pharmaceutically acceptable salt thereof.
  • nl, n2 and n3 are independently an integer from 0 to 4.
  • ml, m2, m3, vl, v2 and v3 are independently 1 or 2.
  • L 1 is a bond, -0-, -S-, - R 1L - - R 1L C(0)-, -C(O)-, -C(0)0-, -S(O) -, -S(0) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 1 is hydrogen, halogen, -CX 1.1 3 , -CHX 1.1 2, -Cn 2 X 1.1 , -CN, -SOniR 1A , -SOviNR 1B R 1C , -NHNR 1B R 1C , -0NR 1B R 1C ,
  • R 2 is hydrogen, halogen, -CX 2,1 3 , -CHX 2 J 2 ,
  • R 3 is hydrogen, halogen, -CX 3.1 3, -CHX 3.1 2, -CH 2 X 3 .1 , -CN, -SO estate 3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(0)NHNR 3B R 3C , -NHC(0)NR 3B R 3C , -N(0) m3 , -NR 3B R 3C , -C(0)R 3D , -C(0)OR 3D , -C(0)NR 3B R 3C , -OR 3A , -NR 3B S0 2 R 3A , -NR 3B C(0)R 3D ,
  • R 1L , R 2L , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C and R 3D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1B and R 1C , R 2B and R 2C , R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 1 1 , X 2 1 and X 3 1 are independently -C1, -Br, -I or -F.
  • L 2 is -0-, L 1 is a bond, R 1 is or -CH 2 CH 3 and R 3 is hydroxyl, then R 2 is not hydrogen.
  • n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4.
  • m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently 1 or 2.
  • L 3 is a bond, -0-, -S-, -NR 3L -, -NR 3L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or
  • R 4 is hydrogen, halogen, -CX 4 J 3 , -CHX 4 J 2 , -CH 2 X 4 ⁇ , -CN,
  • R 5 is hydrogen, halogen, -CX 5 - . C 1 3H,X 5 .
  • -C(0)NH 2 -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 5 .1 3 -,OCHX 5 .1 2 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • R 6 is hydrogen, halogen, -CX 6 1 3 , -CHX 6.1 2, -CH 2 X 6 1 , -CN, -SO n6 H, -SO v6 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m6 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 6 .1 3, -OCHX 6.1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstitute
  • R 7 is hydrogen, halogen, -CX 7,1 3 , -CHX 7.1 2, -CH 2 X 7 1 , -CN, -SOnvH, -SOvvNH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m v, -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 7 .1 3, -OCHX 7.1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroary
  • R 8 is hydrogen, halogen, -CX 8 1 3 , -CHX 8 J 2 , -CH 2 X 8 1 , -CN, -SOnsH, -SO v8 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -N(0) m8 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 8 .1 3, -OCHX 8.1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubsti
  • R 9 is hydrogen, halogen, -CX 9 J 3 , -CHX 9 J 2 , -CH 2 X 9 1 , -CN, -SO n9 H, -SO v9 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -N(0) m9 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 9 .1 3, -OCHX 9.1 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsub
  • R 3L , R 4A , R 4B , R 4C and R 4D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • X 4 X .1 , 5 1 , X 6 1 , X 7 - 1 , X 8 - 1 , X 9 1 and X 10 1 are independently -C1, -Br, -I or
  • L 3 is -O- and R 6 , R 7 , R 8 , R 9 and R 10 are
  • a pharmaceutical composition including a compound described herein, including in an aspect or embodiment, and a pharmaceutically acceptable excipient.
  • FKBP FK506 binding protein
  • a method of treating a Pin-1 associated disease or disorder including administering to a patient in need thereof a compound as set forth herein, including embodiments thereof.
  • a method of treating an FKBP51 -mediated disease or disorder including administering to a patient in need thereof a compound as set forth herein, including embodiments thereof.
  • L 1 , L 2 , R 1 , and R 3 are as described herein.
  • a method of preparing a compound of structural Formula (II) as set forth herein including contacting a compound of structural Formula (lie) with ammonia: L 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R are as described herein.
  • FIGS. 1A-1B Structure of Pinl with key features highlighted.
  • the active site pocket within the PPIase domain is composed of antiparallel ⁇ -sheets that position a short a-helix.
  • the WW domain consists of two, short antiparallel ⁇ -sheets connected to the PPIase domain by a flexible linker (not resolved in this structure).
  • FIG. IB Surface representation of the active site.
  • the hydrophobic proline pocket (gray) orients substrate to interact with the catalytic cysteine and the cationic groove that binds phosphate groups. (Protein Data Bank reference, PDB: 1PIN).
  • FIG. 2 Natural product inhibitors of Pinl .
  • FIG. 3 Representative pipecolic acid-based phosphopeptide inhibitor of Pinl .
  • the phosphopeptide, pintide is bound to Pinl (shown as the surface electrostatic map).
  • the pipecolate ring is anchored in the proline binding pocket, positioning the phosphate group to interact with the cationic groove. Further affinity is gained via the napthyl interaction with the hydrophobic shelf of the active site.
  • FIG. 4 Small molecule Pinl inhibitors based on pipecolic acid, demonstrating
  • FKBP inhibitors such as SLF.
  • FIG. 5 Bi-aryl amides potently bind Pinl .Bi-aryl amides potently bind Pinl .
  • Co- crystallization with 65c revealed a new binding orientation with the phenyl ring oriented in the proline-binding pocket and the phosphate group oriented between Arg-68 and Arg-
  • FIG. 6 Optimization of the bi-aryl amide scaffold to enhance cellular permeability.
  • the phosphate group was replaced with a carboxylic acid, which retained a similar binding pose as (compound 4.5a) with the orientation of the carboxylate facing Lys-63 as in the phosphopeptide inhibitors. (PDB: 4TYO).
  • FIG. 7 Alternative bi-aryl scaffold engages peripheral residues of the Pinl cationic groove. Spanning the phosphate-binding region (Lys-63, Arg-68, Arg-69) enhances affinity for Pinl, even without engagement of the hydrophobic shelf.
  • FIGS. 8A-8B Overlay of the bound conformation of FK506 compared to the pintide phosphopeptide, highlighting the potential modification site.
  • FIG. 8A Aligning the pipecolate ring in FK506 to the pintide phosphopeptide demonstrates the binding pose similarity of each compound and proximity to the cationic phosphate binding site.
  • FIG. 8B FK506 and Rapamycin shown with the FKBP binding motif highlighted. The tertiary hydroxyl is highlighted (FIG. 8 A, third panel; black arrow in FIG. 8B).
  • FIG. 9 Semisynthetic modification of FK506 and rapamycin, demonstrating modification of the tertiary hydroxyl of FK506 and Rapamycin into a primary amine for further derivatization.
  • FIG. 10 Conversion of FK506 into FK-NH2. Within 30 minutes, a significant portion of FK506 is converted into the amine-containing derivative. Order of curves: top peak to bottom at about 3.4 min: control, 30min, 60min, 90min, 120min, 180min.
  • FIG. 11 Reaction rate of the FK506 conversion. Data were fit to a one-phase exponential.
  • FIG. 12 Comparison of FK-NH2 and FK506 by MS. In the converted FK-NH2, the parent amine is readily ionized, unlike in FK506.
  • FIG. 13 Downfield region of the FK-NH2 13 C NMR spectrum. The C1 O peak
  • corresponding to the tertiary hydroxyl attachment point is typically at 97ppm (left highlight), but appears shifted after conversion to the amine (right highlight).
  • FIG. 14 Determination of concentration effects on the conversion of FK506.HPLC traces are shown of the reaction after two hours in various concentrations of ammonia without and with peak highlighting (left and right, respectively). Increasing ammonia concentration results in formation of a new species that is less polar than FK-NH2.
  • FIG. 15. Solvent dramatically effects the conversion of FK506. Alcohols are heavily preferred in the conversion of FK506, with other polar and protic solvents leading to only minimal product formation after three hours. Bins (left to right): DCM, Dioxane, DMPU, EtOH, TFE, IPA,m N-BuOH, MeOH. Order within each bin: FK-NH2 (left), FK506 (right).
  • FIG. 16 Deuterated methanol slightly enhances the rate of reaction. Bins (left to right): Methanol (-d) at 30min, 60min, 240min; Methanol at 30min, 60min, 240min.
  • FIG. 17 Semisynthetic scheme to derivatize FK-NH2.i) 2M ammonia, ethanol; ii) FK- NH2, 3-chlorobenzyl bromide (3eq), DIPEA (6 eq), DMAP (0. leq), DCM. Order within each bin: FK-NH2 (left), FK506 (right).
  • FIGS. 18A-18B The phosphopeptide WFYpSPFLE binds to Pinl and is competed by 34.
  • FIG. 18 A Wild-type Pinl and the PPIase domain (see B legend) bind with good affinity to the phosphopeptide tracer. The smaller PPIase domain has a lower AmP corresponding to its smaller molecular mass.
  • FIG. 18B The phosphopeptide tracer is competed by 34, which contains an electronegative sulfamic acid group that likely engages the Pinl cationic groove. Experiments are the average of at least two experiments with duplicate measurements. Error is SEM.
  • FIGS. 19A-19B Competitive binding to FKBP12 of FK506 derivatives.
  • FIGS. 20A-20I MS spectra for compounds 15 (FIG. 20 A), 16 (FIG. 20 A), 18 (FIG. 20 A), 19 (FIG. 20A), 22 (FIG. 20A), 24 (FIG. 20A), 27 (FIG. 20 A), 29 (FIG. 20A), and 34 (FIG. 20A).
  • Axes relative abundance (y-axis); m/z (x-axis).
  • FIG. 21 Binding of FK506 to natural target FKBP12.
  • FIG. 22 Schematic of multiple binding functionality incorporated into a compound.
  • FIG. 23 Computational model showing binding functionality incorporated into a compound.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by,
  • alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be
  • heteroatom(s) e.g., N, S, Si, or P
  • heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Heteroalkyl is an uncyclized chain. Examples include, but are not limited to:
  • 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 eight optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -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).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0)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. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • 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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2) W , where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • 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.
  • monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic.
  • Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl.
  • bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2) W , where w is 1, 2, or 3).
  • bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl.
  • fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems
  • the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • a heterocycloalkyl is a heterocyclyl.
  • heterocyclyl as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle.
  • the heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.
  • heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
  • the heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3
  • heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
  • Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.
  • multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin-10-yl, 9, 10-dihydroacridin-9-yl, 9, 10-dihydroacridin- 10-yl, 1 OH-phenoxazin- 10-yl, 10, 11 -dihydro-5H- dibenzo[b,f]azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin- 12-yl, and dodecahydro-lH-carbazol-9-yl.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 - C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroaryl ene 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 heteroaryl ene 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-imidazo
  • arylene and heteroarylene are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom.
  • the individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula:
  • An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , -CF 3 , -CCb, -CBr 3 , -C1 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 2 CH 3 -S0 3 H, -OS0 3 H, -S0 2 NH 2 , -NHNH2, -ONH2, -NHC(0)NHNH 2 , substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
  • the alkylarylene is unsubstituted.
  • 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(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like.
  • Substituents for rings 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(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -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'-, -0-, -NR-, -S-, -S(0) -, -S(0) 2 -, - S(0) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is - 0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • the substituents R, R, R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or
  • 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:
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S 0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H,
  • 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO4H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 ,-NHC(0)NH 2 , -NHS0 2 H,
  • -NHC(0)H 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 C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to
  • -NHSO2H 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI2, -OCHF2, 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
  • a "size-limited substituent” or " size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 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 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, and each substituted or unsubstituted heteroaryl is a group selected
  • 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 C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 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 heteroalkyl ene 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 or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkyl ene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
  • heterocycloalkyl ene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroaryl ene.
  • 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 C 1 -C 8 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 C 6 - 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 heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively).
  • 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. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted
  • heterocycloalkylene, substituted arylene, and/or substituted 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.
  • 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.
  • a "nitrogen-containing functional group”, as used herein, means any substituent group containing nitrogen atom.
  • the nitrogen-containing functional group is an amino group, primary amino group, secondary amino group, tertiary amino group, ammonium ion, primary ketamine, secondary ketamine, primary aldimine, secondary aldimine, imide, azide, diimide, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy group, nitro group, nitroso group, oxime, nitrogen-containing 2 to 8 membered heteroalkyl , nitrogen-containing 3 to 8 membered heterocycloalkyl, or nitrogen-containing 5 to 9 membered heteroaryl.
  • Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the presentdisclosure.
  • 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 presently disclosed compounds include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • 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 hereof.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope hereof.
  • 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 ( 1 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scope of the presentdisclosure.
  • 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.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • a "detectable moiety” as used herein refers to a moiety that can be covalently or noncovalently attached to a compound (e.g. biomolecule) that can be detected for instance, using techniques known in the art.
  • the detectable moiety is covalently attached.
  • the detectable moiety may provide for imaging of the attached compound or biomolecule.
  • the detectable moiety may indicate the contacting between two compounds.
  • Exemplary detectable moieties are fluorophores, antibodies, reactive dies, radio-labeled moieties, magnetic contrast agents, and quantum dots.
  • Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes.
  • Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64.
  • Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese.
  • test compound refers to an experimental compound used in a screening process to identify activity, non-activity, or other modulation of a particularized biological target or pathway.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present invention may exist as salts, such as with
  • the present invention includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • peptidyl-prolyl cis/trans isomerase or "PPIase” refer to a protein or proteins (including homologs, isoforms, and functional fragments thereof) that isomerizes the peptide bond of prolines.
  • PPIase refers to a protein or proteins (including homologs, isoforms, and functional fragments thereof) that isomerizes the peptide bond of prolines.
  • the term includes any recombinant or naturally-occurring form of a PPIase and variants thereof that maintain PPIase activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%), or 100%) activity compared to wildtype Pin 1).
  • the term includes any mutant form of PPIase variants (e.g., frameshift mutations) thereof that maintain PPIase activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to
  • Pin 1 peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
  • the enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function.
  • the term includes any recombinant or naturally-occurring form of Pin 1 variants thereof that maintain Pin 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Pin 1).
  • the term includes any mutant form of Pin 1 variants (e.g., frameshift mutations) thereof that maintain Pin 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Pin 1).
  • the term "Pin 1" refers to NCBI Accession No. NP_006212, and proteins having sequence homology to Pin 1 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
  • a "Pin 1 inhibitor” refers to a compound (e.g., compounds described herein) that reduces the activity of Pin 1 when compared to a control, such as absence of the compound or a compound with known inactivity.
  • a "Pin-1 mediated disease or disorder” refers to a diasease or disorder associated with modulated levels of expression of Pin-1 or levels of DNA/RNA encoding Pin-1 in a subject and/or changes in cellular regulation mediated by Pin-1.
  • FKBP or "FK506 binding protein” refer to a family of proteins (including homologs, isoforms, and functional fragments thereof) that have prolyl isomerase activity and are related to the cyclophilins in function.
  • the terms include any recombinant or naturally-occurring form of FKBP variants thereof that maintain FKBP activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP).
  • the term includes any mutant form of FKBP variants (e.g., frameshift mutations) thereof that maintain FKBP activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP).
  • FK506-binding protein 5" FKBP5
  • FKBP51 FKBP54
  • P54 Ptg- 10
  • the terms include any recombinant or naturally-occurring form of FKBP 5 and variants thereof that maintain FKBP 5 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP5).
  • the term includes any mutant form of FKBP5 variants (e.g., frameshift mutations) thereof that maintain FKBP5 activity (e.g.
  • FKBP5 refers to Entrez 2289, UniProt Q13451, NM_004117, NM_004117.3, NP_004108.1, or NP_004108.
  • the term “FKBP38” refers to NCBI Accession No. NP 36313, and proteins having sequence homology to FKBP38 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
  • the term “FKBP51” refers to NCBI Accession No.
  • FKBP52 proteins having sequence homology to FKBP51 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
  • FKBP52 refers to NCBI Accession No.
  • FKBP 12 proteins having sequence homology to FKBP 52 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
  • term "FKBP 12" refers to NCBI Accession No.
  • NP 463460 and proteins having sequence homology to FKBP12 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
  • an "FKBP inhibitor” refers to a compound (e.g., compounds described herein) that reduces the activity of an FKBP (e.g., FKBP51, FKBP52 and/or FKBP38) when compared to a control, such as absence of the compound or a compound with known inactivity.
  • FKBP inhibitor refers to a compound (e.g., compounds described herein) that reduces the activity of an FKBP (e.g., FKBP51, FKBP52 and/or FKBP38) when compared to a control, such as absence of the compound or a compound with known inactivity.
  • polypeptide peptide
  • protein protein
  • amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • polypeptide refers to a polymeric form of amino acids of any length, which can include genetically coded and non-genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones.
  • the terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence; fusion proteins with heterologous and homologous leader sequences, with or without N-terminus methionine residues; immunologically tagged proteins; and the like.
  • a polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type).
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
  • species e.g. chemical compounds including biomolecules or cells
  • contacting may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • activation As defined herein, the term “activation”, “activate”, “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state.
  • the terms reference activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
  • agonist refers to a substance capable of detectably increasing the expression or activity of a given gene or protein.
  • the agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.
  • an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target.
  • activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, or cell.
  • the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor.
  • inhibition refers to reduction of a disease or symptoms of disease.
  • inhibition refers to a reduction in the activity of a particular protein target.
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein).
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
  • inhibitor refers to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
  • the antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.
  • An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.
  • inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell.
  • An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity.
  • An "antagonist” is a molecule that opposes the action(s) of an agonist.
  • expression includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
  • the terms "disease,” “disorder” 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 cancer.
  • the disease may be a mental illness (e.g.
  • the disease may be depression.
  • the disease may be pain (e.g. chronic pain or neuropathic pain).
  • 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 MDS, AML, ALL, ATLL and CML), or multiple myeloma.
  • cancer refers to all types of cancer, neoplasm, or malignant tumors found in mammals, 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,
  • cancers 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, uterus, Hodgkin's Disease, and Non-Hodgkin's Lymphoma.
  • 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, melanoma, medulloblastoma, multiple myeloma, metastatic bone cancer, 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, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma,
  • Treating” or “treatment” as used herein 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, fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things. In embodiments, treating does not include preventing.
  • Treating” and “treatment” as used herein include prophylactic treatment.
  • Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein.
  • 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 the compound, the activity of the compositions used in the treatment, or a combination thereof.
  • 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.
  • the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • 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. In embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.
  • 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, such as bovines, rats, mice, dogs, monkeys, goats, sheeps, cows, deers, and other animals.
  • a patient is human.
  • an “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
  • An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques ⁇ see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like.
  • measurement of the serum level of a CCR4 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.
  • 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.
  • 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. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity 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 individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • 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).
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.
  • Modulation refers to the process of changing or varying one or more properties.
  • to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • the terms “modulate,” “modulation” and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of PPIases, either directly or indirectly, relative to the absence of the molecule.
  • aberrant refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • the phrase "in a sufficient amount to affect a change” means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy.
  • Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's feeling of well-being).
  • the "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like.
  • the term "proliferative activity” encompasses an activity that promotes, that is necessary for, or that is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.
  • substantially pure indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%), at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).
  • signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components.
  • extra-cellular components e.g., proteins, nucleic acids, small molecules, ions, lipids
  • nucleic acid refers to a polymeric form of nucleotides of any length, either
  • deoxyribonucleotides or ribonucleotides, or analogs thereof include linear and circular nucleic acids, DNA, RNA, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers and the like.
  • variants are used interchangeably to refer to amino acid or nucleic acid sequences that are similar to reference amino acid or nucleic acid sequences, respectively.
  • the term encompasses naturally-occurring variants and non-naturally- occurring variants.
  • Naturally-occurring variants include homologs (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one species to another), and allelic variants (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one individual to another within a species).
  • variants and homologs encompass naturally occurring amino acid and nucleic acid sequences encoded thereby and their isoforms, as well as splice variants of a protein or gene.
  • the terms also encompass nucleic acid sequences that vary in one or more bases from a naturally-occurring nucleic acid sequence but still translate into an amino acid sequence that corresponds to the naturally-occurring protein due to degeneracy of the genetic code.
  • Non-naturally-occurring variants and homologs include polypeptides and nucleic acids that comprise a change in amino acid or nucleotide sequence, respectively, where the change in sequence is artificially introduced; for example, the change is generated in the laboratory by human intervention ("hand of man"). Therefore, non-naturally occurring variants and homologs may also refer to those that differ from the naturally-occurring sequences by one or more conservative substitutions and/or tags and/or conjugates.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for a mental illness or pain).
  • additional therapies e.g. anti-cancer agent, chemotherapeutic, or treatment for a mental illness or pain.
  • the compound of the invention can be administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
  • the compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • the compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely- divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212, 162; and 4,861,760. The entire contents of these patents are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212, 162; and 4,861,760. The entire contents of these patents are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212, 162; and 4,
  • compositions of the present invention can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as
  • the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • compositions of the present invention can also be delivered as nanoparticles.
  • composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient.
  • compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g. colon cancer), mental illness, pain or depression.
  • cancer e.g. colon cancer
  • other active agents known to be useful in treating cancer e.g. colon cancer
  • mental illness e.g., mental illness, pain or depression.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent.
  • Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • the compounds described herein may be combined with treatments for cancer (e.g. colon cancer), mental illness (e.g.
  • schizophrenia e.g. chronic pain or neuropathic pain
  • depression e.g. depression
  • a position equivalent to C1 O of FK506 means a carbon position on a macrolide compound (e.g. FK506, rapamycin, ascomycin or derivative or variant thereof) that is chemically or functionally equivalent to the C1 O of FK506 (e.g. the C1 O of rapamycin (or variant or derivative thereof) or the C1 O of ascomycin (or variant or derivative thereof).
  • the position equivalent to C1 O of FK506 is the C1 O position of rapamycin, or a variant, derivative or pharmaceutically acceptable salt thereof, or C1 O position of ascomycin, or a variant, derivative or pharmaceutically acceptable salt thereof.
  • a peptidyl-prolyl cis-trans isomerase NEVIA-interacting 1 (Pin 1) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is an FK506 compound, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C-10 position.
  • the nitrogen- containing functional group is an amino group.
  • the nitrogen-containing functional group is a primary amino group.
  • the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
  • the compound is an FK506 compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in FK506.
  • the amino is unsubstituted.
  • the amino is mono- substituted.
  • the amino is di-substituted.
  • the amino is tri- substituted.
  • the amino is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted amino 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.
  • the compound is an FK506 compound, or a derivative thereof, including an electronegative group at the C-10 position.
  • the electronegative group is not -OH.
  • the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
  • the compound is an FK506 compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the compound is an FK506 compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in FK506.
  • the linker is covalently bound to an electronegative moiety.
  • the electronegative moiety is a phosphate isostere moiety.
  • the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
  • the FK-506 compound is an ascomycin derivative or variant.
  • FK-506 or “FK506” refers, in the usual and customary sense, to (3S,4R,5S,8R,9E, 12S,14S,15R, 16S,18R,19R,26aS)- 5,6,8, 11,12, 13,14, 15,16, 17, 18,19,24,25,26,26a-Hexadecahydro-5,19-dihydroxy-3-[(lE)-2- [(lR,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethenyl]-14,16-dimethoxy-4,10, 12,18- tetramethyl-8-(2-propen- 1 -yl)- 15, 19-epoxy-3H-pyrido[2, 1 -c] [ 1 ,4]oxaazacyclotricosine-
  • the derivative of the FK-506 compound is an ascomycin compound.
  • the compound is an ascomycin, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C1 O position.
  • the nitrogen- containing functional group is an amino group.
  • the nitrogen-containing functional group is a primary amino group.
  • the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
  • the compound is an ascomycin, or a derivative thereof, including an electronegative group at the C-10 position.
  • the electronegative group is not -OH.
  • the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
  • the compound is an ascomycin, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • the compound is an ascomycin, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the compound is ascomycin, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in FK506.
  • the linker is covalently bound to an electronegative moiety.
  • the electronegative moiety is a phosphate isostere moiety.
  • the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
  • the compound is a rapamycin compound, or a derivative thereof, including a nitrogen-containing functional group at the C-10 position.
  • the nitrogen-containing functional group is an amino group.
  • the nitrogen-containing functional group is a primary amino group.
  • the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
  • the compound is a rapamycin compound, or a derivative thereof, including an electronegative group at the C-10 position.
  • the electronegative group is not -OH.
  • the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
  • the compound is a rapamycin compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin.
  • the amino is unsubstituted.
  • the amino is mono-substituted.
  • the amino is di-substituted.
  • the amino is tri- substituted.
  • the amino is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted amino 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.
  • the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in rapamycin.
  • the linker is covalently bound to an electronegative moiety.
  • the electronegative moiety is a phosphate isostere moiety.
  • the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
  • electronegative group is used according to its plain, ordinary meaning and refers to a chemical substituent (e.g., an atom or a functional group) that attracts electrons or electron density towards itself.
  • electronegative group and “electronegative substituent” are used synonymously.
  • electronegative atoms include, but are not limited to, nitrogen, oxygen, phosphorus, sulfur, chlorine, bromine and fluorine.
  • the foregoing groups bearing these atoms, (e.g., -NO2, -CN, -CO2H, etc.) may be said to be “electronegative groups.”
  • electronegative groups e.g., -NO2, -CN, -CO2H, etc.
  • the electronegative group is a phosphate isostere.
  • phosphate isostere is used according to its plain, ordinary meaning and refers to a chemical substituent with similar physical or chemical properties as a phosphate, which produces similar biological properties (e.g. in a method disclosed herein) to a phosphate.
  • the phosphate isostere is a phosphonate, a tetrahedral sulphate, or a tetrahedral sulphonate.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • an FK506 binding protein (FKBP) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof,.
  • the compound is a rapamycin compound, or a derivative thereof, including a nitrogen-containing functional group at the C-10 position.
  • the nitrogen-containing functional group is an amino group.
  • the nitrogen-containing functional group is a primary amino group.
  • the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
  • the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
  • the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • the linker is covalently bound to an electronegative group.
  • the electronegative group is a phosphate isostere.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • a macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506 or a pharmaceutically acceptable salt thereof.
  • the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative or an ascomycin compound derivative.
  • an FK506 binding protein (FKBP) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
  • the FK506 binding protein (FKBP) inhibitor compound is a rapamycin compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin.
  • the amino is unsubstituted.
  • the amino is mono-substituted.
  • the amino is di-substituted.
  • the amino is tri- substituted.
  • the amino is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted amino 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.
  • the compound is a rapamycin compound, or a derivative thereof, including an electronegative group at the C-10 position.
  • the electronegative group is not -OH.
  • the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
  • the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in rapamycin.
  • the linker is covalently bound to an electronegative moiety.
  • the electronegative moiety is a phosphate isostere moiety.
  • the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
  • a macrolide compound covalently attached to an electronegative group at a position equivalent to C1 O of FK506 or a pharmaceutically acceptable salt thereof.
  • the electronegative group is not -OH.
  • the electronegative group is not -OH.
  • the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size- limited substituent group, or lower substituent group).
  • the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative, or an ascomycin compound derivative.
  • the macrolide compound is capable of inhibiting a peptidyl-prolyl cis- trans isomerase NIMA-interacting 1 (Pin 1) protein.
  • the K D for inhibition is less than 1000 nM, 100 nM, 10 nM, or even 1 nM. In embodiments, the K D for inhibition is in the range 0.1-1000 nM, 0.1-100 nM, 0.1-10 nM, or even 0.1-1 nM.
  • the macrolide compound is capable of inhibiting an FK506 binding protein.
  • the K D for inhibition is less than 1000 nM, 100 nM, 10 nM, or even 1 nM.
  • the K D for inhibition is in the range 0.1-1000 nM, 0.1-100 nM, 0.1-10 nM, or even 0.1-1 nM.
  • the electronegative group is a phosphate isostere.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • nl, n2 and n3 are independently an integer from 0 to 4.
  • ml, m2, m3, vl, v2 and v3 are independently 1 or 2.
  • L 1 is a bond, -0-, -S-, -NR 1L - -NR 1L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(O)-, -C(0)0-, -S(O) -, -S(0) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted
  • heterocycloalkylene substituted or unsubstituted arylene, or substituted or unsubstituted
  • R 1 is hydrogen, halogen, -CX 1 -C .1 H3,X 1 . - 1 C2H, zX 1 - 1 , -CN, -SO n iR 1A ,
  • R 2 is hydrogen, halogen, -CX 2 .1 -3C,HX 2 .1 3 -,CH 2 X 2 .1 -,CN, -SO existence2R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(0)NHNR 2B R 2C , -NHC(0)NR 2B R 2C , -N(0) m2 , -NR 2B R 2C , -C(0)R 2D ,
  • R 3 is hydrogen, halogen, -CX 3,1 3 ,
  • R 3B , R 3C and R 3D are independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -C1 3 ,-COOH,
  • X 1 1 , X 2 1 and X 3 1 are independently
  • R 2 is not hydrogen. In embodiments, when L 2 is -O- then R 2 is not hydrogen. In embodiments, when R 1 is ⁇ 55 ⁇ then R 2 is not hydrogen. In embodiments, when R 1 is -CH 2 CH 3
  • R 2 is not hydrogen.
  • R 3 is hydroxyl then R 2 is not hydrogen.
  • R 1 is ⁇ 5 ⁇ or -CH 2 CH 3 and R 3 is
  • R 2 is not hydroxyl. In embodiments, when L 2 is a bond then R 2 is not hydroxyl. In embodiments, when L 2 is a bond then R 2 is not hydroxyl.
  • R 2 when L 1 is a bond then R 2 is not hydroxyl. In embodiments, when R 1 is -CH 2 CH 3 then R 2 is not hydroxyl. In embodiments, when R 1 is then R 2 is not hydroxyl. In embodiments, when R 1 is then R 2 is not hydroxyl.
  • R 3 when R 3 is hydroxyl then R 2 is not hydroxyl.
  • L 2 is not -0-.
  • L 1 is not a bond.
  • R 1 is not ⁇ - ⁇ 5 ⁇ or -CH 2 CH 3 .
  • R 1 is not unsubstituted alkyl.
  • R 3 is not hydroxyl.
  • R 2 is not hydrogen.
  • L 1 is a bond, -0-, -S-, -NR 1L - -NR 1L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 - 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 bond, -0-, -S-, -NR 1L - -NR 1L C(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0) 2 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 cycloalkylene, C 3 -C 6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8
  • L 1 is a bond, -0-, -S-, -NR 1L - -NR 1L C(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0) 2 -, R 11 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene), R 11 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R 11 -substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 cycloalkylene, C 3 -C 6 cycloalkylene, or C5-C6 cycloalkylene), R 11
  • L 1 is R 11 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 1 is R 11 -substituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 1 is an unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene).
  • L 1 is R 11 - 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 1 is R 11 -substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L 1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
  • heteroalkylene or 2 to 4 membered heteroalkylene.
  • L 1 is R 11 - substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 1 is R 11 -substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 1 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 1 is R 11 - substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 1 is R 11 -substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 1 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 1 is R 11 - substituted or unsubstituted arylene (e.g., C 6 -C 10 arylene, C 10 arylene, or phenylene). In embodiments, L 1 is R 11 -substituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene). In embodiments, L 1 is an unsubstituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene).
  • L 1 is R 11 -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 1 is R 11 -substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 1 is an
  • L 1 is a bond and R 1 is (R)-ethyl.
  • L 1 is a bond and R 1 is ethylene.
  • L 1 is a bond and R 1 is propylene.
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0) 2 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 cycloalkylene, C 3 -C 6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 -, R 14 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene), R 14 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered
  • alkylene e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene
  • heteroalkylene e.g., 2 to 8 membered
  • heteroalkylene 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene
  • R 14 - substituted or unsubstituted cycloalkylene e.g., C 3 -C 8 cycloalkylene, C 3 -C 6 cycloalkylene, or C5-C6 cycloalkylene
  • R 14 -substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered
  • R 14 -substituted or unsubstituted arylene e.g., C 6 -C 10 arylene, C10 arylene, or phenylene
  • R 14 -substituted or unsubstituted heteroarylene e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • L 2 is R 14 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 2 is R 14 -substituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 2 is an unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene).
  • L 2 is R 14 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 2 is R 14 -substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 2 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
  • heteroalkylene or 2 to 4 membered heteroalkylene.
  • L 2 is R 14 -substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 2 is R 14 -substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 2 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 2 is R 14 -substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 2 is R 14 -substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 2 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 2 is R 14 -substituted or unsubstituted arylene (e.g., C 6 -C 10 arylene, C 10 arylene, or phenylene). In embodiments, L 2 is R 14 -substituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene). In embodiments, L 2 is an unsubstituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene).
  • L 2 is R 14 -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 2 is R 14 -substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 2 is an
  • L 2 is a bond; and R 2 is NH 2 .
  • L 2 is a bond, -NR 2L -, -NR 2L C(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • L 2 is -NR 2L -.
  • L 2 is -NR 2L C(0)-.
  • L 2 is substituted or unsubstituted alkylene.
  • L 2 is substituted or unsubstituted heteroalkylene.
  • L 2 is a bond,-NR 2L - -NR 2L C(0)-.
  • L 2 is a bond.
  • L 2 is -NH-.
  • L 2 is -NHC(O)-.
  • L 2 is -NHCH 2 -.
  • L 2 is -NHCH 2 CH 2 -.
  • R 1 is hydrogen, halogen, -CX 1 -C .1 H3X, 1 - . C 1 H3, 2 X 1-1 , -CN, -SO n iR 1A , -SOviNR 1B R 1C , -NHNR 1B R 1C , -0NR 1B R 1C , -NHC(0)NHNR 1B R 1C , -NHC(0)NR 1B R 1C , -N(0) m i, -NR 1B R 1C , -C(0)R 1D , -C(0)OR 1D , -C(0)NR 1B R 1C , -OR 1A , -NR 1B S0 2 R 1A , -NR 1B C(0)R 1D , -NR 1B C(0)OR 1D , -NR 1B OR 1D , -OCX 1 -O .1 C3H, X 1.1 2, R 17 -substit
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17 - substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 17 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1 is R 17 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 1 is R 17 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 1 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 1 is R 17 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 1 is R 17 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 1 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 1 is R 17 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 1 is R 17 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 1 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 1 is R 17 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 1 is R 17 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 1 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 1 is R 17 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 1 is R 17 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 1 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 1 is R 17 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 1 is R 17 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 1 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 2 is hydrogen, halogen, -CX 2 -C .1 H3X, 2.1 2, -CH 2 X 2 -C .1 N, , -SO Rule2R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(0)NHNR 2B R 2C , -NHC(0)NR 2B R 2C , -N(0)m2, -NR 2B R 2C , -C(0)R 2D , -C(0)OR 2D , -C(0)NR 2B R 2C , -OR 2A , -NR 2B S0 2 R 2A , -NR 2B C(0)R 2D , -NR 2B C(0)OR 2D , -NR 2B OR 2D , -OCX 2 -O .1 C3H, X 2 su .1 b2s,tit
  • R 2 is hydrogen, halogen, -CX 2 -C .1 H3X, 2.1 2, -CH 2 X 2 -C .1 N, , -SO Rule2R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(0)NHNR 2B R 2C , -NHC(0)NR 2B R 2C , -N(0)m2, -NR 2B R 2C , -C(0)R 2D , -C(0)OR 2D , -C(0)NR 2B R 2C , -OR 2A , -NR 2B S0 2 R 2A , -NR 2B C(0)R 2D , -NR 2B C(0)OR 2D , -NR 2B OR 2D , -OCX 2 -O .1 C3H, X 2.1 2, R 20 -substituted
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 20 - substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • R 20 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2 is R 20 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 2 is R 20 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 2 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 2 is an unsubstituted ethyl. In embodiments, R 2 is an unsubstituted C3 alkyl. In embodiments, R 2 is an unsubstituted C 4 alkyl.
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 al
  • R 2 is R 20 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 2 is R 20 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 2 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 2 is R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 2 is R 20 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 2 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 2 is R 20 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 2 is R 20 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 2 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 2 is R 20 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 2 is R 20 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 2 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 2 is R 20 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 2 is R 20 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 2 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 2 is a phosphate isostere group.
  • R 2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • R 2 is a tetrazole group.
  • R 2 is a triazole group.
  • R 2 is a carboxylic acid group.
  • R 2 is a phosphonate group. In embodiments, R 2 is a boranophosphate group. In embodiments, R 2 is a sulfate group. In embodiments, R 2 is a sulfamic acid group. In embodiments, R 2 is a sulphonate group. In embodiments, R 2 is a nitro group. In embodiments, R 2 is a
  • R 2 is a thiazolidinone group.
  • R 2 is a thiazolidinone group.
  • R 2 is a squaric acid group.
  • R 2 is a hydroxyl group.
  • R 2 is a boronic acid group.
  • R 2 is halogen.
  • R 2 is unsubstituted C5-C6 cycloalkyl.
  • R 2 is substituted or unsubsttuted phenyl.
  • R 2 is -COOH. In embodiments, R 2 is hydrogen. In embodiments, R 2 is -C(0)R 2D . In embodiments, R 2 is -SO3H. In embodiments, R 2 is substituted or unsubstituted alkyl. In embodiments, R 2 is substituted alkyl. In embodiments, R 2 is substituted methyl. In embodiments, R 2 is R 20 -substituted alkyl. In embodiments, R 2 is R 20 -substituted methyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is substituted ethyl. In embodiments, R 2 is R 20 - substituted ethyl.
  • R 2 is unsubstituted ethyl. In embodiments, R 2 is substituted n-propyl. In embodiments, R 2 is R 20 -substituted n-propyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted C 1 -C 8 alkyl. In embodiments, R 2 is R 20 -substituted C 1 -C 8 alkyl. In embodiments, R 2 is substituted or unsubstituted heteroalkyl. In embodiments, R 2 is substituted heteroalkyl.
  • R 2 is R 20 -substituted heteroalkyl. In embodiments, R 2 is substituted or unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R 2 is substituted 5 to 8 membered heteroalkyl. In embodiments, R 2 is R 20 -substituted 5 to 8 membered heteroalkyl. In embodiments, R 2 is substituted or unsubstituted 10 to 15 membered heteroalkyl. In embodiments, R 2 is substituted 10 to 15 membered heteroalkyl. In embodiments, R 2 is R 20 -substituted 10 to 15 membered heteroalkyl. In embodiments, R 2 is substituted or unsubstituted cycloalkyl.
  • R 2 is substituted cycloalkyl. In embodiments, R 2 is substituted cyclohexyl. In embodiments, R 2 is unsubstituted cyclohexyl. In embodiments, R 2 is R 20 -substituted cycloalkyl. In embodiments, R 2 is R 20 - substituted cyclohexyl. In embodiments, R 2 is substituted C3-C8 cycloalkyl. In embodiments, R 2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 2 is R 20 -substituted C3-C8 cycloalkyl. In embodiments, R 2 is substituted or unsubstituted aryl. In embodiments, R 2 is substituted aryl. In embodiments, R 2 is substituted phenyl. In embodiments, R 2 is unsubstituted phenyl. In
  • R 2 is R 20 -substituted aryl. In embodiments, R 2 is R 20 -substituted phenyl.
  • R 3 is hydrogen, halogen, -CX 3 -C .1 H3X, 3.1 2, -CH 2 X 3 -C .1 N, , -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(0)NHNR 3B R 3C , -NHC(0)NR 3B R 3C , -N(0) m3 , -NR 3B R 3C , -C(0)R 3D , -C(0)OR 3D , -C(0)NR 3B R 3C , -OR 3A , -NR 3B S0 2 R 3A , -NR 3B C(0)R 3D , -NR 3B C(0)OR 3D , -NR 3B OR 3D , -OCX 3 -O .1 C3H, X 3 su .1 b2
  • R 3 is hydrogen, halogen, -CX 3 -C .1 H3X, 3.1 2, -CH 2 X 3 -C .1 N, , -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(0)NHNR 3B R 3C , -NHC(0)NR 3B R 3C , -N(0) m3 , -NR 3B R 3C , -C(0)R 3D , -C(0)OR 3D , -C(0)NR 3B R 3C , -OR 3A , -NR 3B S0 2 R 3A , -NR 3B C(0)R 3D , -NR 3B C(0)OR 3D , -NR 3B OR 3D , -OCX 3 -O .1 C3H, X 3.1 2, R 23 -sub
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23 - substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 23 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 3 is R 23 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 3 is R 23 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 3 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 3 is R 23 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 3 is R 23 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 3 is R 23 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 3 is R 23 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 3 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 3 is R 23 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 3 is R 23 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 3 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 3 is R 23 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 3 is R 23 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 3 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 3 is R 23 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 3 is R 23 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 3 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 3 is hydroxyl group.
  • R 1L , R 2L , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C and R 3D are independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -C1 3 ,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1B and R 1C , R 2B and R 2C , R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 1L is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 ,-COOH, -CONH2, R 11L -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 11L - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11L - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 11L -substituted or unsubstituted heterocycloalkyl
  • R 2L is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 14L -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 14L - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14L -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 14L -substituted or unsubstituted heterocyclo
  • alkyl e
  • R 1A is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2,
  • R 17A -substituted or unsubstituted alkyl e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl
  • R 17A - substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 17A -substituted or unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • R 17A -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 2A is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 20A -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 20A - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 20A - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 20A -substituted or unsubstituted heterocycloalkyl
  • R 3A is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 23A -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 23A - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 23A -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 23A -substituted or unsubstituted heterocyclo
  • alkyl e
  • R 1B is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 17B -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 17B - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 17B -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 17B -substituted or unsubstituted heterocyclo
  • alkyl e
  • R 1B and R 1C substituents bonded to the same nitrogen atom may optionally be joined to form a R 17B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 17B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 17B -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17B -substituted or unsubstituted heteroaryl e.g.,
  • R 2B is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 20B -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 20B - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 20B -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 20B -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 20B -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 20B -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2B and R 2C substituents bonded to the same nitrogen atom may optionally be joined to form a R 20B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 20B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 20B -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 20B -substituted or unsubstituted heteroaryl e.g.,
  • R 3B is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 23B -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 23B - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 23B -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 23B -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23B -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 23B -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a R -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 23B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23B -substituted or unsubstituted heteroaryl e.g., 5 to 10 member
  • R 1C is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 17C -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 17C - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 17C -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 17C -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17C -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 17C -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1B and R 1C substituents bonded to the same nitrogen atom may optionally be joined to form a R 17C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 17C -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 17C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17C -substituted or unsubstituted heteroaryl e.g.,
  • R 2C is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 20C -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 20C - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 20C -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 20C -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 20C -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 20C -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2B and R 2C substituents bonded to the same nitrogen atom may optionally be joined to form a R 20C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 20C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted heteroaryl e.g., 5 to 10 member
  • R 3C is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 23C -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 23C - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 23C -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 23C -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23C -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 23C -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a R 23C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 23C -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 23C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23C -substituted or unsubstituted heteroaryl e.g.,
  • R 1D is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 17D -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 17D - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 17D -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 17D -substituted or unsubstituted or unsubstitute
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17D -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 17D -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2D is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 20D -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 20D - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 20D -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 20D -substituted or unsubstituted or unsubstituted
  • R 2D is substituted or unsubstituted alkyl. In embodiments, R 2D is substituted alkyl. In embodiments, R 2D is substituted methyl. In embodiments, R 2D is R 20D - substituted alkyl. In embodiments, R 2D is R 20D -substituted methyl. In embodiments, R 2D is substituted ethyl. In embodiments, R 2D is R 20D -substituted ethyl. In embodiments, R 2D is unsubstituted ethyl. In embodiments, R 2D is unsubstituted methyl. In embodiments, R 2D is substituted n-propyl.
  • R 2D is R 20D -substituted n-propyl. In embodiments, R 2D is unsubstituted n-propyl. In embodiments, R 2D is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 2D is substituted C 1 -C 8 alkyl. In embodiments, R 2D is R 20D -substituted C 1 -C 8 alkyl. In embodiments, R 2D is -CF 3 . In embodiments, R 2D is substituted or unsubstituted aryl. In embodiments, R 2D is substituted aryl. In embodiments, R 2D is substituted phenyl. In embodiments, R 2D is unsubstituted phenyl. In embodiments, R 2D is substituted or unsubstituted phenyl.
  • R 20D is halogen. In embodiments, R 20D is -C1. In embodiments, R 20D is - F. In embodiments, R 20D is -Br. In embodiments, R 20D is oxo. In embodiments, R 20D is -COOH. In embodiments, R 20D is -OH. In embodiments, R 20D is -SO3H. In embodiments, R 20D is substituted or unsubstituted aryl. In embodiments, R 20D is substituted aryl. In embodiments, R 20D is substituted phenyl. In embodiments, R 20D is unsubstituted phenyl. In embodiments, R 20D is substituted or unsubstituted phenyl.
  • R 3D is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 23D -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 23D - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 23D -substituted or unsubstituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 23D -substituted or unsubstituted or unsubstituted alkyl
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 23D -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 23D -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 11 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 12 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 12 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 12 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 12 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • heterocycloalkyl R 12 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl), or R 12 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 11 is R 12 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 11 is R 12 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 11 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 11 is R 12 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 11 is R 12 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 11 is R 12 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 11 is R 12 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 11 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 11 is R 12 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is R 12 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 11 is R 12 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 11 is R 12 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 11 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 11 is R 12 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 11 is R 12 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 12 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 13 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 13 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 13 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 13 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • heterocycloalkyl R 13 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or R 13 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 12 is R 13 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 12 is R 13 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 12 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 12 is R 13 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 12 is R 13 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 12 is R 13 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 12 is R 13 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 12 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • cycloalkyl e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl.
  • R 12 is R 13 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 12 is R 13 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 12 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 12 is R 13 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 12 is R 13 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 12 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 12 is R 13 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 12 is R 13 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 12 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 14 is independently oxo
  • R 15 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 15 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R -substituted or unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • R 15 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • heterocycloalkyl R 15 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or R 15 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 14 is R 15 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 14 is R 15 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 14 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 14 is R 15 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 14 is R 15 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 14 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 14 is R 15 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 14 is R 15 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 14 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 14 is R 15 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 14 is R 15 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 14 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 14 is R 15 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 14 is R 15 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 14 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 14 is R 15 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 14 is R 15 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 14 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 15 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 16 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 16 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 16 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 16 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 16 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 16 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 15 is R 16 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 15 is R 16 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 15 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 15 is R 16 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 15 is R 16 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 15 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 15 is R 16 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 15 is R 16 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 15 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 15 is R 16 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 15 is R 16 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 15 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 15 is R 16 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 15 is R 16 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 15 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 15 is R 16 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 15 is R 16 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 15 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 17 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 18 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 18 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 18 - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 18 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 18 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • R 18 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 17 is R 18 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 17 is R 18 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 17 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 17 is R 18 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 17 is R 18 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 17 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 17 is R 18 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 17 is R 18 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 17 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 17 is R 18 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 17 is R 18 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 17 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 17 is R 18 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 17 is R 18 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 17 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 17 is R 18 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 17 is R 18 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 17 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 18 is independently oxo
  • R -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 19 - substituted or unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • R 19 -substituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • heterocycloalkyl R 19 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl), or R 19 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 18 is R 19 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 18 is R 19 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 18 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 18 is R 19 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 18 is R 19 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 18 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 18 is R 19 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 18 is R 19 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 18 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl.
  • R 18 is R 19 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 18 is R 19 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 18 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 18 is R 19 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 18 is R 19 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 18 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 18 is R 19 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 18 is R 19 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 18 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 20 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 21 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 21 - substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 21 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 21 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • R 21 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 20 is R 21 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 20 is R 21 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 20 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 20 is R 21 - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 20 is R 21 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 20 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 20 is R 21 - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 20 is R 21 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 20 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 20 is R 21 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 20 is R 21 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 20 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 20 is R 21 - substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 20 is R 21 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 20 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 20 is R 21 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 20 is R 21 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 20 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 20 is substituted or unsubstituted aryl. In embodiments, R 20 is substituted or unsubstituted phenyl. In embodiments, R 20 is substituted phenyl. In embodiments, R 20 is unsubstituted phenyl. In embodiments, R 20 is substituted or unsubstituted C10-C12 aryl. In embodiments, R 20 is substituted C10-C12 aryl. In embodiments, R 20 is unsubstituted C10-C12 aryl. In embodiments, R 20 is substituted or unsubstituted fluorenyl. In embodiments, R 20 is substituted fluorenyl.
  • R 20 is unsubstituted fluorenyl. In embodiments, R 20 is halogen. In embodiments, R 20 is -C1. In embodiments, R 20 is -F. In embodiments, R 20 is -Br. In embodiments, R 20 is oxo. In embodiments, R 20 is -COOH. In embodiments, R 20 is -OH. In embodiments, R 20 is -SO3H. In embodiments, R 20 is R 21 - substituted or unsubstituted aryl. In embodiments, R 20 is R 21 -substituted or unsubstituted phenyl. In embodiments, R 20 is R 21 -substituted phenyl. In embodiments, R 20 is R 21 -substituted fluorenyl. [0292] R 21 is independently oxo,
  • halogen -CC13, -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO4H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 22 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 22 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 22 - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 22 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 22 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 22 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 21 is R 22 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 21 is R 22 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 21 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 21 is R 22 -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 22 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 21 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 21 is R 22 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 21 is R 22 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 21 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 21 is R 22 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 21 is R 22 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 21 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 21 is R 22 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 21 is R 22 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 21 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 21 is R 22 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 21 is R 22 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 21 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 21 is halogen. In embodiments, R 21 is -C1. In embodiments, R 21 is -F. [0300] R 23 is independently oxo,
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 24 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 24 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 24 - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 24 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 24 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • R 24 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 23 is R 24 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 23 is R 24 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 23 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 23 is R 24 -substituted or 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 24 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 23 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 23 is R 24 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 23 is R 24 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 23 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 23 is R 24 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 23 is R 24 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 23 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 23 is R 24 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 23 is R 24 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 23 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 23 is R 24 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 23 is R 24 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 23 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 24 is independently oxo
  • R 25 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 25 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 25 -substituted or unsubstituted cycloalkyl e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • R 25 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • heterocycloalkyl R 25 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or R 25 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 24 is R 25 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 24 is R 25 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 24 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 24 is R 25 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 24 is R 25 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 24 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 24 is R 25 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 24 is R 25 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 24 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 24 is R 25 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 24 is R 25 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 24 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 24 is R 25 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 24 is R 25 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 24 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 24 is R 25 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 24 is R 25 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 24 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 11L R 13 R 14L R 16 R 17A R 17B R 17C R 17D R 19 R 20A R 20B R 20C R 20D R 22 R 23A R 23B R 23C , R 23D and R 25 are independently hydrogen, oxo,
  • -SO4H -SO2NH2, -NHNH2, -ONH2, -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF 3 , -OCBr 3 , -OC1 3 ,-OCHCl 2 , -OCHBr 2 , -OCHI2, -OCHF2, 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., C 3 -C 8 cycloalkyl, C 3 -C 6 cycl
  • 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
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 1 1 , X 2 1 and X 3 1 are independently -C1, -Br, -I or -F. In embodiments, X 1 1 is -C1. In embodiments, X 1 1 is -F. In embodiments, X 1 1 is -Br. In embodiments, X 1 1 is -I. In embodiments, X 2 1 is -C1. In embodiments, X 2 1 is -F. In embodiments, X 2 1 is -Br. In
  • X 2 1 is -I.
  • X 3 1 is -C1.
  • X 3 1 is -F.
  • X 3 1 is -Br.
  • X 3 1 is -I.
  • nl is an integer from 0 to 4. In embodiments, nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4.
  • ml and vl are independently 1 or 2. In embodiments, ml is
  • n2 is an integer from 0 to 4. In embodiments, n2 is 0. In
  • n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4.
  • m2 and v2 are independently 1 or 2. In embodiments, m2 is
  • m2 is 2.
  • v2 is 1.
  • v2 is 2.
  • n3 is an integer from 0 to 4. In embodiments, n3 is 0. In
  • n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3. In embodiments, n3 is 4.
  • m3 and v3 are independently 1 or 2. In embodiments, m3 is
  • n4, n5, n6, n7, n8, n9 and nlO are independently single bonds or double bonds.
  • L 3 is a bond, -0-, -S-, -NR 3L - -NR 3L C(0)-, -C(O)-, -C(0)0- -S(O) -,
  • R 4 is hydrogen
  • R 5 is hydrogen, halogen, -CX 5,1 3 , -CHX 5.1 2, -CH 2 X 5 ⁇ , -CN, -SOnsH, -SO v5 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m5 , -NH 2 ,
  • R 6 is hydrogen, halogen, -CX 6 J 3 , -CHX 6.1 2, -CH 2 X 6 1 ,
  • R 7 is hydrogen, halogen, -CX 7 J 3 , -CHX 7.1 2, -CH 2 X 7 1 ,
  • R 8 is hydrogen, halogen, -CX 8 J 3 , -CHX 8.1 2, -CH 2 X 8 1 ,
  • R 9 is hydrogen, halogen, -CX 9 J 3 , -CHX 9.1 2, -CH 2 X 9 1 ,
  • R 10 is hydrogen, halogen, -CX 10 J 3 , -CHX 10 - ⁇
  • R 4D are independently hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X 4 X .15 , 1 , X 6 X 7.1 , X 8.1 , X 9.11 , and X 10 1 are independently -C1, -Br, -I or -F.
  • R 4 when are double bonds, L 3 is -O- and R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, then R 4 is not hydrogen. In embodiments, when is a double bond then R 4 is not hydrogen. In embodiments, when is a double bond then R 4 is not
  • R 4 is not hydrogen. In embodiments, when L 3 is
  • R 4 is not hydrogen.
  • when and are double bonds L 3 is a bond and R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, then R 4 is not hydroxyl.
  • R 4 when is a double bond then R 4 is not hydroxyl. In embodiments, when is a double bond then R 4 is not hydroxyl. In embodiments, when L 3 is a bond then R 4 is not hydroxyl. In embodiments, when R 6 is hydrogen then R 4 is not hydroxyl. In embodiments, when R 7 is hydrogen then R 4 is not hydroxyl. In embodiments, when R 8 is hydrogen, then R 4 is not hydroxyl. In embodiments, when R 9 is hydrogen then R 4 is not hydroxyl. In embodiments, when R 10 is hydrogen then R 4 is not hydroxyl.
  • L 3 is a bond, -0-, -S-, -NR 3L - -NR 3L C(0)-, -C(O)-, -C(0)0- -S(O)-, -S(0) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
  • L 3 is a bond, -0-, -S-, -NR 3L - -NR 3L C(0)-, -C(O)-, -C(0)0- -S(O)-, -S(0) 2 -, substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C 1 - C 4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membere
  • alkylene e
  • L 3 is a bond, -0-, -S-, -NR 3L - -C(O)-, -C(0)0- -S(O) -, -S(0) 2 -
  • R 26 -substituted or unsubstituted alkylene e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene
  • R 26 -substituted or unsubstituted heteroalkylene e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene
  • R 26 -substituted or unsubstituted cycloalkylene e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene
  • L 3 is R 26 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 3 is R 26 -substituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene). In embodiments, L 3 is an unsubstituted alkylene (e.g., C 1 -C 8 alkylene, C 1 -C 6 alkylene, or C1-C4 alkylene).
  • L 3 is R 26 - 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 3 is R 26 -substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L 3 is an
  • unsubstituted heteroalkylene e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
  • L 3 is R 26 - substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L 3 is R 26 -substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L 3 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
  • L 3 is R 26 - substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 3 is R 26 -substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 3 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
  • L 3 is R 26 - substituted or unsubstituted arylene (e.g., C 6 -C 10 arylene, C 10 arylene, or phenylene). In embodiments, L 3 is R 26 - substituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene). In embodiments, L 3 is an unsubstituted arylene (e.g., C 6 -C 10 arylene, C10 arylene, or phenylene).
  • L 3 is R 26 - substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 3 is R 26 -substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L 3 is an
  • unsubstituted heteroarylene e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • L 3 is -NR 3L or a bond.
  • L 3 is -NR 3L C(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • L 3 is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • L 3 is a bond, -NR 3L - -NR 3L C(0)-.
  • L 3 is a bond.
  • L 3 is -NH-.
  • L 3 is -NHC(O)-.
  • L 3 is -NHCH2-.
  • L 3 is
  • R 4 is hydrogen, halogen, -CX 4 -C .1 H3X, 4.1 2, -CH 2 X 4 -C .1 N, , -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(0)NHNR 4B R 4C , -NHC(0)NR 4B R 4C , -N(0) m4 , -NR 4B R 4C , -C(0)R 4D , -C(0)OR 4D , -C(0)NR 4B R 4C , -OR 4A , -NR 4B S0 2 R 4A , -NR 4B C(0)R 4D , -NR 4B C(0)OR 4D , -NR 4B OR 4D , -OCX 4 -O .1 C3H, X
  • R 4 is hydrogen, halogen, -CX 4 -C .1 H3X, 4.1 2, -CH 2 X 4 -C .1 N, , -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(0)NHNR 4B R 4C , -NHC(0)NR 4B R 4C , -N(0) m4 , -NR 4B R 4C , -C(0)R 4D , -C(0)OR 4D , -C(0)NR 4B R 4C , -OR 4A , -NR 4B S0 2 R 4A , -NR 4B C(0)R 4D , -NR 4B C(0)OR 4D , -NR 4B OR 4D , -OCX 4 1 3 , -OCHX 4 R 29 - .
  • s 1 u2b stituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 29 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 29 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 29 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 29 - substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 29 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 4 is -CN, -C(0)NH 2, -CF 3 , -CH 3 or -C(CH 3 ) 2 OH .
  • R 4 is -CN.
  • R 4 is -C(0)NH 2 .
  • R 4 is -CF 3 .
  • R 4 is -CH 3 .
  • R 4 is -C(CH 3 ) 2 OH.
  • R 4 is R 29 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is R 29 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 4 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 4 is R 29 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 4 is R 29 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 4 is R 29 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 4 is R 29 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 4 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 4 is R 29 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 4 is R 29 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 4 is R 29 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 4 is R 29 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 4 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 4 is R 29 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 4 is R 29 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 4 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 4 is a phosphate isostere group.
  • R 4 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • R 4 is substituted or unsubstituted alkyl.
  • R 4 is substituted or unsubstituted aryl.
  • R 4 is substituted or unsubstituted benzyl.
  • R 4 is -COOH. In embodiments, R 4 is hydrogen. In embodiments, R 4 is - C(0)R 4D . In embodiments, R 4 is -SO3H. In embodiments, R 4 is substituted or unsubstituted alkyl. In embodiments, R 4 is substituted alkyl. In embodiments, R 4 is substituted methyl. In embodiments, R 4 is R 29 -substituted alkyl. In embodiments, R 4 is R 29 -substituted methyl. In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is substituted ethyl. In embodiments, R 4 is R 29 - substituted ethyl.
  • R 4 is unsubstituted ethyl. In embodiments, R 4 is substituted n- propyl. In embodiments, R 4 is R 29 -substituted n-propyl. In embodiments, R 4 is unsubstituted n- propyl. In embodiments, R 4 is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4 is substituted C 1 -C 8 alkyl. In embodiments, R 4 is R 29 -substituted C 1 -C 8 alkyl. In embodiments, R 4 is substituted or unsubstituted heteroalkyl. In embodiments, R 4 is substituted heteroalkyl.
  • R 4 is R 29 -substituted heteroalkyl. In embodiments, R 4 is substituted or unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R 4 is substituted 5 to 8 membered heteroalkyl. In embodiments, R 4 is R 29 -substituted 5 to 8 membered heteroalkyl. In embodiments, R 4 is substituted or unsubstituted 10 to 15 membered heteroalkyl. In embodiments, R 4 is substituted 10 to 15 membered heteroalkyl. In embodiments, R 4 is R 29 -substituted 10 to 15 membered heteroalkyl. In embodiments, R 4 is substituted or unsubstituted cycloalkyl.
  • R 4 is substituted cycloalkyl. In embodiments, R 4 is substituted cyclohexyl. In embodiments, R 4 is unsubstituted cyclohexyl. In embodiments, R 4 is R 29 -substituted cycloalkyl. In embodiments, R 4 is R 29 - substituted cyclohexyl. In embodiments, R 4 is substituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is R 29 -substituted C 3 -C 8 cycloalkyl.
  • R 4 is substituted or unsubstituted aryl. In embodiments, R 4 is substituted aryl. In embodiments, R 4 is substituted phenyl. In embodiments, R 4 is unsubstituted phenyl. In
  • R 4 is R 29 -substituted aryl. In embodiments, R 4 is R 29 -substituted phenyl.
  • R 5 is hydrogen, halogen, -CX 5 -C .1 H3X, 5.1 2, -CH 2 X 5 -C .1 N, , -SO n5 H, -SO v5 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m5 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 5 .1 -3O, CHX 5 ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
  • R 5 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 5 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 5 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 5 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 5 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 5 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 5 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 5 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 5 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 5 is substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 5 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 5 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 5 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 6 is hydrogen, halogen, -CX 6 -C .1 H3X, 6.1 2, -CH 2 X 6 -C .1 N, , -SO n6 H, -SO v6 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m6 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 6 .1 -3O, CHX 6 ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
  • R 6 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 6 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 6 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 6 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 6 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 6 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 6 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 6 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 6 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 6 is substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 6 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 6 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 6 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 7 is hydrogen, halogen, -CX 7 -C .1 H3X, 7.1 2, -CH 2 X 7 -C .1 N, , -SO n vH, -SOvvNH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m v, -NH 2 , -C(0)H, - C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 7 .1 3 -,OCHX 7 ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
  • R is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 7 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group” as described herein, a “size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 7 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 7 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 7 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 7 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 7 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 7 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 7 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 7 is substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 7 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 7 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 7 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 8 is hydrogen, halogen, -CX 8 -C .1 H3X, 8.1 2, -CH 2 X 8 -C .1 N, , -SO n8 H, -SO v8 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m8 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 8 .1 -3O, CHX 8 ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
  • R 8 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 8 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 8 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 8 is substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 8 is substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 8 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 8 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 8 is substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 8 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 8 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 8 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 9 is hydrogen, halogen, -CX 9 -C .1 H3X, 9.1 2, -CH 2 X 9 -C .1 N, , -SO n9 H, -SO v9 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m9 , -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 9 .1 -3O, CHX 9 ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted, substituted or unsubsti
  • R 9 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 9 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 9 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 9 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 9 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 9 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 9 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 9 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 9 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 9 is substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 9 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 9 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 9 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 10 is hydrogen, halogen, -CX 10 -CH .1 X3, 10.1 2, -CH 2 X 10 -CN .1 ,, -SOnioH, -SOvioNH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , -NHC(0)NH 2 , -N(0) m io, -NH 2 , -C(0)H, -C(0)OH, -C(0)NH 2 , -OH, -NHS0 2 H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX 10 .1 3, -OCHX 10 .1 2 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted hetero
  • R 10 is substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 10 is substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 10 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 10 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 10 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 10 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 10 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 10 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 10 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 10 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 10 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 10 is substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 10 is substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group” as described herein, a "size-limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 10 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 10 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 10 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group” as described herein, a "size- limited substituent” as described herein, or “lower substituent group” as described herein.
  • R 10 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 3L , R 4A , R 4B , R 4C and R 4D are independently hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or
  • R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 3L is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 26L -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 26L - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 26L - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 26L - substituted or unsubstituted heterocycloalkyl (e.
  • R 4A is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2, R 29A -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 29A - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 29A -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 29A -substituted or unsubstituted heterocyclo
  • alkyl e
  • R 4B is hydrogen, halogen, -CF 3 , -CC13, -CBr 3 , -C1 3 ,-COOH, -CONH2,
  • R 29B -substituted or unsubstituted alkyl e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl
  • R 29B - substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 29B -substituted or unsubstituted cycloalkyl e.g.,
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or
  • R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a R 29B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 29B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 29B -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 29B -substituted or unsubstituted heteroaryl e.g.,
  • R 4C is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 29C -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 29C - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 29C -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 29C -substituted or unsubstituted or unsubstitute
  • R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a R 29C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R 29C -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • a R 29C -substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 29C -substituted or unsubstituted heteroaryl e.g.,
  • R 4D is hydrogen, halogen, -CF 3 , -CC1 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , R 29D -substituted or unsubstituted alkyl (e.g., C 1 -Ce alkyl, C 1 -Ce alkyl, or C1-C4 alkyl), R 29D - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 29D -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl), R 29D -substituted or unsubstituted or unsubstitute
  • R 4D is substituted or unsubstituted alkyl. In embodiments, R 4D is substituted alkyl. In embodiments, R 4D is substituted methyl. In embodiments, R 4D is R 29D - substituted alkyl. In embodiments, R 4D is R 29D -substituted methyl. In embodiments, R 4D is substituted ethyl. In embodiments, R 4D is R 29D -substituted ethyl. In embodiments, R 4D is unsubstituted ethyl. In embodiments, R 4D is unsubstituted methyl. In embodiments, R 4D is substituted n-propyl.
  • R 4D is R 29D -substituted n-propyl. In embodiments, R 4D is unsubstituted n-propyl. In embodiments, R 4D is substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 4D is substituted C 1 -C 8 alkyl. In embodiments, R 4D is R 29D -substituted C 1 -C 8 alkyl. In embodiments, R 4D is -CF 3 . In embodiments, R 4D is substituted or unsubstituted aryl. In embodiments, R 4D is substituted aryl. In embodiments, R 4D is substituted phenyl. In embodiments, R 4D is unsubstituted phenyl. In embodiments, R 4D is substituted or unsubstituted phenyl.
  • R 26 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -SO2NH2, -NHNH2, -ONH2, -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHSO2H, -NHC(0)H,
  • R 27 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 27 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 27 - substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 27 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 27 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 27 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 26 is R 27 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 26 is R 27 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 26 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 26 is R 27 -substituted or 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 27 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 26 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 26 is R 27 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 26 is R 27 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 26 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • cycloalkyl e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl.
  • R 26 is R 27 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 26 is R 27 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 26 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 26 is R 27 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 26 is R 27 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 26 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 26 is R 27 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 26 is R 27 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 26 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 27 is independently oxo
  • R 28 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 28 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R -substituted or unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • R 28 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 28 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • R 28 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 27 is R 28 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 27 is R 28 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 27 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 27 is R 28 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 27 is R 28 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 27 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 27 is R 28 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 27 is R 28 -substituted cycloalkyl (e.g., C3- C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 27 is an unsubstituted cycloalkyl (e.g., C3-C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 27 is R 28 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 27 is R 28 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 27 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 27 is R 28 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 27 is R 28 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 27 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 27 is R 28 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 27 is R 28 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 27 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 29 is independently oxo
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -C1 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H, -NHC(0)H,
  • R 30 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 30 -substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 30 -substituted or unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • R 30 -substituted or unsubstituted alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl
  • R 30 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 30 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 29 is R 30 -substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 29 is R 30 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 29 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).
  • R 29 is R 30 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 29 is R 30 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 29 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 29 is R 30 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 29 is R 30 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
  • R is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 29 is R 30 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 29 is R 30 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 29 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 29 is R 30 -substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 29 is R 30 -substituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl). In embodiments, R 29 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C10 aryl, or phenyl).
  • R 29 is R 30 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 29 is R 30 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 29 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 29 is substituted or unsubstituted aryl. In embodiments, R 29 is substituted or unsubstituted phenyl. In embodiments, R 29 is substituted phenyl. In embodiments, R 29 is unsubstituted phenyl. In embodiments, R 29 is substituted or unsubstituted C10-C12 aryl. In embodiments, R 29 is substituted C10-C12 aryl. In embodiments, R 29 is unsubstituted C10-C12 aryl. In embodiments, R 29 is substituted or unsubstituted fluorenyl. In embodiments, R 29 is substituted fluorenyl.
  • R 29 is unsubstituted fluorenyl. In embodiments, R 29 is halogen. In embodiments, R 29 is -C1. In embodiments, R 29 is -F. In embodiments, R 29 is -Br. In embodiments, R 29 is oxo. In embodiments, R 29 is -COOH. In embodiments, R 29 is -OH. In embodiments, R 29 is - S0 3 H. In embodiments, R 29 is R 30 -substituted or unsubstituted aryl. In embodiments, R 29 is R 30 - substituted or unsubstituted phenyl. In embodiments, R 29 is R 30 -substituted phenyl. In embodiments, R 29 is halogen. In embodiments, R 29 is -C1. In embodiments, R 29 is -F. In embodiments, R 29 is -Br. In embodiments, R 29 is oxo. In embodiments, R 29 is -COOH. In embodiments
  • R 29 is R 30 -substituted fluorenyl.
  • R 30 is independently oxo
  • R 31 -substituted or unsubstituted aryl e.g., C 6 -C 10 aryl, C10 aryl, or phenyl
  • R 31 -substituted or unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 30 is R 31 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 30 is R 31 -substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl). In embodiments, R 30 is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1-C4 alkyl).
  • R 30 is R 31 - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 30 is R 31 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 30 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 30 is R 31 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 30 is R 31 -substituted cycloalkyl (e.g., C 3 - C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 30 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 30 is R 31 - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 30 is R 31 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 30 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
  • R 30 is R 31 - substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 30 is R 31 -substituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 30 is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).
  • R 30 is R 31 - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 30 is R 31 - substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 30 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 30 is halogen. In embodiments, R 30 is -C1. In embodiments, R 30 is -F.
  • R 26L , R 28 , R 29A , R 29B , R 29C , R 29D and R 31 are independently hydrogen, oxo,
  • heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered
  • R 26L , R 28 , R 29A , R 29B , R 29C , R 29D and R 31 are independently oxo
  • 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
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 29D is halogen. In embodiments, R 29D is -C1. In embodiments, R 29D is - F. In embodiments, R 29D is -Br. In embodiments, R 29D is oxo. In embodiments, R 29D is -COOH. In embodiments, R 29D is -OH. In embodiments, R 29D is -SO3H. In embodiments, R 29D is substituted or unsubstituted aryl. In embodiments, R 29D is substituted aryl. In embodiments, R 29D is substituted phenyl. In embodiments, R 29D is unsubstituted phenyl. In embodiments, R 29D is substituted or unsubstituted phenyl.
  • X 4 1 is -C1. In embodiments, X 4 1 is -F. In embodiments, X 4 1 is -Br. In embodiments, X 4 1 is -I. In embodiments, X 5 1 is -C1. In embodiments, X 5 1 is -F. In embodiments, X 5 1 is -Br. In embodiments, X 5 1 is -I. In embodiments, X 6 1 is -C1. In embodiments, X 6 1 is -F. In embodiments, X 6 1 is -Br. In embodiments, X 6 1 is -I. In embodiments, X 7 1 is -C1. In embodiments, X 4 1 is -F. In embodiments, X 4 1 is -Br. In embodiments, X 4 1 is -I. In embodiments, X 7 1 is -C1. In embodiments, X 4 1 is -F. In embodiments, X 4 1 is -Br. In embodiments, X
  • X 7 1 is -F. In embodiments, X 7 1 is -Br. In embodiments, X 7 1 is -I. In embodiments, X 8 1 is -C1. In embodiments, X 8 1 is -F. In embodiments, X 8 1 is -Br. In embodiments, X 8 1 is -I. In embodiments, X 9 1 is -C1. In embodiments, X 9 1 is -F. In embodiments, X 9 1 is -Br. In
  • X 9 1 is -I. In embodiments, X 10 1 is -C1. In embodiments, X 10 1 is -F. In
  • X 10 1 is -Br. In embodiments, X 10 1 is -I.
  • the symbol 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. In embodiments, the symbol n5 is an integer from 0 to 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4. In
  • n6 is an integer from 0 to 4. In embodiments, n6 is 0. In embodiments, n6 is 1. In embodiments, n6 is 2. In embodiments, n6 is 3. In embodiments, n6 is 4. In
  • n7 is an integer from 0 to 4. In embodiments, n7 is 0. In embodiments, n7 is 1. In embodiments, n7 is 2. In embodiments, n7 is 3. In embodiments, n7 is 4. In
  • n8 is an integer from 0 to 4. In embodiments, n8 is 0. In embodiments, n8 is 1. In embodiments, n8 is 2. In embodiments, n8 is 3. In embodiments, n8 is 4. In
  • the symbol n9 is an integer from 0 to 4. In embodiments, n9 is 0. In embodiments, n9 is 1. In embodiments, n9 is 2. In embodiments, n9 is 3. In embodiments, n9 is 4. In embodiments, the symbol nlO is an integer from 0 to 4. In embodiments, nlO is 0. In embodiments, nlO is 1. In embodiments, nlO is 2. In embodiments, nlO is 3. In embodiments, nlO is 4.
  • the symbols m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently 1 or 2.
  • m4 is 1.
  • m4 is 2.
  • v4 is 1.
  • v4 is 2.
  • m5 is 1.
  • m5 is 2.
  • v5 is 1.
  • v5 is 2.
  • m6 is 1.
  • m6 is 2.
  • v6 is 1.
  • v6 is 2.
  • m7 is 1.
  • m7 is 2.
  • v7 is 1. In embodiments, v7 is 2. In embodiments, m8 is 1. In embodiments, m8 is 2. In embodiments, v8 is 1. In embodiments, v8 is 2. In embodiments, m9 is 1. In embodiments, m9 is 2. In embodiments, v9 is 1. In embodiments, v9 is 2. In embodiments, mlO is 1. In embodiments, mlO is 2. In embodiments, vlO is 1. In embodiments, vlO is 2.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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).
  • 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. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted
  • heterocycloalkylene, substituted arylene, and/or substituted 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.
  • 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.
  • a pharmaceutical composition including a compound described herein (e.g., compound of any aspect disclosed herein and embodiments thereof), and a pharmaceutically acceptable excipient.
  • RESULTS [0440] In another aspect, there is provided a method of inhibiting Pin 1, including contacting Pin 1 with a compound as described herein, including embodiments thereof.
  • FKBP FK506 binding protein
  • the FKBP is FKBP38, FKBP 51 or FKBP52. In embodiments, the FKBP is FKBP51.
  • a method of treating a Pin 1 -mediated disease or disorder including administering to a patient in need thereof a compound as described herein, including embodiments thereof.
  • the Pin 1 -mediated disease or disorder is cancer.
  • the cancer is prostate cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer or skin cancer (e.g., melanoma).
  • the cancer is prostate cancer.
  • the cancer is brain cancer.
  • the cancer is brest cancer.
  • the cancer is ovarian cancer.
  • the cancer is cervical cancer.
  • the cancer is skin cancer.
  • the skin cancer is melanoma.
  • the Pin 1 -mediated disease or disorder is a neurodegenerative disease.
  • the neurodegenerative disease is a tauopathy.
  • the neurodegenerative disease is Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, Chronic traumatic encephalopathy, including dementia pugilistica, Progressive supranuclear palsy, Corticobasal degeneration, Frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis, encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Parkinsons Disease, Alzheimers Disease, Huntington's Disease, Pick's Disease, schizophrenia or cortico
  • PART Primary age-related tauopathy
  • the Pin 1 -mediated disease or disorder is depression. In embodiments, the method further includes administering to the subject an anti-depressant. [0447] In embodiments, the Pin 1 -mediated disease or disorder is pain. In embodiments, the pain is chronic pain or neuropathic pain.
  • the method further includes administering to the subject a chemotherapeutic agent.
  • a method of treating an FKBP51 -mediated disease or disorder including administering to a patient in need thereof a compound as described herein, including embodiments thereof.
  • the compound of Formula (lie) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • Pinl is unique among the prolyl isomerases (PPIases) because it only binds to prolines that directly follow phosphorylated serine or threonine residues (pS/T-P motif). This activity is important as the phosphate of the pS/T-P motif sterically hinders the local peptide backbone and dramatically slows the spontaneous ci ' s-trans isomerization of the proline. Thus, Pinl activity becomes essential for isomerization of this motif on a relevant physiological time scale. Moreover, Pinl 's clients include multiple cell cycle regulators, modulators of stress responses, and transcription factors.
  • Pinl Plays a Diverse Role in Cellular Homeostasis.
  • Pinl has a unique role among all of the PPIases in that it only recognizes prolines immediately following phosphorylated serine or threonine residues (known as the pS/T-P motif) [1].
  • This unique feature of Pinl bindings is mediated by a cationic groove formed by Lys-63, Arg-68 and Arg-69, which makes contact with the pS/T group (FIG. 1) [2].
  • isomerization of bound substrate is thought to be mediated by the nearby residue Cys-113 [3].
  • Pinl also has a hydrophobic "shelf adjacent to the proline pocket that it uses to gain additional contacts.
  • Pinl In addition to its PPIase domain, Pinl has an N-terminal WW domain, that seems to contribute to the binding of phosphopeptide substrates.
  • the WW domain does not possess intrinsic isomerase activity, and the reason for overlapping substrate preference with the PPIase domain is unclear. It is thought that the WW domain may initially localize with relevant clients, but the hand- off mechanism to the PPIase domain for isomerization is unknown.
  • Pinl and its orthologs have been discovered in all eukaryotes and they are known to be critical for cell cycle regulation and cellular homeostasis.
  • Saccharomyces cerevisiae the Pinl homolog Essl is essential [4], and complementation with human Pinl rescues viability [1].
  • One essential activity of Pinl is in regulation of the cell cycle, through its activity on numerous phosphorylation-dependent regulatory pathways. Pinl works in tandem with 'proline-directed' kinases and phosphatases, binding and isomerizing the peptide backbone of the pS/T-P motifs to alter the prolyl cis/trans conformation.
  • Pinl has been implicated in both cancer and neurodedgeneration. Pinl interacts with multiple oncogenes, such as p53, and often enhances their oncogenic activity.
  • Pinl overexpression has been found in numerous cancer types, including prostate, brain, breast, ovary, cervical and melanomas [8]. Conversely, low Pinl expression has been correlated to increased neuronal vulnerability and enhanced degeneration of neurons and neurofibrillary tangle formation during AD-like pathologies [9]. Pinl is often sequestered into paired helical filaments (PHF) of hyperphosphorylated tau [10] while soluble Pinl is deactivated by oxidative stress at its catalytic cysteine [11]. Thus, Pinl expression and activity is often inversely correlated with disease; it is upregulated and highly active in cancer, or downregulated and inactive in neurodegenerative diseases [12]. For these reasons, Pinl inhibitors are of significant interest as potential anti-cancer therapeutics, where modulation of Pinl levels have been shown to be effective at preventing tumorigenesis. Further, Pinl inhibition may have some therapeutic benefit in certain
  • neurodegenerative diseases such as in tauopathies, where specific destabilizing mutations in tau have exhibited a decrease in pathogenesis when Pinl levels are reduced [13].
  • Juglone (FIG. 2) functions by covalent modification of Cys-113 in the active site [15].
  • Juglone (5- hydroxy-l,4-naphtha!enedione) is produced by the Black Walnut tree and its inhibition of Pinl activity has been suggested to contribute to the toxicity of Black Walnuts.
  • the exact binding interaction of Juglone is unclear and this compound has proven to have other cellular targets, possibly acting non-specifically [16]. To date, no inhibitors are known to mimic this mode of inhibition.
  • Juglone does not inhibit the FKBPs or cyclophilins, whereas Pinl has not been shown to have any appreciable affinity for the natural products, rapamycin, FK506 or cyclosporin.
  • dexamethasone-21 -phosphate was shown to bind across the proline pocket to the cationic groove formed by Lys-63, Arg-68 and Arg-69.
  • the cyclohexene ring is anchored into the proline binding pocket with the alkene chain extending the carboxylic acid into the cationic phosphate-binding region.
  • ATRA Treatment with ATRA suppresses proliferation of mouse embryonic fribroblasts and leads to Pinl degradation but has no effect in Pinl knockout cells or those harboring inactivating mutations in the binding site.
  • APL acute promyelocytic leukemia
  • PML-RAR-a fusion oncoprotein promyelocytic leukemia-retinoic acid receptor a
  • PML-RAR-a fusion oncoprotein promyelocytic leukemia-retinoic acid receptor a
  • Carboxylate-based scaffold was the subject of a limited SAR series [22].
  • phosphate bioisosteres such as tetrazoles
  • P-glycoprotein efflux pumps may be responsible for the limited activity of this series.
  • the amidyl carboxylate moiety in particular was implicated in recognition by P-glycoprotein, and it was concluded that further optimization of the scaffold was necessary to achieve improved cellular activity.
  • these small molecules are the first Pinl inhibitors that possess cellular activity.. Critical to the design of these small molecules, they all engage the cationic phosphate-binding site. Additional affinity is gained from either interacting with the hydrophobic shelf or residues adjacent to the phosphate binding site.
  • FK506 Semisynthetic Modification of FK506 and Rapamycin.
  • FK506 was treated with methanolic ammonia (2M) and monitored by HPLC (FIG. 10). Within 30 minutes, we saw conversion of FK506 into a more polar product (13, herein FK- H2), which we attributed to the primary amine. At the same time, we noticed that the unreacted FK506 peak appeared to develop a slightly more polar shoulder and that a small number of minor side products were produced. It had previously been suggested that treatment of FK506 with ammonia could also result in formation of the imine at the adjacent carbonyl, so we hypothesize that the "shoulder" might be the less polar imine.
  • the pyranose fragment is shown where modification occurs. Yield is approximate as determined by product appearance in MS compared to residual starting material.
  • the pyranose fragment is shown where modification occurs. Yield is approximate as determined by product appearance in MS compared to residual starting material.
  • FK506 could be converted to FK-NH2 at a region that is predicted to be in close proximity to the phosphate-binding region of the Pinl active site. Indeed, compound 34 had affinity for Pinl in vitro with FKBP12 binding considerably reduced.
  • Pinl has been well validated as a target in a variety of cell lines, including its impact on cell viability in numerous human cancers, so we propose to use these established models to test the cellular activity of the molecules.
  • the Pinl constructs were transformed into E. coli BL21 cells and grown in Terrific Broth for six hours at 37 °C, followed by induction with 1 mM IPTG at 20 °C for 12 hours. Cells were collected, lysed by sonication (25 mM Tris, 500 mM NaCl, 10 mM imidazole, 10% glycerol, pH 8.0) and was bound on Ni-NTA resin.
  • Resin was washed once with wash buffer 1 (25 mM Tris, 500 mM NaCl, 30 mM imidazole, 3% ethanol, 10% glycerol, pH 8.0), once with wash buffer 2 (25mM Tris, lOOmM NaCl, 30mM imidazole, 3% ethanol, 10% glycerol, pH 8.0), once with wash buffer 3 (25mM Tris, 300mM NaCl, 30mM imidazole, 10% glycerol, pH 8.0) and eluted (25 mM Tris, 300 mM NaCl, 300 mM Imidazole, 10% glycerol, pH 8.0). Eluted protein was dialyzed overnight (lOmM HEPES, lOOmM NaCl, 5% glycerol, pH 7.5) and purified by Size Exclusion
  • Pinl Fluorescence Polarization Assay Binding to Pinl was measured by fluorescence polarization. The assay was performed at 60 ⁇ ⁇ final volume in MOPS (pH 7.5) with 0.01% Triton X-100 using Corning 384-well flat-bottom black plates. For initial binding analysis of the fluorescent compound, recombinant Pinl was serially diluted 3 -fold from 80 ⁇ initial
  • Fluorescent phosphopeptide WFYpSPFLE was initially dissolved in DMSO at 100 ⁇ then dissolved into assay buffer and 30 ⁇ _, of this solution was added to each well to give a final concentration of 75 nM. The plate was covered and equilibrated at room temperature for 30 minutes then read on a SpectraMax M5 at wavelength 488/515 ex/em.
  • Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chemistry & biology 13, 99-107 (2006); [5]. Ruan, B., et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proceedings of the National Academy of Sciences of the United States of America 105, 33-38 (2008); [6]. Sedrani, R., Thai, B., France, J. & Cottens, S. Dihydroxylation of the Triene Subunit of Rapamycin. The Journal of Organic Chemistry 63, 10069-10073 (1998); [7]. Karanam, B.V., et al.
  • L-732,531 a potent immunosuppressant, in rats and baboons. Drug metabolism and disposition: the biological fate of chemicals 26, 949-957 (1998); [8].
  • Gupta, A.K. & Chow, M. Pimecrolimus a review. Journal of the European Academy of Dermatology and Venereology : JEADV 17, 493-503 (2003); [10]. Faivre, S., Kroemer, G.
  • FK-NH2 substituted with chlorosulfonic acid to generate a sulfamic containing derivative binds to the peptidyl-prolyl isomerase Pinl .
  • Pinl binds to a fluorescent peptide which is then competed away by compound 2a.
  • Unmodified FK506 has no affinity for Pinl and is not capable of inhibiting the binding interaction with the fluorescent peptide.
  • Compound 2a is capable of competing the fluorescent peptide away from the wild type protein as well as just the isolated peptidyl-prolyl isomerase domain.
  • IC50 and Span are 7.065 and 104.0, respectively.
  • IC50 and Span are 15.25 and 47.49, respectively.
  • Example 6 Binding of a Modified FK506 Derivative to FKBP12.
  • the parent compound, FK506 binds to its native target FKBP12 with high affinity.
  • Embodiment 1 A peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
  • (Pin 1) inhibitor compound or a pharmaceutically acceptable salt thereof, comprising a macrolide with a pipecolyl moiety.
  • Embodiment 2 The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C-10 position.
  • Embodiment 3 The compound of embodiment 2, wherein the nitrogen- containing functional group is an amino group.
  • Embodiment 4 The compound of embodiment 2, wherein the nitrogen- containing functional group is a primary amino group.
  • Embodiment 5 The compound of embodiment 2, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an
  • Embodiment 6 The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
  • Embodiment 7 The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • Embodiment 8 The compound of embodiment 7, wherein the linker is covalently bound to an electronegative group.
  • Embodiment 9 The compound of embodiment 5, 6 or 8, wherein the electronegative group is a phosphate isostere.
  • Embodiment 10. The compound of embodiment 5, 6, 8 or 9, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • Embodiment 11 The compound of any one of embodiments 1-10, wherein the FK-506 compound is an ascomycin derivative or variant.
  • Embodiment 12 The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
  • Embodiment 13 The compound of embodiment 12, wherein the nitrogen- containing functional group is an amino group.
  • Embodiment 14 The compound of embodiment 12, wherein the nitrogen- containing functional group is a primary amino group.
  • Embodiment 15 The compound of embodiment 12, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an electronegative group.
  • Embodiment 16 The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
  • Embodiment 17 The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • Embodiment 18 The compound of embodiment 17, wherein the linker is covalently bound to an electronegative group.
  • Embodiment 19 The compound of embodiment 15, 16 or 18, wherein the electronegative group is a phosphate isostere.
  • Embodiment 20 The compound of embodiment 15, 16, 18 or 19, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • Embodiment 21 An FK506 binding protein (FKBP) inhibitor compound, or a pharmaceutically acceptable salt thereof, comprising a macrolide with a pipecolyl moiety.
  • FKBP FK506 binding protein
  • Embodiment 22 The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
  • Embodiment 23 The compound of embodiment 22, wherein the nitrogen- containing functional group is an amino group.
  • Embodiment 24 The compound of embodiment 22, wherein the nitrogen- containing functional group is a primary amino group.
  • Embodiment 25 The compound of embodiment 22, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an
  • Embodiment 26 The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
  • Embodiment 27 The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
  • Embodiment 28 The compound of embodiment 27, wherein the linker is covalently bound to an electronegative group.
  • Embodiment 29 The compound of embodiment 25, 26 or 28, wherein the electronegative group is a phosphate isostere.
  • Embodiment 30 The compound of embodiment 25, 26, 28 or 29, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • Embodiment 31 A macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506 or a pharmaceutically acceptable salt thereof.
  • Embodiment 32 The compound of embodiment 31, wherein the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative or an ascomycin compound derivative.
  • Embodiment 33 The compound of embodiment 31, wherein the macrolide compound is capable of inhibiting a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) protein.
  • Embodiment 34 The compound of embodiment 31, wherein the macrolide compound is capable of inhibiting an FK506 binding protein.
  • Embodiment 35 The compound of any one of embodiments 31-34, wherein the electronegative group is a phosphate isostere.
  • Embodiment 36 The compound of any one of embodiments 31-34, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • Embodiment 37 A com ound of structural Formula (I):
  • nl, n2 and n3 are independently an integer from 0 to 4.
  • nl, m2, m3, vl, v2 and v3 are independently 1 or 2;
  • L 1 is a bond, -0-, -S-, -NR 1L - -NR 1L C(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • L 2 is a bond, -0-, -S-, -NR 2L - -NR 2L C(0)-, -C(0)-, -C(0)0- -S(0)-, -S(0) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 1 is hydrogen, halogen, -CX 1 .1 -C3,HX 1 * 2 , -CF ⁇ X 1 - . C 1 ,N, -SO n iR 1A , -SOviNR 1B R 1C , -NHNR 1B R 1C , -0NR 1B R 1C , -NHC(0)NHNR 1B R 1C , -NHC(0)NR 1B R 1C , -N(0)mi, -NR 1B R 1C , -C(0)R 1D , -C(0)OR 1D , -C(0)NR 1B R 1C , -0R 1A , -NR 1B S0 2 R 1A ,
  • R 2 is hydrogen, halogen, -CX 2 .1 -C3,HX 2.1 2, -CH 2 X 2 -C . N 1 , , -S0 ll2 R 2A ,
  • R 3 is hydrogen, halogen, -CX 3,1 3 , -CHX 3.1 2, -CH 2 X 3 -CN, .1 -, S0 ll3 R 3A ,
  • L 1L , L 2L , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C and R 3D are independently hydrogen, halogen, -CF 3 , -CCl 3 , -CBr 3 , -C1 3 ,-COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B and R 1C , R 2B and R 2C , R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstitute
  • X 1 - 1 , X 2 1 and X 3 1 are independently -C1, -Br, -I or -F, wherein when L 2 is -0-,
  • L 1 is a bond, R 1 is or -CH 2 CH 3 and R 3 is hydroxyl, then R 2 is not hydrogen.
  • Embodiment 38 The compound of embodiment 37, wherein:
  • L 2 is a bond
  • R 2 is NH 2 .
  • Embodiment 39 The compound of embodiment 37, wherein L 2 is -NR 2L .
  • Embodiment 40 The compound of embodiment 37, wherein L 2 is
  • Embodiment 41 The compound of any one of embodiments 39, 40 or 41, wherein R 2 is a phosphate isostere.
  • Embodiment 42 The compound of any one of embodiments 39, 40 or 41, wherein R 2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • R 2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
  • Embodiment 43 The compound of any one of embodiments 37-42, wherein: L 1 is a bond; and
  • R 1 is (R)-ethyl.
  • Embodiment 44 The com ound of embodiment 37, wherein the compound
  • Embodiment 45 The compound of embodiment 37, wherein the compound is
  • Embodiment 46 A compound of structural Formula (II):
  • n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4.

Abstract

There are provided compounds for the inhibition of Pin 1 and/or FKBP and methods of use thereof.

Description

COMPOUNDS FOR THE INHIBITION OF A PROLYL ISOMERASE
AND METHODS OF USE THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/435,572 filed December 16, 2016, which is incorporated herein by reference in its entirety.
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE
[0002] The Sequence Listing written in file 048536-591001WO Sequence Listing_ST25.TXT, created on December 11, 2017, 769 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.
BACKGROUND
[0003] Peptidyl-prolyl isomerases (PPIases) are a family of proteins that catalyze the cis-trans isomerization of proline bonds. The PPIase super-family includes the FK506-binding proteins (FKBPs), cyclophilins and parvulins. The macrocyclic natural products FK506 and rapamycin inhibit the FKBP class of PPIases and the cyclophilins are inhibited by the macrocyclic natural product, cyclosporin. However, there are not any known inhibitors of peptidyl-prolyl cis-trans isomerase NEVIA-interacting 1 (Pinl). None of the natural or synthetic inhibitors of other PPIase families bind Pinl . Pinl has emerged as a promising drug target in cancer and neurodegeneration.
[0004] PPIases have emerged as important targets in cancer, neurodegeneration, mental illnesses and neuropathic pain. Targeting the peptidyl-prolyl isomerases has been a challenge as most inhibitors have overlapping specificity for multiple family members and are lacking cellular activity. Disclosed herein are novel, selective inhibitors for the peptidyl-prolyl isomerase Pinl to overcome this challenge.
[0005] Developing selective Pinl inhibitors has posed a significant challenge because its active site is shallow and requires candidate compounds to possess a highly electronegative group (e.g. phosphate) to bind. Pinl inhibitors that contain these electronegative substituents often lack membrane permeability and have poor pharmacokinetics. Macrocyclic natural products, including FK506 and rapamycin, possess exceptional activity and are biologically active. [0006] Accordingly, there is a need in the art for inhibitors of the peptidyl-prolyl isomerase, Pinl, for the treatment of Pinl -dependent diseases, such as cancer or neurodegeneration. Provided herein are solutions to these and other problems in the art.
BRIEF SUMMARY
[0007] Disclosed herein, inter alia, are selective inhibitors of Pin 1 which can utilize a chemotype known to possess exceptional biological activity, addressing the limited cellular activity of previous Pin 1 inhibitors.
[0008] In a first aspect, there is provided a peptidyl-prolyl cis-trans isomerase NFMA-interacting 1 (Pin 1) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
[0009] In another aspect, there is provided an FK506 binding protein (FKBP) inhibitor compound including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
[0010] In another aspect, there is provided a macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506, or a pharmaceutically acceptable salt thereof. 0011] In another aspect, there is provided a compound of structural Formula (I):
Figure imgf000003_0001
(I), or a pharmaceutically acceptable salt thereof. In the compounds of structural Formula (I): nl, n2 and n3 are independently an integer from 0 to 4. ml, m2, m3, vl, v2 and v3 are independently 1 or 2. L1 is a bond, -0-, -S-, - R1L- - R1LC(0)-, -C(O)-, -C(0)0-, -S(O) -, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R1 is hydrogen, halogen, -CX1.1 3, -CHX1.12, -Cn2X1.1, -CN, -SOniR1A, -SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C,
-NHC(0)NHNR1BR1C, -NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D,
-C(0)NR1BR1C, -OR1A, -NR1BS02R1A, -NR1BC(0)R1D, -NR1BC(0)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R2 is hydrogen, halogen, -CX2,1 3, -CHX2 J 2,
-CH2X2.1, -CN, -SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -OR2A,
-NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.13, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3 .1, -CN, -SO„3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A, -NR3BC(0)R3D,
-NR3BC(0)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, 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. R1L, R2L, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C and R3D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1B and R1C, R2B and R2C, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X1 1, X2 1 and X3 1 are independently -C1, -Br, -I or -F. When L2 is -0-, L1 is a bond, R1 is or -CH2CH3 and R3 is hydroxyl, then R2 is not hydrogen.
Figure imgf000004_0001
0012] In another aspect, there is provided a compound of structural Formula (II):
Figure imgf000005_0001
(II), or a pharmaceutically acceptable salt thereof. In the compounds of structural Formula (II),
Figure imgf000005_0002
are independently single bonds or double bonds. n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4. m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently 1 or 2. L3 is a bond, -0-, -S-, -NR3L-, -NR3LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene. R4 is hydrogen, halogen, -CX4 J 3, -CHX4 J 2, -CH2X4 Λ, -CN,
-SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A,
-NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 -OC.H13X,4 1 2, 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. R5 is hydrogen, halogen, -CX5 -.C13H,X5 . -1C3H, 2X5 -.1C, N, -SOnsH, -SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2, -C(0)H, -C(0)OH,
-C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .13 -,OCHX5 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R6 is hydrogen, halogen, -CX6 1 3, -CHX6.12, -CH2X6 1, -CN, -SOn6H, -SOv6NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m6, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6 .13, -OCHX6.12, 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. R7 is hydrogen, halogen, -CX7,1 3, -CHX7.12, -CH2X7 1, -CN, -SOnvH, -SOvvNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mv, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13, -OCHX7.12, 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. R8 is hydrogen, halogen, -CX8 1 3, -CHX8 J 2, -CH2X8 1, -CN, -SOnsH, -SOv8NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m8, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8 .13, -OCHX8.12, 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. R9 is hydrogen, halogen, -CX9 J 3, -CHX9 J 2, -CH2X9 1, -CN, -SOn9H, -SOv9NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m9, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .13, -OCHX9.12, 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. R10 is hydrogen, halogen, -CX10 1 3, -CHX10 -\
-CH2X10 1, -CN, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX10 1 3, -OCHX10 s.u1b2,stituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R3L, R4A, R4B, R4C and R4D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X4 X.1,5 1, X6 1, X7 -1, X8 -1, X9 1 and X10 1 are independently -C1, -Br, -I or
-F. When— ,— and— are double bonds, L3 is -O- and R6, R7, R8, R9 and R10 are
independently hydrogen, then R4 is not hydrogen. [0013] In another aspect, there is provided a pharmaceutical composition, including a compound described herein, including in an aspect or embodiment, and a pharmaceutically acceptable excipient.
[0014] In another aspect, there is provided a method of inhibiting Pinl, including contacting Pinl with a compound as set forth herein, including embodiments thereof.
[0015] In another aspect, there is provided a method of inhibiting an FK506 binding protein (FKBP), including contacting the FKBP with a compound as set forth herein, including
embodiments thereof.
[0016] In another aspect, there is provided a method of treating a Pin-1 associated disease or disorder, including administering to a patient in need thereof a compound as set forth herein, including embodiments thereof.
[0017] In another aspect, there is provided a method of treating an FKBP51 -mediated disease or disorder, including administering to a patient in need thereof a compound as set forth herein, including embodiments thereof.
[0018] In another aspect, there is provided a method of preparing a compound of structural Formula (I) as set forth herein, including contacting a compound of structural Formula (Ic) with ammonia:
Figure imgf000007_0001
(Ic). L1, L2, R1, and R3 are as described herein.
[0019] In another aspect, there is provided a method of preparing a compound of structural Formula (II) as set forth herein, including contacting a compound of structural Formula (lie) with ammonia:
Figure imgf000008_0001
L3, R5, R6, R7, R8, R9, and R are as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIGS. 1A-1B. Structure of Pinl with key features highlighted. A) Ribbon diagram. The active site pocket within the PPIase domain is composed of antiparallel β-sheets that position a short a-helix. The WW domain consists of two, short antiparallel β-sheets connected to the PPIase domain by a flexible linker (not resolved in this structure). FIG. IB) Surface representation of the active site. The hydrophobic proline pocket (gray) orients substrate to interact with the catalytic cysteine and the cationic groove that binds phosphate groups. (Protein Data Bank reference, PDB: 1PIN).
[0021] FIG. 2. Natural product inhibitors of Pinl .
[0022] FIG. 3. Representative pipecolic acid-based phosphopeptide inhibitor of Pinl . The phosphopeptide, pintide, is bound to Pinl (shown as the surface electrostatic map). Significantly, the pipecolate ring is anchored in the proline binding pocket, positioning the phosphate group to interact with the cationic groove. Further affinity is gained via the napthyl interaction with the hydrophobic shelf of the active site.
[0023] FIG. 4. Small molecule Pinl inhibitors based on pipecolic acid, demonstrating
resemblance to FKBP inhibitors, such as SLF.
[0024] FIG. 5. Bi-aryl amides potently bind Pinl .Bi-aryl amides potently bind Pinl . Co- crystallization with 65c (PDB: 3IKG) revealed a new binding orientation with the phenyl ring oriented in the proline-binding pocket and the phosphate group oriented between Arg-68 and Arg-
69. (PDB: 3IKG). [0025] FIG. 6. Optimization of the bi-aryl amide scaffold to enhance cellular permeability. The phosphate group was replaced with a carboxylic acid, which retained a similar binding pose as (compound 4.5a) with the orientation of the carboxylate facing Lys-63 as in the phosphopeptide inhibitors. (PDB: 4TYO).
[0026] FIG. 7. Alternative bi-aryl scaffold engages peripheral residues of the Pinl cationic groove. Spanning the phosphate-binding region (Lys-63, Arg-68, Arg-69) enhances affinity for Pinl, even without engagement of the hydrophobic shelf.
[0027] FIGS. 8A-8B. Overlay of the bound conformation of FK506 compared to the pintide phosphopeptide, highlighting the potential modification site. FIG. 8A) Aligning the pipecolate ring in FK506 to the pintide phosphopeptide demonstrates the binding pose similarity of each compound and proximity to the cationic phosphate binding site. FIG. 8B) FK506 and Rapamycin shown with the FKBP binding motif highlighted. The tertiary hydroxyl is highlighted (FIG. 8 A, third panel; black arrow in FIG. 8B).
[0028] FIG. 9. Semisynthetic modification of FK506 and rapamycin, demonstrating modification of the tertiary hydroxyl of FK506 and Rapamycin into a primary amine for further derivatization.
[0029] FIG. 10. Conversion of FK506 into FK-NH2. Within 30 minutes, a significant portion of FK506 is converted into the amine-containing derivative. Order of curves: top peak to bottom at about 3.4 min: control, 30min, 60min, 90min, 120min, 180min.
[0030] FIG. 11. Reaction rate of the FK506 conversion. Data were fit to a one-phase exponential.
[0031] FIG. 12. Comparison of FK-NH2 and FK506 by MS. In the converted FK-NH2, the parent amine is readily ionized, unlike in FK506.
[0032] FIG. 13. Downfield region of the FK-NH2 13C NMR spectrum. The C1 O peak
corresponding to the tertiary hydroxyl attachment point is typically at 97ppm (left highlight), but appears shifted after conversion to the amine (right highlight).
[0033] FIG. 14. Determination of concentration effects on the conversion of FK506.HPLC traces are shown of the reaction after two hours in various concentrations of ammonia without and with peak highlighting (left and right, respectively). Increasing ammonia concentration results in formation of a new species that is less polar than FK-NH2. [0034] FIG. 15. Solvent dramatically effects the conversion of FK506. Alcohols are heavily preferred in the conversion of FK506, with other polar and protic solvents leading to only minimal product formation after three hours. Bins (left to right): DCM, Dioxane, DMPU, EtOH, TFE, IPA,m N-BuOH, MeOH. Order within each bin: FK-NH2 (left), FK506 (right).
[0035] FIG. 16. Deuterated methanol slightly enhances the rate of reaction. Bins (left to right): Methanol (-d) at 30min, 60min, 240min; Methanol at 30min, 60min, 240min.
[0036] FIG. 17. Semisynthetic scheme to derivatize FK-NH2.i) 2M ammonia, ethanol; ii) FK- NH2, 3-chlorobenzyl bromide (3eq), DIPEA (6 eq), DMAP (0. leq), DCM. Order within each bin: FK-NH2 (left), FK506 (right).
[0037] FIGS. 18A-18B. The phosphopeptide WFYpSPFLE binds to Pinl and is competed by 34. FIG. 18 A) Wild-type Pinl and the PPIase domain (see B legend) bind with good affinity to the phosphopeptide tracer. The smaller PPIase domain has a lower AmP corresponding to its smaller molecular mass. FIG. 18B) The phosphopeptide tracer is competed by 34, which contains an electronegative sulfamic acid group that likely engages the Pinl cationic groove. Experiments are the average of at least two experiments with duplicate measurements. Error is SEM.
[0038] FIGS. 19A-19B. Competitive binding to FKBP12 of FK506 derivatives. A) Modification of FK506 at this position dramatically reduces affinity for FKBP12 depending on the functional group properties. B) Ki calculations of the FK506 derivatives in comparison to FK506. Results are the average of triplicates, and error is SEM.
[0039] FIGS. 20A-20I. MS spectra for compounds 15 (FIG. 20 A), 16 (FIG. 20 A), 18 (FIG. 20 A), 19 (FIG. 20A), 22 (FIG. 20A), 24 (FIG. 20A), 27 (FIG. 20 A), 29 (FIG. 20A), and 34 (FIG. 20A). Axes: relative abundance (y-axis); m/z (x-axis).
[0040] FIG. 21. Binding of FK506 to natural target FKBP12.
[0041] FIG. 22. Schematic of multiple binding functionality incorporated into a compound.
[0042] FIG. 23. Computational model showing binding functionality incorporated into a compound. DETAILED DESCRIPTION
DEFINITIONS
[0043] 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.
[0044] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
[0045] 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). 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, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
[0046] 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. [0047] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be
quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to:
-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3,
-CH=CH-N(CH3)-CH3, -0-CH3, -0-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, 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 eight optionally different heteroatoms (e.g., O, N, S, Si, or P).
[0048] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2R'- represents both -C(0)2R'- and -R'C(0)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0)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.
[0049] 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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)W , where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. [0050] 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. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)W, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems
independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In
embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
[0051] In embodiments, a heterocycloalkyl is a heterocyclyl. The term "heterocyclyl" as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1 dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3
dihydrobenzofuran 2 yl, 2,3 dihydrobenzofuran 3 yl, indolin 1 yl, indolin 2 yl, indolin 3 yl, 2,3 dihydrobenzothien 2 yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro 1H indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin-10-yl, 9, 10-dihydroacridin-9-yl, 9, 10-dihydroacridin- 10-yl, 1 OH-phenoxazin- 10-yl, 10, 11 -dihydro-5H- dibenzo[b,f]azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin- 12-yl, and dodecahydro-lH-carbazol-9-yl.
[0052] 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.
[0053] The term "acyl" means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0054] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroaryl ene 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 heteroaryl ene 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.
[0055] 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.
[0056] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0057] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.
[0058] The term "alkylarylene" as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:
Figure imgf000018_0001
[0059] 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, -CCb, -CBr3, -C13, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02CH3 -S03H, -OS03H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.
[0060] 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.
[0061] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkyl ene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-OR', -NR'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, - CO2R, -CONR'R", -OC(0)NR'R", -NR"C(0)R, -NR'-C(0)NR"R", -NR"C(0)2R, -NR- C(NR'R"R")=NR"", -NR-C(NR'R")=NR"', -S(0)R, -S(0)2R, -S(0)2NR'R", -NRSO2R,
-NR'NR"R", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, -NO2, -NRSO2R", -NRC(0)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present. When R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -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(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like).
[0062] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR, -NR'R", -SR, -halogen, - SiRR'R", -OC(0)R, -C(0)R, -C02R, -CONR'R", -OC(0)NR'R", -NR"C(0)R, -NR'-C(0)NR"R", -NR"C(0)2R, -NR-C(NRR"R")=NR"", -NR-C(NR'R")=NR"', -S(0)R, -S(0)2R, -S(0)2NR'R", - NRS02R, -NR'NR"R", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, -N02, -R, -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'S02R", -NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.
[0063] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkyl ene, arylene, or heteroaryl ene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
[0064] 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.
[0065] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR')q-U-, wherein T and U are independently -NR-, -0-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(0) -, -S(0)2-, - S(0)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 - 0-, -NR'-, -S-, -S(O)-, -S(0)2-, or -S(0)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.
[0066] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
[0067] A "substituent group," as used herein, means a group selected from the following moieties:
(A) oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S 04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H,
-NHC(0)H, -NHC(0)OH, -NHOH, -0CC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -O CHI2, -OCHF2, 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, CIO aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(i) oxo,
halogen, -CC13, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2 ,-NHC(0)NH2, -NHS02H,
-NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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, CIO 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, -CC13, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2,-NHC(0)NH2,
-NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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, CIO aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,
halogen, -CC13, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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, C1 O aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0068] 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.
[0069] 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.
[0070] 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. [0071] 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 heteroalkyl ene 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
heterocycloalkyl ene 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 heteroaryl ene.
[0072] 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. [0073] 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).
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] A "nitrogen-containing functional group", as used herein, means any substituent group containing nitrogen atom. In embodiments, the nitrogen-containing functional group is an amino group, primary amino group, secondary amino group, tertiary amino group, ammonium ion, primary ketamine, secondary ketamine, primary aldimine, secondary aldimine, imide, azide, diimide, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy group, nitro group, nitroso group, oxime, nitrogen-containing 2 to 8 membered heteroalkyl , nitrogen-containing 3 to 8 membered heterocycloalkyl, or nitrogen-containing 5 to 9 membered heteroaryl.
[0079] Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the presentdisclosure. 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 presently disclosed compounds 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.
[0080] 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.
[0081] 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.
[0082] It will be apparent to one skilled in the art that certain compounds may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope hereof.
[0083] 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 hereof.
[0084] 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 hereof. [0085] 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 (1H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scope of the presentdisclosure.
[0086] 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.
[0087] "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.
[0088] 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.
[0089] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally differently.
[0090] A "detectable moiety" as used herein refers to a moiety that can be covalently or noncovalently attached to a compound (e.g. biomolecule) that can be detected for instance, using techniques known in the art. In embodiments, the detectable moiety is covalently attached. The detectable moiety may provide for imaging of the attached compound or biomolecule. The detectable moiety may indicate the contacting between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive dies, radio-labeled moieties, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese.
[0091] 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.
[0092] A "test compound" as used herein refers to an experimental compound used in a screening process to identify activity, non-activity, or other modulation of a particularized biological target or pathway.
[0093] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0094] Thus, the compounds of the present invention may exist as salts, such as with
pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
[0095] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure. [0096] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration.
Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
[0097] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
[0098] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such
preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[0099] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0100] The terms "peptidyl-prolyl cis/trans isomerase" or "PPIase" refer to a protein or proteins (including homologs, isoforms, and functional fragments thereof) that isomerizes the peptide bond of prolines. The term includes any recombinant or naturally-occurring form of a PPIase and variants thereof that maintain PPIase activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%), or 100%) activity compared to wildtype Pin 1). The term includes any mutant form of PPIase variants (e.g., frameshift mutations) thereof that maintain PPIase activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to the wildtype PPIase).
[0101] The term "peptidyl-prolyl cis-trans isomerase NIMA-interacting 1" ("Pin 1") refer to a protein or proteins (including homologs, isoforms, and functional fragments thereof) that isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. The term includes any recombinant or naturally-occurring form of Pin 1 variants thereof that maintain Pin 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Pin 1). The term includes any mutant form of Pin 1 variants (e.g., frameshift mutations) thereof that maintain Pin 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype Pin 1). In embodiments, the term "Pin 1" refers to NCBI Accession No. NP_006212, and proteins having sequence homology to Pin 1 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
[0102] A "Pin 1 inhibitor" refers to a compound (e.g., compounds described herein) that reduces the activity of Pin 1 when compared to a control, such as absence of the compound or a compound with known inactivity.
[0103] A "Pin-1 mediated disease or disorder" refers to a diasease or disorder associated with modulated levels of expression of Pin-1 or levels of DNA/RNA encoding Pin-1 in a subject and/or changes in cellular regulation mediated by Pin-1.
[0104] The terms "FKBP" or "FK506 binding protein" refer to a family of proteins (including homologs, isoforms, and functional fragments thereof) that have prolyl isomerase activity and are related to the cyclophilins in function. The terms include any recombinant or naturally-occurring form of FKBP variants thereof that maintain FKBP activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP). The term includes any mutant form of FKBP variants (e.g., frameshift mutations) thereof that maintain FKBP activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP).
[0105] The terms "FK506-binding protein 5" "FKBP5," "FKBP51," "FKBP54," "P54" and "Ptg- 10" refer to a specific enzyme of the FKBP family of proteins (including homologs, isoforms, and functional fragments thereof). The terms include any recombinant or naturally-occurring form of FKBP 5 and variants thereof that maintain FKBP 5 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP5). The term includes any mutant form of FKBP5 variants (e.g., frameshift mutations) thereof that maintain FKBP5 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype FKBP5). In embodiments, the term "FKBP5" refers to Entrez 2289, UniProt Q13451, NM_004117, NM_004117.3, NP_004108.1, or NP_004108.
[0106] In embodiments, the term "FKBP38" refers to NCBI Accession No. NP 36313, and proteins having sequence homology to FKBP38 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%. In embodiments, the term "FKBP51" refers to NCBI Accession No. AAC51189, and proteins having sequence homology to FKBP51 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%. In embodiments, the term "FKBP52" refers to NCBI Accession No. AAC36111, and proteins having sequence homology to FKBP 52 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%. In embodiments, term "FKBP 12" refers to NCBI Accession No. NP 463460, and proteins having sequence homology to FKBP12 of at least 80%, e.g., 80, 81, 82, 83, 84, 85, 86 ,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%.
[0107] An "FKBP inhibitor" refers to a compound (e.g., compounds described herein) that reduces the activity of an FKBP (e.g., FKBP51, FKBP52 and/or FKBP38) when compared to a control, such as absence of the compound or a compound with known inactivity.
[0108] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. In embodiments, the terms "polypeptide," "peptide," and "protein", used interchangeably herein, refer to a polymeric form of amino acids of any length, which can include genetically coded and non-genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence; fusion proteins with heterologous and homologous leader sequences, with or without N-terminus methionine residues; immunologically tagged proteins; and the like.
[0109] A polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.
[0110] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
[0111] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
[0112] As defined herein, the term "activation", "activate", "activating" and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
[0113] The terms "agonist," "activator," "upregulator," etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target. In embodiments, activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, or cell.
[0114] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
[0115] The terms "inhibitor," "repressor" or "antagonist" or "downregulator" interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist. In embodiments, inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An "antagonist" is a molecule that opposes the action(s) of an agonist.
[0116] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
[0117] The terms "disease," "disorder" 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 cancer. The disease may be a mental illness (e.g.
schizophrenia). The disease may be depression. The disease may be pain (e.g. chronic pain or neuropathic pain). 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 MDS, AML, ALL, ATLL and CML), or multiple myeloma.
[0118] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumors found in mammals, 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, uterus, Hodgkin's Disease, and Non-Hodgkin's Lymphoma. 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, melanoma, medulloblastoma, multiple myeloma, metastatic bone cancer, 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, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
[0119] "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, fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things. In embodiments, treating does not include preventing.
[0120] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. 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 the compound, 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.
[0121] 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. In embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.
[0122] "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, such as bovines, rats, mice, dogs, monkeys, goats, sheeps, cows, deers, and other animals. In some embodiments, a patient is human.
[0123] An "effective amount" is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce 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). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like. By way of example, measurement of the serum level of a CCR4 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.
[0124] 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.
[0125] 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. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0126] 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.
[0127] 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 individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0128] "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).
[0129] The term "modulate" is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. In embodiments, the terms "modulate," "modulation" and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of PPIases, either directly or indirectly, relative to the absence of the molecule.
[0130] The term "aberrant" as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
[0131] The phrase "in a sufficient amount to affect a change" means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's feeling of well-being).
[0132] The "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like. The term "proliferative activity" encompasses an activity that promotes, that is necessary for, or that is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.
[0133] The term "substantially pure" indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content. More typically, "substantially pure" refers to compositions in which at least 75%, at least 85%), at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).
[0134] The terms "specifically binds" and "selectively binds," when referring to a ligand/receptor, antibody/antigen, or other binding pair, indicates a binding reaction which is determinative of the presence of the protein in a heterogeneous population of proteins and other biologies. Thus, under designated conditions, a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample.
[0135] The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components.
[0136] The terms "nucleic acid," "nucleic acid molecule," "polynucleotide" and the like are used interchangeably herein to refer to a polymeric form of nucleotides of any length, either
deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include linear and circular nucleic acids, DNA, RNA, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers and the like.
[0137] As used herein, the terms "variants" and "homologs" are used interchangeably to refer to amino acid or nucleic acid sequences that are similar to reference amino acid or nucleic acid sequences, respectively. The term encompasses naturally-occurring variants and non-naturally- occurring variants. Naturally-occurring variants include homologs (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one species to another), and allelic variants (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one individual to another within a species). Thus, variants and homologs encompass naturally occurring amino acid and nucleic acid sequences encoded thereby and their isoforms, as well as splice variants of a protein or gene. The terms also encompass nucleic acid sequences that vary in one or more bases from a naturally-occurring nucleic acid sequence but still translate into an amino acid sequence that corresponds to the naturally-occurring protein due to degeneracy of the genetic code. Non-naturally-occurring variants and homologs include polypeptides and nucleic acids that comprise a change in amino acid or nucleotide sequence, respectively, where the change in sequence is artificially introduced; for example, the change is generated in the laboratory by human intervention ("hand of man"). Therefore, non-naturally occurring variants and homologs may also refer to those that differ from the naturally-occurring sequences by one or more conservative substitutions and/or tags and/or conjugates.
[0138] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for a mental illness or pain). The compound of the invention can be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely- divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212, 162; and 4,861,760. The entire contents of these patents are
incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as
biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13 :293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, ^w. J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.
[0139] By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[0140] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g. colon cancer), mental illness, pain or depression.
[0141] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for cancer (e.g. colon cancer), mental illness (e.g.
schizophrenia), pain (e.g. chronic pain or neuropathic pain) or depression.
[0142] As used herein, numbering of atoms for FK506, ascomycin and rapamycin follows:
Figure imgf000045_0001
rapamycin:
Figure imgf000045_0002
[0143] As used herein, the phrase "a position equivalent to C1 O of FK506" means a carbon position on a macrolide compound (e.g. FK506, rapamycin, ascomycin or derivative or variant thereof) that is chemically or functionally equivalent to the C1 O of FK506 (e.g. the C1 O of rapamycin (or variant or derivative thereof) or the C1 O of ascomycin (or variant or derivative thereof). Thus, in embodiments, the position equivalent to C1 O of FK506 is the C1 O position of rapamycin, or a variant, derivative or pharmaceutically acceptable salt thereof, or C1 O position of ascomycin, or a variant, derivative or pharmaceutically acceptable salt thereof. Accordingly, the phrase "a position equivalent to C1 O of FK506," "C1 O of FK506," "C1 O of an FK506, "C1 O of ascomycin," and/or "C1 O of rapamycin" are used interchangeably.
[0144] As used herein, compounds FK-NH2, "2a," "2c" and "2d" have the structures following:
Figure imgf000046_0001

Figure imgf000047_0001
Compound "2d":
COMPOUNDS
[0145] In a first aspect, there is provided a peptidyl-prolyl cis-trans isomerase NEVIA-interacting 1 (Pin 1) inhibitor compound, including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
[0146] In embodiments, the compound is an FK506 compound, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C-10 position. In embodiments, the nitrogen- containing functional group is an amino group. In embodiments, the nitrogen-containing functional group is a primary amino group. In embodiments, the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
[0147] In embodiments, the compound is an FK506 compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in FK506. In embodiments, the amino is unsubstituted. In embodiments, the amino is mono- substituted. In embodiments, the amino is di-substituted. In embodiments, the amino is tri- substituted. In embodiments, the amino is substituted with at least one substituent group, size- limited substituent group, or lower substituent group; wherein if the substituted amino 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.
[0148] In embodiments, the compound is an FK506 compound, or a derivative thereof, including an electronegative group at the C-10 position. In embodiments, the electronegative group is not -OH. In embodiments, the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
[0149] In embodiments, the compound is an FK506 compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position. In embodiments, the linker is covalently bound to an electronegative group. In embodiments, the electronegative group is a phosphate isostere. In embodiments, the
electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. In embodiments, the compound is an FK506 compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in FK506. In embodiments, the linker is covalently bound to an electronegative moiety. In embodiments, the electronegative moiety is a phosphate isostere moiety. In embodiments, the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
[0150] Further to any aspect above or embodiments thereof, in embodiments the FK-506 compound is an ascomycin derivative or variant. As indicated, the term "FK-506" or "FK506" refers, in the usual and customary sense, to (3S,4R,5S,8R,9E, 12S,14S,15R, 16S,18R,19R,26aS)- 5,6,8, 11,12, 13,14, 15,16, 17, 18,19,24,25,26,26a-Hexadecahydro-5,19-dihydroxy-3-[(lE)-2- [(lR,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethenyl]-14,16-dimethoxy-4,10, 12,18- tetramethyl-8-(2-propen- 1 -yl)- 15, 19-epoxy-3H-pyrido[2, 1 -c] [ 1 ,4]oxaazacyclotricosine- 1, 7,20,2 l(4H,23H)-tetrone. In embodiments the derivative of the FK-506 compound is an ascomycin compound. [0151] In embodiments the compound is an ascomycin, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C1 O position. In embodiments, the nitrogen- containing functional group is an amino group. In embodiments, the nitrogen-containing functional group is a primary amino group. In embodiments, the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
[0152] In embodiments, the compound is an ascomycin, or a derivative thereof, including an electronegative group at the C-10 position. In embodiments, the electronegative group is not -OH. In embodiments, the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
[0153] In embodiments, the compound is an ascomycin, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position. In embodiments, the linker is covalently bound to an electronegative group. In embodiments, the electronegative group is a phosphate isostere. In embodiments, the
electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. In embodiments, the compound is ascomycin, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in FK506. In embodiments, the linker is covalently bound to an electronegative moiety. In embodiments, the electronegative moiety is a phosphate isostere moiety. In embodiments, the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
[0154] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including a nitrogen-containing functional group at the C-10 position. In embodiments, the nitrogen-containing functional group is an amino group. In embodiments, the nitrogen-containing functional group is a primary amino group. In embodiments, the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group. [0155] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an electronegative group at the C-10 position. In embodiments, the electronegative group is not -OH. In embodiments, the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
[0156] In embodiments, the compound is a rapamycin compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin. In embodiments, the amino is unsubstituted. In embodiments, the amino is mono-substituted. In embodiments, the amino is di-substituted. In embodiments, the amino is tri- substituted. In embodiments, the amino is substituted with at least one substituent group, size- limited substituent group, or lower substituent group; wherein if the substituted amino 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.
[0157] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position. In embodiments, the linker is covalently bound to an electronegative group. In embodiments, the electronegative group is a phosphate isostere. In embodiments, the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in rapamycin. In embodiments, the linker is covalently bound to an electronegative moiety. In embodiments, the electronegative moiety is a phosphate isostere moiety. In embodiments, the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
[0158] The term "electronegative group" is used according to its plain, ordinary meaning and refers to a chemical substituent (e.g., an atom or a functional group) that attracts electrons or electron density towards itself. The terms "electronegative group" and "electronegative substituent" are used synonymously. Examples of electronegative atoms include, but are not limited to, nitrogen, oxygen, phosphorus, sulfur, chlorine, bromine and fluorine. The foregoing groups bearing these atoms, (e.g., -NO2, -CN, -CO2H, etc.) may be said to be "electronegative groups." For a more in depth discussion of electronegative groups, see Taft, R. W. Progress in Physical Organic Chemistry, Volume 13. New York: John Wiley & Sons, 1981, which is incorporated herein by reference in its entirety for all purposes.
[0159] In embodiments, the electronegative group is a phosphate isostere. The term "phosphate isostere" is used according to its plain, ordinary meaning and refers to a chemical substituent with similar physical or chemical properties as a phosphate, which produces similar biological properties (e.g. in a method disclosed herein) to a phosphate. In embodiments, the phosphate isostere is a phosphonate, a tetrahedral sulphate, or a tetrahedral sulphonate. For a more in depth discussion of useful phosphate isosteres, see Elliott et al., "The use of phosphate bioisosteres in medicinal chemistry and chemical biology," Med. Chem. Commun., 2012,3, 735-751, which is incorporated herein by reference in its entirety for all purposes.
[0160] In embodiments, the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
[0161] In another aspect, there is provided an FK506 binding protein (FKBP) inhibitor compound, including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof,.
[0162] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including a nitrogen-containing functional group at the C-10 position. In embodiments, the nitrogen-containing functional group is an amino group. In embodiments, the nitrogen-containing functional group is a primary amino group. In embodiments, the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
[0163] In embodiments, the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
[0164] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position. In embodiments, the linker is covalently bound to an electronegative group. In embodiments, the electronegative group is a phosphate isostere. In embodiments, the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
[0165] In another aspect, there is provided a macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506 or a pharmaceutically acceptable salt thereof.
[0166] In embodiments, the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative or an ascomycin compound derivative.
[0167] In another aspect, there is provided an FK506 binding protein (FKBP) inhibitor compound, including a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
[0168] In embodiments, the FK506 binding protein (FKBP) inhibitor compound is a rapamycin compound, or a derivative thereof, covalently bound to a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin. In embodiments, the amino is unsubstituted. In embodiments, the amino is mono-substituted. In embodiments, the amino is di-substituted. In embodiments, the amino is tri- substituted. In embodiments, the amino is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted amino 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.
[0169] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an electronegative group at the C-10 position. In embodiments, the electronegative group is not -OH. In embodiments, the electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size-limited substituent group, or lower substituent group).
[0170] In embodiments, the compound is a rapamycin compound, or a derivative thereof, including an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position, in place of the -OH in rapamycin. In embodiments, the linker is covalently bound to an electronegative moiety. In embodiments, the electronegative moiety is a phosphate isostere moiety. In embodiments, the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
[0171] In another aspect, there is provided a macrolide compound covalently attached to an electronegative group at a position equivalent to C1 O of FK506 or a pharmaceutically acceptable salt thereof. In embodiments, the electronegative group is not -OH. In embodiments, the
electronegative group is not a substituted hydroxyl (e.g., substituted with a substituent group, size- limited substituent group, or lower substituent group). In embodiments, the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative, or an ascomycin compound derivative.
[0172] In embodiments, the macrolide compound is capable of inhibiting a peptidyl-prolyl cis- trans isomerase NIMA-interacting 1 (Pin 1) protein. In embodiments, the KD for inhibition is less than 1000 nM, 100 nM, 10 nM, or even 1 nM. In embodiments, the KD for inhibition is in the range 0.1-1000 nM, 0.1-100 nM, 0.1-10 nM, or even 0.1-1 nM.
[0173] In embodiments, the macrolide compound is capable of inhibiting an FK506 binding protein. In embodiments, the KD for inhibition is less than 1000 nM, 100 nM, 10 nM, or even 1 nM. In embodiments, the KD for inhibition is in the range 0.1-1000 nM, 0.1-100 nM, 0.1-10 nM, or even 0.1-1 nM. [0174] In embodiments, the electronegative group is a phosphate isostere.
[0175] In embodiments, the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. 0176] In an aspect is provided a compound of structural Formula (I):
Figure imgf000054_0001
(I), or a pharmaceutically acceptable salt thereof, nl, n2 and n3 are independently an integer from 0 to 4. ml, m2, m3, vl, v2 and v3 are independently 1 or 2. L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(O)-, -C(0)0-, -S(O) -, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted
heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted
heteroarylene. R1 is hydrogen, halogen, -CX1 -C.1H3,X1 . -1C2H, zX1-1, -CN, -SOniR1A,
-SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C, -NHC(0)NHNR1BR1C, -NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D, -C(0)NR1BR1C, -OR1A, -NR1BS02R1A, -NR1BC(0)R1D,
-NR1BC(0)OR1D, -NR1BOR1D, -OCX1 -O.1C3H, X1 . s1u2b,stituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R2 is hydrogen, halogen, -CX2 .1 -3C,HX2 .13 -,CH2X2 .1 -,CN, -SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D,
-C(0)OR2D, -C(0)NR2BR2C, -OR2A, -NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D,
-OCX2 13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydrogen, halogen, -CX3,1 3,
-CHX3 .12 -,CH2X3 .1, -CN, -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C,
-NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D,
-C(0)NR3BR3C, -OR3A, -NR3BS02R3A, -NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 .13, -OCHX3.12, 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. R1L, R2L, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A,
R3B, R3C and R3D, are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -C13,-COOH,
-CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl. R1B and R1C, R2B and R2C, R3B and R3C substituents
bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl. X1 1, X2 1 and X3 1 are independently
-C1, -Br, -l or -F.
[0177] In embodiments, when L2 is -0-, L1 is a bond, R1 is 0r -CH2CH3 and R3 is
hydroxyl, then R2 is not hydrogen. In embodiments, when L2 is -O- then R2 is not hydrogen. In embodiments, when R1 is ^^55^ then R2 is not hydrogen. In embodiments, when R1 is -CH2CH3
then R2 is not hydrogen. In embodiments, when R3 is hydroxyl then R2 is not hydrogen. In embodiments, when L2 and L1 are independently a bond, R1 is ^^^5^ or -CH2CH3 and R3 is
hydroxyl, then R2 is not hydroxyl. In embodiments, when L2 is a bond then R2 is not hydroxyl. In
embodiments, when L1 is a bond then R2 is not hydroxyl. In embodiments, when R1 is -CH2CH3 then R2 is not hydroxyl. In embodiments, when R1 is then R2 is not hydroxyl. In
embodiments, when R3 is hydroxyl then R2 is not hydroxyl. In embodiments, L2 is not -0-. In embodiments. L1 is not a bond. In embodiments, R1 is not ^-^5^ or -CH2CH3. In embodiments, R1 is not unsubstituted alkyl. In embodiment, R3 is not hydroxyl. In embodiments, R2 is not hydrogen.
[0178] In embodiments, L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- 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.
[0179] In embodiments, L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0)2- substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0180] In embodiments, L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0)2-, R11-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), R11-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R11 -substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), R11- substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R11 -substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or R11-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0181] In embodiments, L1 is R11-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is R11 -substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L1 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). [0182] In embodiments, L1 is R11- substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L1 is R11-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L1 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
heteroalkylene, or 2 to 4 membered heteroalkylene).
[0183] In embodiments, L1 is R11- substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L1 is R11-substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L1 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
[0184] In embodiments, L1 is R11- substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L1 is R11-substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L1 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
[0185] In embodiments, L1 is R11- substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L1 is R11-substituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L1 is an unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene).
[0186] In embodiments, L1 is R11-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 R11-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L1 is an
unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). [0187] In embodiments, L1 is a bond and R1 is (R)-ethyl. In embodiments, L1 is a bond and R1 is ethylene. In embodiments, L1 is a bond and R1 is propylene.
[0188] In embodiments, L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- 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.
[0189] In embodiments, L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(O)-, -C(0)0- -S(O) - , -S(0)2- substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0190] In embodiments, L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2-, R14-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), R14-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered
heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R14- substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), R14-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered
heterocycloalkylene), R14-substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or R14-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0191] In embodiments, L2 is R14-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L2 is R14-substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L2 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). [0192] In embodiments, L2 is R14-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L2 is R14-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L2 is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
heteroalkylene, or 2 to 4 membered heteroalkylene).
[0193] In embodiments, L2 is R14-substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L2 is R14-substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L2 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
[0194] In embodiments, L2 is R14-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L2 is R14-substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L2 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
[0195] In embodiments, L2 is R14-substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L2 is R14-substituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L2 is an unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene).
[0196] In embodiments, L2 is R14-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L2 is R14-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L2 is an
unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). [0197] In embodiments, L2 is a bond; and R2 is NH2. In embodiments, L2 is a bond, -NR2L-, -NR2LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L2 is -NR2L-. In embodiments, L2 is -NR2LC(0)-. In embodiments, L2 is substituted or unsubstituted alkylene. In embodiments, L2 is substituted or unsubstituted heteroalkylene. In embodiments, L2 is a bond,-NR2L- -NR2LC(0)-. In embodiments, L2 is a bond. In embodiments, L2 is -NH-. In embodiments, L2 is -NHC(O)-. In embodiments, L2 is -NHCH2-. In embodiments, L2 is -NHCH2CH2-.
[0198] In embodiments, R1 is hydrogen, halogen, -CX1 -C.1H3X, 1 -.C1H3,2X1-1, -CN, -SOniR1A, -SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C, -NHC(0)NHNR1BR1C, -NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D, -C(0)NR1BR1C, -OR1A, -NR1BS02R1A, -NR1BC(0)R1D, -NR1BC(0)OR1D, -NR1BOR1D, -OCX1 -O.1C3H, X1.12, R17-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R17-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0199] In embodiments, R1 is R17-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R1 is R17-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R1 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0200] In embodiments, R1 is R17-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R1 is R17-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R1 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0201] In embodiments, R1 is R17-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is R17-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0202] In embodiments, R1 is R17-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R1 is R17-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R1 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0203] In embodiments, R1 is R17-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is R17-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0204] In embodiments, R1 is R17-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1 is R17- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0205] In embodiments, R2 is hydrogen, halogen, -CX2 -C.1H3X, 2.12, -CH2X2 -C.1N, , -SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -OR2A, -NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2 -O.1C3H, X2 su.1b2s,tituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0206] In embodiments, R2 is hydrogen, halogen, -CX2 -C.1H3X, 2.12, -CH2X2 -C.1N, , -SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -OR2A, -NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2 -O.1C3H, X2.12, R20-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R20-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0207] In embodiments, R2 is R20-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is R20-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is an unsubstituted ethyl. In embodiments, R2 is an unsubstituted C3 alkyl. In embodiments, R2 is an unsubstituted C4 alkyl.
[0208] In embodiments, R2 is R20-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R2 is R20-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R2 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0209] In embodiments, R2 is R20-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R2 is R20-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R2 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0210] In embodiments, R2 is R20-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R2 is R20-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R2 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0211] In embodiments, R2 is R20-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 is R20-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0212] In embodiments, R2 is R20-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2 is R20- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0213] In embodiments, R2 is a phosphate isostere group. In embodiments, R2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. In embodiments, R2 is a tetrazole group. In embodiments, R2 is a triazole group. In embodiments, R2 is a carboxylic acid group. In
embodiments, R2 is a phosphonate group. In embodiments, R2 is a boranophosphate group. In embodiments, R2 is a sulfate group. In embodiments, R2 is a sulfamic acid group. In embodiments, R2 is a sulphonate group. In embodiments, R2 is a nitro group. In embodiments, R2 is a
thiazolidinone group. In embodiments, R2 is a thiazolidinone group. In embodiments, R2 is a squaric acid group. In embodiments, R2 is a hydroxyl group. In embodiments, R2 is a boronic acid group. In embodiments, R2 is halogen. In embodiments, R2 is unsubstituted C5-C6 cycloalkyl. In embodiments, R2 is substituted or unsubsttuted phenyl.
[0214] In embodiments, R2 is -COOH. In embodiments, R2 is hydrogen. In embodiments, R2 is -C(0)R2D. In embodiments, R2 is -SO3H. In embodiments, R2 is substituted or unsubstituted alkyl. In embodiments, R2 is substituted alkyl. In embodiments, R2 is substituted methyl. In embodiments, R2 is R20-substituted alkyl. In embodiments, R2 is R20-substituted methyl. In embodiments, R2 is unsubstituted methyl. In embodiments, R2 is substituted ethyl. In embodiments, R2 is R20- substituted ethyl. In embodiments, R2 is unsubstituted ethyl. In embodiments, R2 is substituted n-propyl. In embodiments, R2 is R20-substituted n-propyl. In embodiments, R2 is unsubstituted n-propyl. In embodiments, R2 is substituted or unsubstituted C1-C8 alkyl. In embodiments, R2 is substituted C1-C8 alkyl. In embodiments, R2 is R20-substituted C1-C8 alkyl. In embodiments, R2 is substituted or unsubstituted heteroalkyl. In embodiments, R2 is substituted heteroalkyl. In embodiments, R2 is R20-substituted heteroalkyl. In embodiments, R2 is substituted or unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R2 is substituted 5 to 8 membered heteroalkyl. In embodiments, R2 is R20-substituted 5 to 8 membered heteroalkyl. In embodiments, R2 is substituted or unsubstituted 10 to 15 membered heteroalkyl. In embodiments, R2 is substituted 10 to 15 membered heteroalkyl. In embodiments, R2 is R20-substituted 10 to 15 membered heteroalkyl. In embodiments, R2 is substituted or unsubstituted cycloalkyl. In embodiments, R2 is substituted cycloalkyl. In embodiments, R2 is substituted cyclohexyl. In embodiments, R2 is unsubstituted cyclohexyl. In embodiments, R2 is R20-substituted cycloalkyl. In embodiments, R2 is R20- substituted cyclohexyl. In embodiments, R2 is substituted C3-C8 cycloalkyl. In embodiments, R2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R2 is R20-substituted C3-C8 cycloalkyl. In embodiments, R2 is substituted or unsubstituted aryl. In embodiments, R2 is substituted aryl. In embodiments, R2 is substituted phenyl. In embodiments, R2 is unsubstituted phenyl. In
embodiments, R2 is R20-substituted aryl. In embodiments, R2 is R20-substituted phenyl.
[0215] In embodiments, R3 is hydrogen, halogen, -CX3 -C.1H3X, 3.12, -CH2X3 -C.1N, , -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A, -NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 -O.1C3H, X3 su.1b2s,tituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[0216] In embodiments, R3 is hydrogen, halogen, -CX3 -C.1H3X, 3.12, -CH2X3 -C.1N, , -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A, -NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 -O.1C3H, X3.12, R23-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R23 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R23 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0217] In embodiments, R3 is R23 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is R23 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0218] In embodiments, R3 is R23 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R3 is R23-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R3 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0219] In embodiments, R3 is R23 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is R23 -substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0220] In embodiments, R3 is R23 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R3 is R23 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R3 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0221] In embodiments, R3 is R23 -substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is R23 -substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0222] In embodiments, R3 is R23 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3 is R23- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0223] In embodiments, R3 is hydroxyl group. [0224] In embodiments, R1L, R2L, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C and R3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0225] In embodiments, R1B and R1C, R2B and R2C, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0226] In embodiments, R1L is hydrogen, halogen, -CF3, -CC13, -CBr3, -CI3,-COOH, -CONH2, R11L-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R11L- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11L- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R11L-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11L-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R11L-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0227] In embodiments, R2L is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R14L-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R14L- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14L-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14L-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14L-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R14L-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0228] In embodiments, R1A is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2,
R17A-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R17A- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17A-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R17A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0229] In embodiments, R2A is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R20A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R20A- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20A- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20A- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20A- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0230] In embodiments, R3A is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R23A-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R23A- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23A-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R23A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0231] In embodiments, R1B is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R17B-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R17B- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17B-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1B and R1C substituents bonded to the same nitrogen atom may optionally be joined to form a R17B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R17B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0232] In embodiments, R2B is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R20B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R20B- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20B-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20B-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20B-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2B and R2C substituents bonded to the same nitrogen atom may optionally be joined to form a R20B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R20B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0233] In embodiments, R3B is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R23B-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R23B- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23B-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23B-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23B-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R23B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a R -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R23B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0234] In embodiments, R1C is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R17C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R17C- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17C-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17C-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17C-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R17C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1B and R1C substituents bonded to the same nitrogen atom may optionally be joined to form a R17C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R17C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0235] In embodiments, R2C is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R20C-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R20C- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20C-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20C-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20C-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2B and R2C substituents bonded to the same nitrogen atom may optionally be joined to form a R20C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0236] In embodiments, R3C is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R23C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R23C- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23C-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23C-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23C-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R23C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a R23C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R23C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0237] In embodiments, R1D is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R17D-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R17D- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17D-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17D-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17D-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R17D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0238] In embodiments, R2D is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R20D-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R20D- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20D-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20D-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0239] In embodiments, R2D is substituted or unsubstituted alkyl. In embodiments, R2D is substituted alkyl. In embodiments, R2D is substituted methyl. In embodiments, R2D is R20D- substituted alkyl. In embodiments, R2D is R20D-substituted methyl. In embodiments, R2D is substituted ethyl. In embodiments, R2D is R20D-substituted ethyl. In embodiments, R2D is unsubstituted ethyl. In embodiments, R2D is unsubstituted methyl. In embodiments, R2D is substituted n-propyl. In embodiments, R2D is R20D-substituted n-propyl. In embodiments, R2D is unsubstituted n-propyl. In embodiments, R2D is substituted or unsubstituted C1-C8 alkyl. In embodiments, R2D is substituted C1-C8 alkyl. In embodiments, R2D is R20D-substituted C1-C8 alkyl. In embodiments, R2D is -CF3. In embodiments, R2D is substituted or unsubstituted aryl. In embodiments, R2D is substituted aryl. In embodiments, R2D is substituted phenyl. In embodiments, R2D is unsubstituted phenyl. In embodiments, R2D is substituted or unsubstituted phenyl.
[0240] In embodiments, R20D is halogen. In embodiments, R20D is -C1. In embodiments, R20D is - F. In embodiments, R20D is -Br. In embodiments, R20D is oxo. In embodiments, R20D is -COOH. In embodiments, R20D is -OH. In embodiments, R20D is -SO3H. In embodiments, R20D is substituted or unsubstituted aryl. In embodiments, R20D is substituted aryl. In embodiments, R20D is substituted phenyl. In embodiments, R20D is unsubstituted phenyl. In embodiments, R20D is substituted or unsubstituted phenyl.
[0241] In embodiments, R3D is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R23D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R23D- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23D-substituted or unsubstituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23D-substituted or unsubstituted
heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23D-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R23D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0242] R11 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R12-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R12-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R12-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R12-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R12-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R12- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0243] In embodiments, R11 is R12-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is R12-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0244] In embodiments, R11 is R12-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R11 is R12-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R11 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0245] In embodiments, R11 is R12-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is R12-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0246] In embodiments, R11 is R12-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R11 is R12-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R11 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0247] In embodiments, R11 is R12-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is R12-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0248] In embodiments, R11 is R12-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R11 is R12- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R11 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0249] R12 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R13-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R13 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R13-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R13 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R13-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R13- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0250] In embodiments, R12 is R13 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is R13-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). [0251] In embodiments, R12 is R13 -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 R13-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R12 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0252] In embodiments, R12 is R13 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is R13-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0253] In embodiments, R12 is R13 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R12 is R13-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R12 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0254] In embodiments, R12 is R13 -substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is R13-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0255] In embodiments, R12 is R13 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R12 is R13- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R12 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0256] R14 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R15-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R15 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R15 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R15-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R15- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0257] In embodiments, R14 is R15 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is R15-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0258] In embodiments, R14 is R15 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R14 is R15-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R14 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0259] In embodiments, R14 is R15 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is R15-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0260] In embodiments, R14 is R15 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R14 is R15-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R14 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0261] In embodiments, R14 is R15 -substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R14 is R15-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R14 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0262] In embodiments, R14 is R15 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R14 is R15- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R14 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0263] R15 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R16-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R16-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R16-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R16-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R16-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0264] In embodiments, R15 is R16-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R15 is R16-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R15 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0265] In embodiments, R15 is R16-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R15 is R16-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R15 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0266] In embodiments, R15 is R16-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R15 is R16-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R15 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). [0267] In embodiments, R15 is R16-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R15 is R16-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R15 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0268] In embodiments, R15 is R16-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R15 is R16-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R15 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0269] In embodiments, R15 is R16-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R15 is R16- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R15 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0270] R17 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R18-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R18-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R18- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R18-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R18-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R18-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0271] In embodiments, R17 is R18-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17 is R18-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0272] In embodiments, R17 is R18-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R17 is R18-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R17 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0273] In embodiments, R17 is R18-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17 is R18-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0274] In embodiments, R17 is R18-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R17 is R18-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R17 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0275] In embodiments, R17 is R18-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17 is R18-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0276] In embodiments, R17 is R18-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R17 is R18- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R17 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0277] R18 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -SO4H,
-S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R19- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R19-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R19-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R19- 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, R18 is R19-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18 is R19-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0279] In embodiments, R18 is R19-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R18 is R19-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R18 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0280] In embodiments, R18 is R19-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18 is R19-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0281] In embodiments, R18 is R19-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R18 is R19-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R18 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0282] In embodiments, R18 is R19-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18 is R19-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0283] In embodiments, R18 is R19-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R18 is R19- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R18 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0284] R20 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R21-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R21- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R21-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R21- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R21-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R21-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0285] In embodiments, R20 is R21- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is R21-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0286] In embodiments, R20 is R21- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R20 is R21-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R20 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0287] In embodiments, R20 is R21- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is R21-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0288] In embodiments, R20 is R21- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R20 is R21-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R20 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0289] In embodiments, R20 is R21- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R20 is R21-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R20 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0290] In embodiments, R20 is R21- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R20 is R21- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R20 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0291] In embodiments, R20 is substituted or unsubstituted aryl. In embodiments, R20 is substituted or unsubstituted phenyl. In embodiments, R20 is substituted phenyl. In embodiments, R20 is unsubstituted phenyl. In embodiments, R20 is substituted or unsubstituted C10-C12 aryl. In embodiments, R20 is substituted C10-C12 aryl. In embodiments, R20 is unsubstituted C10-C12 aryl. In embodiments, R20 is substituted or unsubstituted fluorenyl. In embodiments, R20 is substituted fluorenyl. In embodiments, R20 is unsubstituted fluorenyl. In embodiments, R20 is halogen. In embodiments, R20 is -C1. In embodiments, R20 is -F. In embodiments, R20 is -Br. In embodiments, R20 is oxo. In embodiments, R20 is -COOH. In embodiments, R20 is -OH. In embodiments, R20 is -SO3H. In embodiments, R20 is R21- substituted or unsubstituted aryl. In embodiments, R20 is R21-substituted or unsubstituted phenyl. In embodiments, R20 is R21-substituted phenyl. In embodiments, R20 is R21-substituted fluorenyl. [0292] R21 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R22-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R22-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R22- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R22-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R22-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R22-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0293] In embodiments, R21 is R22-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is R22-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0294] In embodiments, R21 is R22-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R21 is R22-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R21 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0295] In embodiments, R21 is R22-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R21 is R22-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R21 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0296] In embodiments, R21 is R22-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R21 is R22-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R21 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0297] In embodiments, R21 is R22-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R21 is R22-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R21 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0298] In embodiments, R21 is R22-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R21 is R22- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R21 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0299] In embodiments, R21 is halogen. In embodiments, R21 is -C1. In embodiments, R21 is -F. [0300] R23 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R24-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R24-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R24- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R24-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R24-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R24-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0301] In embodiments, R23 is R24-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is R24-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0302] In embodiments, R23 is R24-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R23 is R24-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R23 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0303] In embodiments, R23 is R24-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is R24-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0304] In embodiments, R23 is R24-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R23 is R24-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R23 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0305] In embodiments, R23 is R24-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is R24-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0306] In embodiments, R23 is R24-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R23 is R24- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R23 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0307] R24 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R25-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R25-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R25-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R25-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R25-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R25-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, R24 is R25-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R24 is R25-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R24 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0309] In embodiments, R24 is R25-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R24 is R25-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R24 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0310] In embodiments, R24 is R25-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R24 is R25-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R24 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0311] In embodiments, R24 is R25-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R24 is R25-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R24 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0312] In embodiments, R24 is R25-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R24 is R25-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R24 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0313] In embodiments, R24 is R25-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R24 is R25- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R24 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0314] In embodiments, the compound is
Figure imgf000086_0001
[0315] In embodiments, the compound is
Figure imgf000087_0001
((Ia)(R)) or ((Ib)(S)).
[0316] R11L R13 R14L R16 R17A R17B R17C R17D R19 R20A R20B R20C R20D R22 R23A R23B R23C, R23D and R25 are independently hydrogen, oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H,
-SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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).
[0317] In embodiments, X1 1, X2 1 and X3 1 are independently -C1, -Br, -I or -F. In embodiments, X1 1 is -C1. In embodiments, X1 1 is -F. In embodiments, X1 1 is -Br. In embodiments, X1 1 is -I. In embodiments, X2 1 is -C1. In embodiments, X2 1 is -F. In embodiments, X2 1 is -Br. In
embodiments, X2 1 is -I. In embodiments, X3 1 is -C1. In embodiments, X3 1 is -F. In embodiments, X3 1 is -Br. In embodiments, X3 1 is -I.
[0318] In embodiments, the symbol nl is an integer from 0 to 4. In embodiments, nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4.
[0319] In embodiments, the symbols ml and vl are independently 1 or 2. In embodiments, ml is
1. In embodiments, ml is 2. In embodiments, vl is 1. In embodiments, vl is 2. [0320] In embodiments, the symbol n2 is an integer from 0 to 4. In embodiments, n2 is 0. In
embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4.
[0321] In embodiments, the symbols m2 and v2 are independently 1 or 2. In embodiments, m2 is
1. In embodiments, m2 is 2. In embodiments, v2 is 1. In embodiments, v2 is 2.
[0322] In embodiments, the symbol n3 is an integer from 0 to 4. In embodiments, n3 is 0. In
embodiments, n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3. In embodiments, n3 is 4.
[0323] In embodiments, the symbols m3 and v3 are independently 1 or 2. In embodiments, m3 is
1. In embodiments, m3 is 2. In embodiments, v3 is 1. In embodiments, v3 is 2. 0324] In another aspect, there is provided a compound of structural Formula (II): ***
Figure imgf000088_0001
b c
^= and =^ are independently single bonds or double bonds. n4, n5, n6, n7, n8, n9 and nlO are
independently an integer from 0 to 4. m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO
are independently 1 or 2. L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(O)-, -C(0)0- -S(O) -,
-S(0)2- 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. R4 is hydrogen,
halogen, -CX4 .13 -,CHX4.12, -CH2X4 .1 -, CN, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C,
-NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D,
-C(0)NR4BR4C, -OR4A, -NR4BS02R4A, -NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 .13,
-OCHX4.12, 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. R5 is hydrogen, halogen, -CX5,1 3, -CHX5.12, -CH2X5 Λ, -CN, -SOnsH, -SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2,
-C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .13,
-OCHX5.12, 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. R6 is hydrogen, halogen, -CX6 J 3, -CHX6.12, -CH2X6 1,
-CN, -SOn6H, -SOv6NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m6, -NH2,
-C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6 .13,
-OCHX6.12, 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. R7 is hydrogen, halogen, -CX7 J 3, -CHX7.12, -CH2X7 1,
-CN, -SOnvH, -SOvvNH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)mv, -NH2,
-C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13,
-OCHX7.12, 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. R8 is hydrogen, halogen, -CX8 J 3, -CHX8.12, -CH2X8 1,
-CN, -SOnsH, -SOv8NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m8, -NH2,
-C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8 .13,
-OCHX8.12, 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. R9 is hydrogen, halogen, -CX9 J 3, -CHX9.12, -CH2X9 1,
-CN, -SOn9H, -SOv9NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m9, -NH2,
-C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .13,
-OCHX9.12, 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. R10 is hydrogen, halogen, -CX10 J 3, -CHX10 -\
-CH2X10 1, -CN, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2,
-N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH,
-NHOH, -OCX10 13, -OCHX10 s.u1b3,stituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R3L, R4A, R4B, R4C and
R4D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X4 X.15, 1, X6 X7.1, X8.1, X9.11, and X10 1 are independently -C1, -Br, -I or -F.
[0325] In embodiments, when
Figure imgf000090_0001
are double bonds, L3 is -O- and R6, R7, R8, R9 and R10 are independently hydrogen, then R4 is not hydrogen. In embodiments, when
Figure imgf000090_0002
is a double bond then R4 is not hydrogen. In embodiments, when is a double bond then R4 is not
Figure imgf000090_0003
hydrogen. In embodiments, when
Figure imgf000090_0004
is a double bond then R4 is not hydrogen. In embodiments, when L3 is
-O- then R4 is not hydrogen. In embodiments, when R6 is hydrogen then R4 is not hydrogen. In embodiments, when R7 is hydrogen then R4 is not hydrogen. In embodiments, when R8 is hydrogen then R4 is not hydrogen. In embodiments, when R9 is hydrogen then R4 is not hydrogen. In embodiments, when R10 is hydrogen then R4 is not hydrogen. In embodiments, when and are double bonds, L3 is a bond and R6, R7, R8, R9 and R10 are independently hydrogen, then R4 is not hydroxyl. In embodiments, when ^= is a double bond then R4 is not hydroxyl. In
embodiments, when is a double bond then R4 is not hydroxyl. In embodiments, when is a double bond then R4 is not hydroxyl. In embodiments, when L3 is a bond then R4 is not hydroxyl. In embodiments, when R6 is hydrogen then R4 is not hydroxyl. In embodiments, when R7 is hydrogen then R4 is not hydroxyl. In embodiments, when R8 is hydrogen, then R4 is not hydroxyl. In embodiments, when R9 is hydrogen then R4 is not hydroxyl. In embodiments, when R10 is hydrogen then R4 is not hydroxyl.
[0326] In embodiments, L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(O)-, -C(0)0- -S(O)-, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. [0327] In embodiments, L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(O)-, -C(0)0- -S(O)-, -S(0)2-, substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1- C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0328] In embodiments, L3 is a bond, -0-, -S-, -NR3L- -C(O)-, -C(0)0- -S(O) -, -S(0)2- R26-substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), R26-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R26-substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), R26- substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R26-substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or R26-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L3 is a bond.
[0329] In embodiments, L3 is R26- substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L3 is R26-substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L3 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene).
[0330] In embodiments, L3 is R26- substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L3 is R26-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L3 is an
unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered
heteroalkylene, or 2 to 4 membered heteroalkylene). [0331] In embodiments, L3 is R26- substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L3 is R26-substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L3 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).
[0332] In embodiments, L3 is R26- substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L3 is R26-substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In embodiments, L3 is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).
[0333] In embodiments, L3 is R26- substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L3 is R26- substituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L3 is an unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene).
[0334] In embodiments, L3 is R26- substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L3 is R26-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L3 is an
unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0335] In embodiments, L3 is -NR3L or a bond. In embodiments, L3 is -NR3LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L3 is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L3 is a bond, -NR3L- -NR3LC(0)-. In embodiments, L3 is a bond. In embodiments, L3 is -NH-. In embodiments, L3 is -NHC(O)-. In embodiments, L3 is -NHCH2-. In embodiments, L3 is
-NHCH2CH2-. [0336] In embodiments, R4 is hydrogen, halogen, -CX4 -C.1H3X, 4.12, -CH2X4 -C.1N, , -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A, -NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 -O.1C3H, X4 su.1b2s,tituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[0337] In embodiments, R4 is hydrogen, halogen, -CX4 -C.1H3X, 4.12, -CH2X4 -C.1N, , -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A, -NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 1 3, -OCHX4 R29-.s1u2b,stituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R29-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R29-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0338] In embodiments, R4 is -CN, -C(0)NH2, -CF3, -CH3 or -C(CH3)2OH . In embodiments, R4 is -CN. In embodiments, R4 is -C(0)NH2. In embodiments, R4 is -CF3. In embodiments, R4 is -CH3. In embodiments, R4 is -C(CH3)2OH.
[0339] In embodiments, R4 is R29-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R4 is R29-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R4 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0340] In embodiments, R4 is R29-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R4 is R29-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R4 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0341] In embodiments, R4 is R29-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is R29-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0342] In embodiments, R4 is R29-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R4 is R29-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R4 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0343] In embodiments, R4 is R29-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is R29-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0344] In embodiments, R4 is R29-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4 is R29- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0345] In embodiments, R4 is a phosphate isostere group. In embodiments, R4 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group. In embodiments, R4 is 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, R4 is substituted or unsubstituted alkyl. In embodiments, R4 is substituted or unsubstituted aryl. In embodiments, R4 is substituted or unsubstituted benzyl.
[0346] In embodiments, R4 is -COOH. In embodiments, R4 is hydrogen. In embodiments, R4 is - C(0)R4D. In embodiments, R4 is -SO3H. In embodiments, R4 is substituted or unsubstituted alkyl. In embodiments, R4 is substituted alkyl. In embodiments, R4 is substituted methyl. In embodiments, R4 is R29-substituted alkyl. In embodiments, R4 is R29-substituted methyl. In embodiments, R4 is unsubstituted methyl. In embodiments, R4 is substituted ethyl. In embodiments, R4 is R29- substituted ethyl. In embodiments, R4 is unsubstituted ethyl. In embodiments, R4 is substituted n- propyl. In embodiments, R4 is R29-substituted n-propyl. In embodiments, R4 is unsubstituted n- propyl. In embodiments, R4 is substituted or unsubstituted C1-C8 alkyl. In embodiments, R4 is substituted C1-C8 alkyl. In embodiments, R4 is R29-substituted C1-C8 alkyl. In embodiments, R4 is substituted or unsubstituted heteroalkyl. In embodiments, R4 is substituted heteroalkyl. In embodiments, R4 is R29-substituted heteroalkyl. In embodiments, R4 is substituted or unsubstituted 5 to 8 membered heteroalkyl. In embodiments, R4 is substituted 5 to 8 membered heteroalkyl. In embodiments, R4 is R29-substituted 5 to 8 membered heteroalkyl. In embodiments, R4 is substituted or unsubstituted 10 to 15 membered heteroalkyl. In embodiments, R4 is substituted 10 to 15 membered heteroalkyl. In embodiments, R4 is R29-substituted 10 to 15 membered heteroalkyl. In embodiments, R4 is substituted or unsubstituted cycloalkyl. In embodiments, R4 is substituted cycloalkyl. In embodiments, R4 is substituted cyclohexyl. In embodiments, R4 is unsubstituted cyclohexyl. In embodiments, R4 is R29-substituted cycloalkyl. In embodiments, R4 is R29- substituted cyclohexyl. In embodiments, R4 is substituted C3-C8 cycloalkyl. In embodiments, R4 is unsubstituted C3-C8 cycloalkyl. In embodiments, R4 is R29-substituted C3-C8 cycloalkyl. In embodiments, R4 is substituted or unsubstituted aryl. In embodiments, R4 is substituted aryl. In embodiments, R4 is substituted phenyl. In embodiments, R4 is unsubstituted phenyl. In
embodiments, R4 is R29-substituted aryl. In embodiments, R4 is R29-substituted phenyl.
[0347] In embodiments, R5 is hydrogen, halogen, -CX5 -C.1H3X, 5.12, -CH2X5 -C.1N, , -SOn5H, -SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .1 -3O, CHX5 \ 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.
[0348] In embodiments, R5 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R5 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0349] In embodiments, R5 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R5 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0350] In embodiments, R5 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0351] In embodiments, R5 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R5 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0352] In embodiments, R5 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0353] In embodiments, R5 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R5 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R5 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0354] In embodiments, R6 is hydrogen, halogen, -CX6 -C.1H3X, 6.12, -CH2X6 -C.1N, , -SOn6H, -SOv6NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m6, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6 .1 -3O, CHX6 \ 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.
[0355] In embodiments, R6 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R6 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0356] In embodiments, R6 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R6 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0357] In embodiments, R6 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R6 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0358] In embodiments, R6 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R6 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0359] In embodiments, R6 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0360] In embodiments, R6 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R6 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R6 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0361] In embodiments, R7 is hydrogen, halogen, -CX7 -C.1H3X, 7.12, -CH2X7 -C.1N, , -SOnvH, -SOvvNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mv, -NH2, -C(0)H, - C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13 -,OCHX7 \ 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. [0362] In embodiments, R is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R7 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0363] In embodiments, R7 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R7 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0364] In embodiments, R7 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R7 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0365] In embodiments, R7 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R7 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0366] In embodiments, R7 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R7 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0367] In embodiments, R7 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R7 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R7 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0368] In embodiments, R8 is hydrogen, halogen, -CX8 -C.1H3X, 8.12, -CH2X8 -C.1N, , -SOn8H, -SOv8NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m8, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8 .1 -3O, CHX8 \ 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.
[0369] In embodiments, R8 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R8 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0370] In embodiments, R8 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R8 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0371] In embodiments, R8 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0372] In embodiments, R8 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R8 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0373] In embodiments, R8 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0374] In embodiments, R8 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R8 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0375] In embodiments, R9 is hydrogen, halogen, -CX9 -C.1H3X, 9.12, -CH2X9 -C.1N, , -SOn9H, -SOv9NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m9, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .1 -3O, CHX9 \ 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.
[0376] In embodiments, R9 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0377] In embodiments, R9 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R9 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0378] In embodiments, R9 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R9 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0379] In embodiments, R9 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R9 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0380] In embodiments, R9 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R9 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0381] In embodiments, R9 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R9 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R9 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0382] In embodiments, R10 is hydrogen, halogen, -CX10 -CH.1X3,10.12, -CH2X10 -CN.1,, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX10 .13, -OCHX10 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.
[0383] In embodiments, R10 is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R10 is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R10 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0384] In embodiments, R10 is substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R10 is substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0385] In embodiments, R10 is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3- C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R10 is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R10 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0386] In embodiments, R10 is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R10 is substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R10 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0387] In embodiments, R10 is substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R10 is substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl) that is substituted with e.g., a "substituent group" as described herein, a "size-limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R10 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0388] In embodiments, R10 is substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R10 is substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl) that is substituted with e.g., a "substituent group" as described herein, a "size- limited substituent" as described herein, or "lower substituent group" as described herein. In embodiments, R10 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0389] In embodiments, R3L, R4A, R4B, R4C and R4D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0390] In embodiments, R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0391] In embodiments, R3L is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R26L-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R26L- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R26L- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26L- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R26L- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R26L-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0392] In embodiments, R4A is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R29A-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R29A- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29A-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R29A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0393] In embodiments, R4B is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2,
R29B-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R29B- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29B-substituted or unsubstituted cycloalkyl (e.g.,
C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29B-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R29B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a R29B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R29B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0394] In embodiments, R4C is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R29C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-Ce alkyl, or C1-C4 alkyl), R29C- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29C-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R29C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a R29C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R29C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0395] In embodiments, R4D is hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, R29D-substituted or unsubstituted alkyl (e.g., C1-Ce alkyl, C1-Ce alkyl, or C1-C4 alkyl), R29D- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29D-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R29D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0396] In embodiments, R4D is substituted or unsubstituted alkyl. In embodiments, R4D is substituted alkyl. In embodiments, R4D is substituted methyl. In embodiments, R4D is R29D- substituted alkyl. In embodiments, R4D is R29D-substituted methyl. In embodiments, R4D is substituted ethyl. In embodiments, R4D is R29D-substituted ethyl. In embodiments, R4D is unsubstituted ethyl. In embodiments, R4D is unsubstituted methyl. In embodiments, R4D is substituted n-propyl. In embodiments, R4D is R29D-substituted n-propyl. In embodiments, R4D is unsubstituted n-propyl. In embodiments, R4D is substituted or unsubstituted C1-C8 alkyl. In embodiments, R4D is substituted C1-C8 alkyl. In embodiments, R4D is R29D-substituted C1-C8 alkyl. In embodiments, R4D is -CF3. In embodiments, R4D is substituted or unsubstituted aryl. In embodiments, R4D is substituted aryl. In embodiments, R4D is substituted phenyl. In embodiments, R4D is unsubstituted phenyl. In embodiments, R4D is substituted or unsubstituted phenyl.
[0397] R26 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -SO2NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R27-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R27-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R27- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R27-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R27-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R27-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0398] In embodiments, R26 is R27-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is R27-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). [0399] In embodiments, R26 is R27-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R26 is R27-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R26 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0400] In embodiments, R26 is R27-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R26 is R27-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R26 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0401] In embodiments, R26 is R27-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R26 is R27-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R26 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0402] In embodiments, R26 is R27-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is R27-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0403] In embodiments, R26 is R27-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R26 is R27- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R26 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0404] R27 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R28-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R28-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R28-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R28-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R28-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0405] In embodiments, R27 is R28-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R27 is R28-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R27 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0406] In embodiments, R27 is R28-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 is R28-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R27 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0407] In embodiments, R27 is R28-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R27 is R28-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R27 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0408] In embodiments, R27 is R28-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R27 is R28-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R27 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0409] In embodiments, R27 is R28-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R27 is R28-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R27 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). [0410] In embodiments, R27 is R28-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R27 is R28- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R27 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0411] R29 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H,
-NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R30-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R30-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R30-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R30-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R30-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R30-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0412] In embodiments, R29 is R30-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R29 is R30-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R29 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0413] In embodiments, R29 is R30-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R29 is R30-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R29 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0414] In embodiments, R29 is R30-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R29 is R30-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0415] In embodiments, R29 is R30-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R29 is R30-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R29 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
[0416] In embodiments, R29 is R30-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R29 is R30-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R29 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0417] In embodiments, R29 is R30-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R29 is R30- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R29 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0418] In embodiments, R29 is substituted or unsubstituted aryl. In embodiments, R29 is substituted or unsubstituted phenyl. In embodiments, R29 is substituted phenyl. In embodiments, R29 is unsubstituted phenyl. In embodiments, R29 is substituted or unsubstituted C10-C12 aryl. In embodiments, R29 is substituted C10-C12 aryl. In embodiments, R29 is unsubstituted C10-C12 aryl. In embodiments, R29 is substituted or unsubstituted fluorenyl. In embodiments, R29 is substituted fluorenyl. In embodiments, R29 is unsubstituted fluorenyl. In embodiments, R29 is halogen. In embodiments, R29 is -C1. In embodiments, R29 is -F. In embodiments, R29 is -Br. In embodiments, R29 is oxo. In embodiments, R29 is -COOH. In embodiments, R29 is -OH. In embodiments, R29 is - S03H. In embodiments, R29 is R30-substituted or unsubstituted aryl. In embodiments, R29 is R30- substituted or unsubstituted phenyl. In embodiments, R29 is R30-substituted phenyl. In
embodiments, R29 is R30-substituted fluorenyl.
[0419] R30 is independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCC13, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R31-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R31- substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R31-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R31- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R31-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R31-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0420] In embodiments, R30 is R31- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is R31-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).
[0421] In embodiments, R30 is R31- 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 R31-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R30 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
[0422] In embodiments, R30 is R31- substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is R31-substituted cycloalkyl (e.g., C3- C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0423] In embodiments, R30 is R31- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R30 is R31-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments, R30 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).
I l l [0424] In embodiments, R30 is R31- substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is R31-substituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).
[0425] In embodiments, R30 is R31- substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is R31- substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R30 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0426] In embodiments, R30 is halogen. In embodiments, R30 is -C1. In embodiments, R30 is -F.
[0427] R26L, R28, R29A, R29B, R29C, R29D and R31 are independently hydrogen, oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H,
-SO4H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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). In embodiments, R26L, R28, R29A, R29B, R29C, R29D and R31 are independently oxo,
halogen, -CC13, -CBr3, -CF3, -C13,-CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H,
-SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF3, -OCBr3, -OC13,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 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).
[0428] In embodiments, R29D is halogen. In embodiments, R29D is -C1. In embodiments, R29D is - F. In embodiments, R29D is -Br. In embodiments, R29D is oxo. In embodiments, R29D is -COOH. In embodiments, R29D is -OH. In embodiments, R29D is -SO3H. In embodiments, R29D is substituted or unsubstituted aryl. In embodiments, R29D is substituted aryl. In embodiments, R29D is substituted phenyl. In embodiments, R29D is unsubstituted phenyl. In embodiments, R29D is substituted or unsubstituted phenyl.
[0429] In embodiments, X4 1 is -C1. In embodiments, X4 1 is -F. In embodiments, X4 1 is -Br. In embodiments, X4 1 is -I. In embodiments, X5 1 is -C1. In embodiments, X5 1 is -F. In embodiments, X5 1 is -Br. In embodiments, X5 1 is -I. In embodiments, X6 1 is -C1. In embodiments, X6 1 is -F. In embodiments, X6 1 is -Br. In embodiments, X6 1 is -I. In embodiments, X7 1 is -C1. In
embodiments, X7 1 is -F. In embodiments, X7 1 is -Br. In embodiments, X7 1 is -I. In embodiments, X8 1 is -C1. In embodiments, X8 1 is -F. In embodiments, X8 1 is -Br. In embodiments, X8 1 is -I. In embodiments, X9 1 is -C1. In embodiments, X9 1 is -F. In embodiments, X9 1 is -Br. In
embodiments, X9 1 is -I. In embodiments, X10 1 is -C1. In embodiments, X10 1 is -F. In
embodiments, X10 1 is -Br. In embodiments, X10 1 is -I.
[0430] In embodiments, the symbol 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. In embodiments, the symbol n5 is an integer from 0 to 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4. In
embodiments, the symbol n6 is an integer from 0 to 4. In embodiments, n6 is 0. In embodiments, n6 is 1. In embodiments, n6 is 2. In embodiments, n6 is 3. In embodiments, n6 is 4. In
embodiments, the symbol n7 is an integer from 0 to 4. In embodiments, n7 is 0. In embodiments, n7 is 1. In embodiments, n7 is 2. In embodiments, n7 is 3. In embodiments, n7 is 4. In
embodiments, the symbol n8 is an integer from 0 to 4. In embodiments, n8 is 0. In embodiments, n8 is 1. In embodiments, n8 is 2. In embodiments, n8 is 3. In embodiments, n8 is 4. In
embodiments, the symbol n9 is an integer from 0 to 4. In embodiments, n9 is 0. In embodiments, n9 is 1. In embodiments, n9 is 2. In embodiments, n9 is 3. In embodiments, n9 is 4. In embodiments, the symbol nlO is an integer from 0 to 4. In embodiments, nlO is 0. In embodiments, nlO is 1. In embodiments, nlO is 2. In embodiments, nlO is 3. In embodiments, nlO is 4.
[0431] In embodiments, the symbols m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently 1 or 2. In embodiments, m4 is 1. In embodiments, m4 is 2. In embodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2. In embodiments, v5 is 1. In embodiments, v5 is 2. In embodiments, m6 is 1. In embodiments, m6 is 2. In embodiments, v6 is 1. In embodiments, v6 is 2. In embodiments, m7 is 1. In embodiments, m7 is 2. In embodiments, v7 is 1. In embodiments, v7 is 2. In embodiments, m8 is 1. In embodiments, m8 is 2. In embodiments, v8 is 1. In embodiments, v8 is 2. In embodiments, m9 is 1. In embodiments, m9 is 2. In embodiments, v9 is 1. In embodiments, v9 is 2. In embodiments, mlO is 1. In embodiments, mlO is 2. In embodiments, vlO is 1. In embodiments, vlO is 2.
[0432] In embodiments, the compound is
Figure imgf000115_0001
Figure imgf000116_0001
[0434] 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).
[0435] 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.
[0436] 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.
[0437] 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.
[0438] 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.
[0439] In another aspect, there is provided a pharmaceutical composition, including a compound described herein (e.g., compound of any aspect disclosed herein and embodiments thereof), and a pharmaceutically acceptable excipient.
METHODS [0440] In another aspect, there is provided a method of inhibiting Pin 1, including contacting Pin 1 with a compound as described herein, including embodiments thereof.
[0441] In another aspect, there is provided a method of inhibiting an FK506 binding protein (FKBP), including contacting the FKBP with a compound as described herein, including
embodiments thereof.
[0442] In embodiments, the FKBP is FKBP38, FKBP 51 or FKBP52. In embodiments, the FKBP is FKBP51.
[0443] In another aspect, there is provided a method of treating a Pin 1 -mediated disease or disorder, including administering to a patient in need thereof a compound as described herein, including embodiments thereof.
[0444] In embodiments, the Pin 1 -mediated disease or disorder is cancer. In embodiments, the cancer is prostate cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer or skin cancer (e.g., melanoma). In embodiments, the cancer is prostate cancer. In embodiments, the cancer is brain cancer. In embodiments, the cancer is brest cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is skin cancer. In embodiments, the skin cancer is melanoma.
[0445] In embodiments, the Pin 1 -mediated disease or disorder is a neurodegenerative disease. In embodiments, the neurodegenerative disease is a tauopathy. In embodiments, the neurodegenerative disease is Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, Chronic traumatic encephalopathy, including dementia pugilistica, Progressive supranuclear palsy, Corticobasal degeneration, Frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis, encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Parkinsons Disease, Alzheimers Disease, Huntington's Disease, Pick's Disease, schizophrenia or corticobasal degeneration.
[0446] In embodiments, the Pin 1 -mediated disease or disorder is depression. In embodiments, the method further includes administering to the subject an anti-depressant. [0447] In embodiments, the Pin 1 -mediated disease or disorder is pain. In embodiments, the pain is chronic pain or neuropathic pain.
[0448] Further to any aspect of treating a Pin 1 -mediated disease or disorder, or embodiment thereof, in embodiments the method further includes administering to the subject a chemotherapeutic agent.
[0449] In another aspect, there is provided a method of treating an FKBP51 -mediated disease or disorder, including administering to a patient in need thereof a compound as described herein, including embodiments thereof.
METHOD OF PREPARING
[0450] In another aspect, there is provided a method of preparing a compound of structural Formula (I) as described herein, including contacting a compound of structural Formula (Ic) with ammonia:
Figure imgf000120_0001
(Ic), wherein L1, L2, R1, and R3 are as described herein.
[0451] In embodiments, the compound of Formula (Ic)
Figure imgf000121_0001
[0452] In another aspect, there is provided a method of preparing a compound of structural Formula (II) as described herein, including contacting a compound of structural Formula (lie) with ammonia:
Figure imgf000121_0002
are as described herein.
[0453] In embodiments, the compound of Formula (lie) is
Figure imgf000122_0001
EXAMPLES
[0454] Example 1 - Novel Design of Inhibitors Targeting the PPIase Pinl
[0455] Pinl is unique among the prolyl isomerases (PPIases) because it only binds to prolines that directly follow phosphorylated serine or threonine residues (pS/T-P motif). This activity is important as the phosphate of the pS/T-P motif sterically hinders the local peptide backbone and dramatically slows the spontaneous ci's-trans isomerization of the proline. Thus, Pinl activity becomes essential for isomerization of this motif on a relevant physiological time scale. Moreover, Pinl 's clients include multiple cell cycle regulators, modulators of stress responses, and transcription factors. In these clients, isomerization of pS/T-P motifs is used as an essential regulatory switch, often in tandem with proline-directed kinases. Accordingly, misregulation or overexpression of Pinl is implicated in numerous diseases, including cancer and neurodegeneration, making Pinl an especially attractive target. However, attempts to discover Pinl inhibitors have had limited success. The requirement for a highly electronegative group in the Pinl active site, mimicking the pS/T-P interaction, seems to render many potential inhibitors inactive in cell and animal models because of poor permeability. Accordingly, a useful hypothesis is that the excellent pharmacological properties of FK506 can make it a suitable chemical scaffold for engineering Pinl inhibitors. We reasoned that these molecules might take advantage of the mechanisms to yield potent, selective and long-lived inhibitors. However, FK506 itself has little affinity for Pinl, possibly because it lacks the key, electronegative region essential for Pinl binding. To overcome this potential hurdle, we have designed a novel semisynthetic strategy to modify FK506 at a position likely to improve affinity and selectivity for Pinl . We found that installing a sulfamic acid at the ClO-position of the macrocyclic ring significantly improved the affinity for Pinl (>100-fold) in vitro. This molecule is designed to yield the first high-affinity membrane-permeable inhibitors of Pinl, which should prove to be a powerful chemical probe of this PPIase.
[0456] Pinl Plays a Diverse Role in Cellular Homeostasis. Pinl has a unique role among all of the PPIases in that it only recognizes prolines immediately following phosphorylated serine or threonine residues (known as the pS/T-P motif) [1]. This unique feature of Pinl bindings is mediated by a cationic groove formed by Lys-63, Arg-68 and Arg-69, which makes contact with the pS/T group (FIG. 1) [2]. In turn, isomerization of bound substrate is thought to be mediated by the nearby residue Cys-113 [3]. Like other PPIases, Pinl also has a hydrophobic "shelf adjacent to the proline pocket that it uses to gain additional contacts.
[0457] In addition to its PPIase domain, Pinl has an N-terminal WW domain, that seems to contribute to the binding of phosphopeptide substrates. The WW domain does not possess intrinsic isomerase activity, and the reason for overlapping substrate preference with the PPIase domain is unclear. It is thought that the WW domain may initially localize with relevant clients, but the hand- off mechanism to the PPIase domain for isomerization is unknown.
[0458] Pinl and its orthologs have been discovered in all eukaryotes and they are known to be critical for cell cycle regulation and cellular homeostasis. In Saccharomyces cerevisiae, the Pinl homolog Essl is essential [4], and complementation with human Pinl rescues viability [1]. One essential activity of Pinl is in regulation of the cell cycle, through its activity on numerous phosphorylation-dependent regulatory pathways. Pinl works in tandem with 'proline-directed' kinases and phosphatases, binding and isomerizing the peptide backbone of the pS/T-P motifs to alter the prolyl cis/trans conformation. This is especially important in the context of pS/T-P motifs, as they have been shown to isomerize 8-fold slower than their non-phosphorylated counterparts [5]. This slow rate is driven by specific contacts between the phosphate moiety and the amide backbone [6]. Since proline isomerization already represents a significant bottleneck in protein dynamics phosphoprotein substrates of Pinl require the specific isomerase activity of this chaperone to function. Pinl -mediated conformational changes have been implicated in activating transcription factors, facilitating dephosphorylation or degradation of clients, stabilizing protein-protein interactions and targeting proteins for specific subcellular localization [7]. [0459] The Role of Pinl in Disease. The importance of Pinl for cellular homeostasis and the progression through mitosis suggests that misregulation of this protein may lead to a variety of disease states. Indeed, Pinl has been implicated in both cancer and neurodedgeneration. Pinl interacts with multiple oncogenes, such as p53, and often enhances their oncogenic activity.
Significant Pinl overexpression has been found in numerous cancer types, including prostate, brain, breast, ovary, cervical and melanomas [8]. Conversely, low Pinl expression has been correlated to increased neuronal vulnerability and enhanced degeneration of neurons and neurofibrillary tangle formation during AD-like pathologies [9]. Pinl is often sequestered into paired helical filaments (PHF) of hyperphosphorylated tau [10] while soluble Pinl is deactivated by oxidative stress at its catalytic cysteine [11]. Thus, Pinl expression and activity is often inversely correlated with disease; it is upregulated and highly active in cancer, or downregulated and inactive in neurodegenerative diseases [12]. For these reasons, Pinl inhibitors are of significant interest as potential anti-cancer therapeutics, where modulation of Pinl levels have been shown to be effective at preventing tumorigenesis. Further, Pinl inhibition may have some therapeutic benefit in certain
neurodegenerative diseases, such as in tauopathies, where specific destabilizing mutations in tau have exhibited a decrease in pathogenesis when Pinl levels are reduced [13].
[0460] Natural Product Inhibitors of Pinl . Finding high affinity, cell permeable inhibitors has been an active and ongoing pursuit for many years [14]. Discovered as the first Pinl inhibitor,
Juglone (FIG. 2) functions by covalent modification of Cys-113 in the active site [15]. Juglone (5- hydroxy-l,4-naphtha!enedione) is produced by the Black Walnut tree and its inhibition of Pinl activity has been suggested to contribute to the toxicity of Black Walnuts. However, the exact binding interaction of Juglone is unclear and this compound has proven to have other cellular targets, possibly acting non-specifically [16]. To date, no inhibitors are known to mimic this mode of inhibition. Interestingly, Juglone does not inhibit the FKBPs or cyclophilins, whereas Pinl has not been shown to have any appreciable affinity for the natural products, rapamycin, FK506 or cyclosporin. This observation is perhaps surprising, due to the similarity between active sites across the PPIases. However, Pinl is unique among the PPIases because of its phospho-peptide binding activity through a positively charged surface. Thus, Pinl inhibitors must navigate this feature of the pocket by including highly electronegative substituents. The challenge is that these same features often reduce membrane permeability. Other natural product derivatives (FIG. 2) have been shown to inhibit Pinl while also engaging the phosphate-binding region, providing an alternate approach towards novel scaffolds. Dexamethasone-21 -phosphate is a synthetic corticosteroid prodrug found to modestly inhibits Pinl activity (KD = 2.2uM) [17]. By NMR and X-ray crystallography, dexamethasone-21 -phosphate was shown to bind across the proline pocket to the cationic groove formed by Lys-63, Arg-68 and Arg-69. Using a similar screening strategy, the vitamin A derivative all-trans retinoic acid (ATRA) was found to be a submicromolar inhibitor of Pinl (KD = 0.8uM) and bound similarly to dexamethasone-21 -phosphate [18]. The cyclohexene ring is anchored into the proline binding pocket with the alkene chain extending the carboxylic acid into the cationic phosphate-binding region. Treatment with ATRA suppresses proliferation of mouse embryonic fribroblasts and leads to Pinl degradation but has no effect in Pinl knockout cells or those harboring inactivating mutations in the binding site. In a model of acute promyelocytic leukemia (APL), ATRA facilitates degradation of the fusion oncoprotein promyelocytic leukemia-retinoic acid receptor a (PML-RAR-a) and was shown to be due to the inhibition of the stabilizing effect of Pinl . This was further demonstrated in a breast cancer model where Pinl is highly expressed and possesses pro-oncogenic activity. Inhibition of Pinl by ATRA limited turn origeni city of MDA- MBA-231 cells injected into mice in a dose-dependent manner. Inhibitors based on these natural products may be a promising starting point.
[0461] Peptidomimetics Demonstrate the Necessity for Charged Substituents in Pinl Inhibitors.
Because of the challenges with the Pinl site, early inhibitors were primarily based on peptides.
Although these molecules haven't been useful as probes in cells or animals, they have illustrated the features of the active site. In one approach, a combinatorial library of 5-mer N-acetylated peptides incorporating unnatural amino acids surrounding a phosphothreonine residue was screened against the PPIase domain of Pinl . The strongest hit contained a pipecolate core not unlike those found to strongly inhibit FKBPs that is central to the binding region of FK506 and rapamycin. Optimization of the peptide resulted in "pintide" (Ac-Phe-D-Thr(P03H2)-Pip-Nal-Gln-NH2; FIG. 3), which had a
Ki≈ 18 nM. Addition of the WW domain in the full-length protein did not alter binding preference
[19]. Crystallization of the L- and D-peptide versions of pintide yielded surprising results, with nearly identical conformations of the stereoisomers. In both structures, the electronegative phosphate group was anchored into the phosphate recognition pocket, contacting Lys-63 and Arg-69. The pipecolate core rested in the proline-binding pocket, making hydrophobic contacts with Leu-122,
Met-130 and Phe-134. The naphthylalanine side chain extends up and stacks on a hydrophobic shelf formed by Leu-122 and the top of the Met-130 side chain [20]. Based on these structures, the reasons for the large difference in binding affinity are not obvious. Strikingly, the Pinl active site occupied by these peptides adopted a conformation that is reminiscent of FKBP when bound to rapamycin, with both pipecolic rings in nearly identical orientations. However, rapamycin has no measureable affinity for Pinl so the affinity of the peptides for Pinl may originate through the phosphate-binding surface.
[0462] Early Design of Small Molecule Pinl Inhibitors. Guided by the Pinl crystal structure, FKBP ligands were modeled in the Pinl active site to design novel small molecules. The first compound was found to be a low micromolar inhibitor (Ki - 1.7 μΜ), which was promising for a de novo lead (FIG. 4) [21]. Attempts to optimize the charge by replacing the phosphate with a sulfate resulted in a significant drop in potency (9.5 μΜ). Re-installing the phosphate and appending a propylbenzene to the carbinol center improved potency to 0.8 μΜ and inhibited cell cycle progression of CA46 cells at 15 μΜ (4.4a). The pipecolyl ester found in FK506 and rapamycin was replaced with a phenylalaninol phosphate as the minimum binding epitope. A pilot chemical screen identified a bi-aryl amide scaffold, which inhibited Pin at 100 nM (FIG. 5). Derivatization and co- crystallization of (4.5a) revealed a new binding pose, with the compound rotated to allow the phenyl group to dock into the hydrophobic proline pocket and placing the benzothiophene on the hydrophobic shelf formed by Leu-122 and Met-130. The phosphate group was rotated slightly and bound in-between Arg-68 and Arg-69, losing the interaction with Lys-63 as in the previous phosphopeptide inhibitors. This suggests that there is some flexibility in orienting the phosphate group in these compounds, with the positive charge being spread throughout a large region of the active site. Carboxylate-based scaffold was the subject of a limited SAR series [22]. In addition to modifications of the phenyl ring system, phosphate bioisosteres, such as tetrazoles,
acylaminothiazols and acylsulfonamides, were tried in replacement of the carboxylic acid. The tetrazole retained the same activity as the carboxylate. It was hypothesized that export by
P-glycoprotein efflux pumps may be responsible for the limited activity of this series. The amidyl carboxylate moiety in particular was implicated in recognition by P-glycoprotein, and it was concluded that further optimization of the scaffold was necessary to achieve improved cellular activity.
[0463] In an alternate approach, engagement of peripheral residues flanking the cationic phosphate-binding region was shown to be effective in the development of Pinl inhibitors (FIG. 7). An initial fragment-based screen was performed to inhibit Pinl isomerase activity on a model substrate and confirmed in a follow-up NMR platform [23]. Optimization of the primary hit (4.7a) resulted in a phenyl-imidazole fragment substituted at the 3-position (4.7b; FIG. 7), a site shown previously to be effective in engaging the proline pocket. Subsequent modification of the central imidazole ring resulted in a series of amide substituted 3-chloro-phenyl-imidazole inhibitors with modest affinity for Pinl (4.7c, IC50 ~ 2.0 μΜ) that were cell penetrant and able to inhibit cell division and Pinl-mediated cyclin Dl expression at micromolar levels. Furthermore, these compounds had a unique binding mode in Pinl, flanking Lys-63, Arg-68 and Arg-69 in the phosphate recognition pocket. It is worth noting that these fragments do not engage the hydrophobic shelf, as seen with other potent Pinl inhibitors (4.5a, 4.5b).
[0464] Together, these small molecules are the first Pinl inhibitors that possess cellular activity.. Critical to the design of these small molecules, they all engage the cationic phosphate-binding site. Additional affinity is gained from either interacting with the hydrophobic shelf or residues adjacent to the phosphate binding site.
[0465] Remodeling FK506 and Rapamycin for Anti-Pinl Activity. Without wishing to be bound by theory, it is believed that FK506 effectively drives the partitioning of HIV protease inhibitors into relevant cells. We wondered if a similar strategy may overcome the major problems that have plagued discovery of Pinl inhibitors. As discussed above, early investigation into Pinl inhibitors involved modifying the core scaffold of FKBP ligands based on the pipecolate core, which resulted in a series of compounds with good affinity. We wondered if the favorable properties of FK506 could be leveraged to drive the permeability of analogs containing electronegative groups.
[0466] To design an initial model, we created an overlay of the Pinl active site with bound FK506 and compared it to the known co-crystal structures of Pinl with inhibitors containing a pipecolate core. Analysis of these structures suggested that FK506 analogs might bind to Pinl if the cationic groove could be sufficiently occupied (FIGS. 8A-8B). Likewise, modified analogs of rapamycin were predicted to have a similar interaction.
[0467] Analyzing the structure of both FK506 and Rapamycin highlighted the tertiary hydroxyl as being a potential point for modification. During our initial investigations into the feasibility of engineering Pinl-specific FK506/rapamycin derivatives, we rediscovered an obscure report on modifying the natural products at this position [24]. Specifically, the authors showed that treatment of either of these macrocycles with methanolic ammonia converts the tertiary hydroxyl into a primary amine by an undetermined mechanism (FIG. 9). We predicted that the primary amine substitution at this position would create an orthogonally reactive handle for further derivatization. However, we first wanted to systematically explore the chemistry of this reaction, as it had remained underexplored.
[0468] Results
[0469] Semisynthetic Modification of FK506 and Rapamycin. Using the previously reported conditions, FK506 was treated with methanolic ammonia (2M) and monitored by HPLC (FIG. 10). Within 30 minutes, we saw conversion of FK506 into a more polar product (13, herein FK- H2), which we attributed to the primary amine. At the same time, we noticed that the unreacted FK506 peak appeared to develop a slightly more polar shoulder and that a small number of minor side products were produced. It had previously been suggested that treatment of FK506 with ammonia could also result in formation of the imine at the adjacent carbonyl, so we hypothesize that the "shoulder" might be the less polar imine. However, we have not been able to isolate enough of this compound for an in-depth characterization by NMR and MS. Similarly, we reasoned that the excess ammonia could be modifying FK506 with both the amine and imine, which would explain the other trace product slightly more polar than the FK-NH2 peak. With these caveats, we quantified the HPLC traces to determine the amount of product formation and fit the data to a first order exponential (FIG. 11). We observed approximately 60% product formation.
[0470] Next, we characterized the presumed FK-NH2 product by MS and NMR. The molecular mass was observed by MS (FIG. 12. M+H+: 803.63, expected: 803.50). This represents a slight decrease in mass (~ 1 amu) compared to FK506. However, the imine would also exhibit the same mass loss, so we turned to NMR. Due to the complexity of the compound and the large number of hydrogens (70 in FK-NH2), we opted for 13C NMR. Guided by previous peak assignments, we observed that the C1 O peak was significantly shifted (FIG. 13) [25]. Rather, this carbon was shifted upfield, consistent with attachment of an amine. Interestingly, we observed a slight double peak in the shifted spectrum, possibly due to tautomerization of FK506 in this region of the molecule. We are currently pursuing small molecule X-ray crystallography to further confirm the structure and its absolute stereochemistry as we continue the conversion of FK-NH2 to desired products. [0471] Solvent Screen of the FK506 Substitution Reaction. First, we attempted to optimize the concentration of ammonia to improve yield and minimize residual starting material in subsequent reactions. This led to a characteristic change in the observed peak shapes that progressed as concentration was increased (FIG. 14). At 1M ammonia, little reaction was observed that consisted of primarily unreacted FK506 and only a small amount of the FK- H2 product forming (box 1). The 2M reaction progressed as normal, with increased formation of FK- H2 (box 1) and appearance of the imine "shoulder" (box 3) that overlapped with the FK506 peak. Higher concentration 3.5M ammonia largely converted FK506 (box 4) with a mixture of FK-NH2 (box 1) and a previously not seen side product (box 2). Likewise, 7M ammonia produced only the new peak (box 2), with no FK- H2 formation occurring.
[0472] Using the 2M ammonia conditions, we proceeded to optimize solvent conditions. For these experiments, we chose a series of solvents to represent a range of properties from polar (DMPU) to nonpolar (DCM), as well as protic (methanol) to aprotic (DMPU, dioxane, DCM) solvents. Notably, to this point we were performing the reactions by first diluting a stock 7M ammonia in methanol solution, which is commercially available, to a final concentration of 2M. For the solvent screens we used the same strategy, which resulted in a solvent mixture consisting of the co-solvent plus residual methanol as a by-product of the dilution. None of the solvent mixtures supported conversion to FK-NH2, even at longer reaction times (FIG. 15). This result suggested that solvent effects were critical to the reaction. Because of the reasonable effectiveness of methanol, we next focused on an additional series of alcohols. All of the alcohols supported conversion to FK-NH2, with ethanol being slightly preferred (FIG. 15). Performing the reaction in trifluoroethanol did not lead to significant conversion, which we hypothesized could be due to the lower pKa of the free hydroxyl compared to ethanol (12.5 versus 15.9, respectively). Consistent for the role of the hydroxyl pKa, the reaction progressed slightly faster in methan(ol-d). From these optimization studies, we selected ethanol with 2M ammonia (75% yield) for subsequent experiments.
[0473] Investigating the Reactivity of amino-FK506 and amino-Rapamycin. Our first attempts at derivatization of FK-NH2 involved a simple alkylation of the amine using 3-chlorobenzyl bromide (product 15; FIG. 17). The yield was low, with optimization of the reaction resulting in
approximately 10% product formation. In part, we chose to begin with the 3-chlorobenzyl bromide reagent By 1H NMR the 3-chlorobenzene ring was easily visible, as neither FK506 nor FK-NH2 have any aromatic protons, and the chlorine isotopic signature was observed by MS. This confirmed that the desired product was formed.
[0474] To test the scope of the reaction, we performed alkylations with benzyl (compounds 16 and 17), alkyl (compounds 21 and 22) and carboxyl-containing groups (compounds 18-20; Table 4.1).
Table 1. Alkylations and conditions of FK-NH2.
The pyranose fragment is shown where modification occurs. Yield is approximate as determined by product appearance in MS compared to residual starting material.
Figure imgf000131_0001
[0475] Based on these results, we explored amide formation as an alternative (compounds 23-26; Table 2). Some conversion was observed with the p-nitrophenol ester.
Table 2. Amide formations and conditions of FK-NH2.
The pyranose fragment is shown where modification occurs. Yield is approximate as determined by product appearance in MS compared to residual starting material.
Figure imgf000132_0001
[0476] Thus, we moved to progressively more reactive amide coupling conditions (Table 3). In neat acetic anhydride FK- H2 proceeded to the desired product (27) in quantitative yield. Initial attempts with succinic anhydride (28) were frustrated by addition of multiple succinates, but optimization of reaction conditions allowed for reduction in the number of equivalents that afforded the desired compound. Similar profiles were observed with anhydride reactions yielding 29 and 31. The one outlier was observed with trifluoroacetic anhydride (30). We are actively pursuing 31, as installation of a reactive electrophile would be an additional strategy to append a variety of substituents to the molecule to create potential Pinl inhibitors. A small series of acid chlorides are being explored as an alternate to the anhydrides. The reaction to produce 34 was chosen in an attempt to synthesize the sulfamic acid as a direct phosphate bioisostere and proceeded in low to modest yield (-25%). Further attempts to characterize this compound are underway.
Figure imgf000133_0001
Figure imgf000134_0001
[0477] In summary, a series of FK- H2 derivatives have been prepared in modest yields.
Reactions in nonpolar conditions seem to be heavily favored and the anhydrides were significantly more reactive than other approaches. This synthetic route provides an entry into FK506 analogs designed to bind Pinl .
[0478] Binding of FK506 Derivatives to FKBP12 and Pinl by Fluorescence Polarization. To test binding to Pinl, we chose to employ a fluorescence polarization assay. This assay was based on our FP approach to measurement of binding to FKBP12. We found that a fluorescein-tagged substrate (WFYpSPFLE) bound with tight affinity to wild-type Pinl (KD = 10.1 ± 4.1 nM, FIG. 18A), which was in good agreement with the known phosphopeptide substrates. Binding to the PPIase domain was considerably weaker (KD = 427 ± 98), as the WW domain is known to contribute to binding. Purified compounds were titrated in a competition format against static tracer and Pinl protein. One compound appeared to be active in this format, the sulfamic acid 34, which possessed sub- micromolar activity for the wild-type construct (KiWT = 93 InM, KiPPIase = 4350nM, FIG. 18B). This was promising, as this compound would be most likely to engage the Pinl cationic groove via electrostatic interactions with the charged sulfonate moiety.
[0479] Next, we tested the effects of our modification on FKBP12 binding. Based on the known FK506 binding interaction, we would expect many of these derivatives to have significantly impaired affinity for FKBP12. To test this, we used an FKBP12 binding assay to measure Ki values for the new FK506 analogs (FIG. 19). We found that small alkyl substitutions, such as in 19, were reasonably well tolerated. Larger functional groups (such as in compounds 15 and 24) resulted in a significant drop in affinity, as expected. Lastly, the sulfamic acid substitution in 34 had nearly a 500- fold loss of potency. This result is encouraging as it shows that Pinl binding can be favored at the expense of FKBP12 binding.
[0480] The work disclosed herein is inspired by the natural mechanisms of FK506 and rapamycin.
Despite their high molecular mass and chemical complexity, they possess excellent pharmacological properties, specifically membrane permeability. Early studies on bifunctional molecules took advantage of this trait, and our investigation into this mechanism found that appending a PPIase ligand to HIV protease inhibitors could significantly improve its cellular partitioning. The early small molecules of Pinl were based on the pipecolate scaffold found in FK506 and rapamycin, suggesting that the core recognition motif might be conserved. In addition, it was found that the bound conformation of pipecolate-containing Pinl inhibitors is highly reminiscent of FK506 bound to FKBP12. Despite these similarities, FK506 has no measurable affinity for Pinl, likely because it lacks the electronegative functional group that is unique to Pinl binding. We decided to pursue the semisynthetic modification of FK506 to impart Pinl binding. We found that FK506 could be converted to FK-NH2 at a region that is predicted to be in close proximity to the phosphate-binding region of the Pinl active site. Indeed, compound 34 had affinity for Pinl in vitro with FKBP12 binding considerably reduced.
[0481] One of the goals of this study was to optimize the route for creation of FK- H2. We found that the concentration of ammonia was critical; 1M ammonia resulted in the reaction stalling without significant conversion, while concentrations above 2M caused undesirable side-product formation. Dramatic solvent effects were also observed, with suitable conversion only occurring in alcohols. We found that FK-NH2 would revert to FK506 during purification, so we moved to a one-pot strategy for subsequent derivatization. It was immediately apparent that the installed amine of FK- H2 had limited reactivity, because direct alkylation with alkyl halides or amide coupling with activated carboxylic acids or acyl chlorides was only moderately effective. However, we found that anhydrides allowed robust product formation in excellent yields (-100% in most cases). These systematic studies are expected to facilitate the creation of a larger collection of potential Pinl inhibitors, with the next series of FK- H2 derivatives bearing substituents designed for Pinl binding.
[0482] In collaboration, we are pursuing crystal structures of the free molecules as well as co- crystallized with Pinl . Pinl has been well validated as a target in a variety of cell lines, including its impact on cell viability in numerous human cancers, so we propose to use these established models to test the cellular activity of the molecules.
[0483] Methods [0484] Plasmid Generation and Protein Purification. Wild-type Pinl was obtained in the pMCSG7 vector for bacterial expression and purification. The PPIase domain (45-163) of Pinl was cloned into the pMCSG7 vector using ligation independent cloning (Fwd:
5'-TAC TTC CAA TCC AAT GCA AAA AAC GGG CAG G-3' (SEQ ID NO: 1), Rev: 5'-TTA TCC ACT TCC AAT GTT ACT CAG TGC GGA GGA TGA-3 ' (SEQ ID NO:2)) for bacterial expression and purification.
[0485] The Pinl constructs were transformed into E. coli BL21 cells and grown in Terrific Broth for six hours at 37 °C, followed by induction with 1 mM IPTG at 20 °C for 12 hours. Cells were collected, lysed by sonication (25 mM Tris, 500 mM NaCl, 10 mM imidazole, 10% glycerol, pH 8.0) and was bound on Ni-NTA resin. Resin was washed once with wash buffer 1 (25 mM Tris, 500 mM NaCl, 30 mM imidazole, 3% ethanol, 10% glycerol, pH 8.0), once with wash buffer 2 (25mM Tris, lOOmM NaCl, 30mM imidazole, 3% ethanol, 10% glycerol, pH 8.0), once with wash buffer 3 (25mM Tris, 300mM NaCl, 30mM imidazole, 10% glycerol, pH 8.0) and eluted (25 mM Tris, 300 mM NaCl, 300 mM Imidazole, 10% glycerol, pH 8.0). Eluted protein was dialyzed overnight (lOmM HEPES, lOOmM NaCl, 5% glycerol, pH 7.5) and purified by Size Exclusion
Chromatography using a SD75 column with the dialysis buffer.
[0486] Pinl Fluorescence Polarization Assay. Binding to Pinl was measured by fluorescence polarization. The assay was performed at 60 μΐ^ final volume in MOPS (pH 7.5) with 0.01% Triton X-100 using Corning 384-well flat-bottom black plates. For initial binding analysis of the fluorescent compound, recombinant Pinl was serially diluted 3 -fold from 80 μΜ initial
concentration and then 30 μΐ^ added to each well for a top concentration of 40 μΜ. Fluorescent phosphopeptide WFYpSPFLE was initially dissolved in DMSO at 100 μΜ then dissolved into assay buffer and 30 μΙ_, of this solution was added to each well to give a final concentration of 75 nM. The plate was covered and equilibrated at room temperature for 30 minutes then read on a SpectraMax M5 at wavelength 488/515 ex/em.
[0487] Competition experiments were performed under similar conditions. Separate solutions of Pinl and fluorescent peptide were prepared and then 15 μΐ^ of each were added to each well. The final concentrations used in the assay were 50nM and ΙΟΟΟηΜ for wild-type Pinl and the Pinl PPIase domain, respectively. Compounds were initially dissolved in DMSO to 10 mM, serially diluted 2-fold, then diluted to 400 μΜ with assay buffer and 30 μΙ_, was added to each well to a final top concentration of 200 μΜ and 2% DMSO. The assay was equilibrated at room temperature for 30 minutes and then read as before.
[0488] Synthetic Methods.
[0489] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexyljprop-l -en-2-ylJ -1 -amino-23, 25-dimethoxy-l 4-hydroxy-l 3, 19,21,27-tetramethyl- 17-(prop-2-en-l-yl)-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2, 3, 10,16-tetrone (13)
[0490] To a solution of FK506 (1) (25mg, 0.03 lmmol, leq) in 2.5mL ethanol was added lmL 7M ammonia in methanol to a final concentration of 2M (excess). The reaction was allowed to stir for 3 hours before solvent and ammonia were removed by evaporation. The crude product was dried under high vacuum for 30 minutes to afford 13 as an oily, translucent solid (75% yield). Expected MW: 802.50, Found M+H+: 803.63.
[0491] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S,24R,25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexyl]prop-l-en-2-yl]-l-((3-chlorobenzyl)amino)-23, 25-dimethoxy-l 4-hydroxy- 13, 19,21,27-tetramethyl-17-(prop-2-en-l-yl)-l l,28-dioxa-4-azatricyclo[22.3.1.0(4,9)Joctacos-18- ene-2, 3,10, 16-tetrone (15)
[0492] To a solution of (13) (12.5mg, 0.016mmol, leq) in 2mL DCM was added DMAP (0.6mg, 0.005mmol, 0.3eq) and allowed to stir under N2. 3-chlorobenzyl bromide (9.9mg, 0.048mmol, 3eq) was added dropwise followed by the addition of DIEA (12.4mg, 0.096mmol, 6eq). After 24 hours, the solvent was removed by evaporation and the crude product dissolved in lmL methanol and purified by HPLC (25% yield). Expected MW: 926.51, Found M+ACN+: 968.93.
[0493] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexylJprop-l-en-2-yl] '-l-benzylamino-23, 25-dimethoxy-l 4-hydroxy-l 3, 19,21,27- tetramethyl-17-(prop-2-en-l-yl)-l 1, 28-dioxa-4-azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16- tetrone (16)
[0494] To a solution of (13) (20mg, 0.025mmol, leq) in 2mL DMF was added DMAP (l .Omg, 0.008mmol, 0.3eq) and allowed to stir under N2. Benzyl bromide (42.8mg, 0.25mmol, lOeq) was added dropwise followed by the addition of DIEA (64.8mg, 0.5mmol, 20eq). The reaction temperature was raised to 50°C. After 24 hours, the crude product was purified by HPLC (10% yield). Expected MW: 892.54, Found M+H+: 893.62.
[0495] (IR, 9S, 12S, BR, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexylJprop-l-en-2-ylJ-l-((2-(tert-butoxy)-2-oxoethyl)amino)-23,25-dim
hydroxy-13, 19,21, 27-tetramethyl-l 7-(prop-2-en-l-yl)-l 1, 28-dioxa-4- azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16-tetrone (18)
[0496] To a solution of (13) (25mg, 0.031mmol, leq) in 2mL DCM was added DMAP (1.2mg, O.OlOmmol, 0.3eq) and allowed to stir under N2. Tert-Butyl bromoacetate (18.1mg, 0.093mmol, 3eq) was added dropwise followed by the addition of DIEA (24.1mg, 0.186mmol, 6eq). After 24 hours, the solvent was removed by evaporation and the crude product dissolved in ImL methanol and purified by HPLC (25% yield). Expected MW: 916.57, Found M+ACN+: 959.01.
[0497] (IR, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexyljprop-l -en-2-ylJ -1 -((carboxymethyl)amino)-23, 25-dimethoxy-14-hydroxy- 13, 19, 21,27-tetramethyl-l 7 -(prop-2 -en- l-yl)-l 1, 28-dioxa-4-azatricyclo [22.3.1.0(4,9)] octacos-18- ene-2, 3,10, 16-tetrone (19)
[0498] The protected derivative (18) (5mg, 0.005mmol, leq) was dissolved in a solution of DCM:TFA:TIPS:H20 (45:45:5:5) and stirred for 30 minutes. TIPS was included as a cation scavenger. Solvent was evaporated and the crude product was purified by HPLC (5% yield).
Expected MW: 860.50, Found M+H+: 861.04.
[0499] (IR, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexyl]prop-l-en-2-yl]-23,25-dimethoxy-l-ethylamino-14-hydroxy-13, 19,21,27- tetramethyl-17-(prop-2-en-l-yl)-l 1, 28-dioxa-4-azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16- tetrone (22)
[0500] To a solution of (13) (25mg, 0.031mmol, leq) in 2mL DMF was added DMAP (1.2mg, O.OlOmmol, 0.3eq) and allowed to stir under N2. Ethyl p-toluenesulfonate (124.2mg, 0.62mmol, 20eq) was added dropwise followed by the addition of DIEA (160.6mg, 1.24mmol, 40eq). The reaction temperature was raised to 50°C. After 24 hours, the crude product was purified by HPLC (5% yield). Expected MW: 830.53, Found M+Na+: 853.58. [0501] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S,24R,25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexyl]prop-l-en-2-yl]-l-(2-bromoacetamido)-23,25-dimethoxy-14-hydrox
13, 19,21,27-tetramethyl-17-(prop-2-en-l-yl)-l l,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18- ene-2, 3, 10, 16-tetrone (24)
[0502] To a solution of (13) (12.5mg, 0.016mmol, leq) in 2mL DMF was added DMAP (0.6mg, 0.005mmol, 0.3eq) and allowed to stir under N2. 4-Nitrophenyl bromoacetate (4.2mg, 0.016mmol, leq) was added dropwise followed by the addition of DIEA (6.2mg, 0.048mmol, 3eq). The reaction temperature was raised to 50°C. After 24 hours, the crude product was purified by HPLC (5% yield). Expected MW: 924.42, Found M+ACN+: 966.99.
[0503] (1R, 9S, J2S, J3R, J4S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexylJprop-l-en-2-yl] '-l-acetamido-23,25-dimethoxy-14-hydroxy-l 3, 19,21,27- tetramethyl-17-(prop-2-en-l-yl)-l 1, 28-dioxa-4-azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16- tetrone (27)
[0504] To (13) (12.5mg, 0.016mmol, leq) was added ImL neat acetic anhydride and stirred under N2. After 3 hours, the reaction was diluted with toluene and solvent was evaporated. This was repeated in total 3 times to remove as much unreacted acetic anhydride as possible. The crude product was dissolved in methanol and purified by HPLC (42% yield). Expected MW: 844.51, Found M+Na+: 867.58.
[0505] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R)-12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy-3- methoxycyclohexylJprop-l-en-2-ylJ-l-benzamido-23,25-dimethoxy-14-hydroxy-13,19,21,27- tetramethyl-17-(prop-2-en-l-yl)-l 1, 28-dioxa-4-azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16- tetrone (29)
[0506] To a solution of (13) (12.5mg, 0.016mmol, leq) in 2mL DCM was added DMAP (0.6mg, 0.005mmol, 0.3eq) and allowed to stir under N2. Benzoic anhydride (18. lmg, 0.08mmol, 5eq) was added dropwise followed by the addition of DIEA (20.7mg, 0.16mmol, lOeq). After 24 hours, the solvent was removed, crude product was dissolved in ImL methanol and purified by HPLC (10% yield). Expected MW: 924.42, Found M+ACN+: 966.99.
[0507] (1R, 9S, 12S, 13R, 14S, 17R, 18E, 2 IS, 23S, 24R, 25S, 27R) -12-[(1E)-1-[(1R, 3R, 4R)-4-hydroxy- 3-methoxycyclohexyl]prop-l-en-2-yl]-23,25-dimethoxy-14-hydroxy-l-sulfoamino-13,19,21,27- tetramethyl-17-(prop-2-en-l-yl)-l 1, 28-dioxa-4-azatricyclo[22.3.1.0(4,9) ]octacos-18-ene-2, 3,10, 16- tetrone (34)
[0508] To a solution of (13) (12.5mg, 0.016mmol, leq) in 2mL DCM was added DMAP (0.6mg, 0.005mmol, 0.3eq) and allowed to stir under N2. Chlorosulfonic acid (2.8mg, 0.024mmol, 1.5eq) was added dropwise followed by the addition of DIEA (20.7mg, 0.16mmol, lOeq). After 24 hours, the reaction had gone cloudy and solvent was removed. The crude product was dissolved in lmL methanol and purified by HPLC (25% yield). Expected MW: 882.45, Found M-H+: 881.87.
[0509] References
[0510] [1]. Lu, K.P., Hanes, S.D. & Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544-7 (1996); [2]. Ranganathan, R., Lu, K.P., Hunter, T. & Noel, J. P. Structural and functional analysis of the mitotic rotamase Pinl suggests substrate recognition is phosphorylation dependent. Cell 89, 875-86 (1997); [3]. Barman, A. & Hamelberg, D. Cysteine- mediated dynamic hydrogen-bonding network in the active site of Pinl . Biochemistry 53, 3839-50 (2014); [4]. Hanes, S.D., Shank, P.R. & Bostian, K.A. Sequence and mutational analysis of ESSl, a gene essential for growth in Saccharomyces cerevisiae. Yeast 5, 55-72 (1989); [5]. Schutkowski, M. et al. Role of phosphorylation in determining the backbone dynamics of the serine/threonine-proline motif and Pinl substrate recognition. Biochemistry 37, 5566-75 (1998); [6]. Blister, M.A., Pandey, A.K., Bielska, A.A. & Zondlo, N.J. OGlcNAcylation and phosphorylation have opposing structural effects in tau: phosphothreonine induces particular conformational order. J Am Chem Soc 136, 3803-16 (2014); [7]. Ryo, A., Liou, Y.C., Lu, K.P. & Wulf, G. Prolyl isomerase Pinl : a catalyst for oncogenesis and a potential therapeutic target in cancer. J Cell Sci 116, 773-83 (2003); [8]. Bao, L. et al. Prevalent overexpression of prolyl isomerase Pinl in human cancers. Am J Pathol 164, 1727- 37 (2004); [9]. Liou, Y.C. et al. Role of the prolyl isomerase Pinl in protecting against age- dependent neurodegeneration. Nature 424, 556-61 (2003); [10]. Lu, P.J., Wulf, G., Zhou, X.Z., Davies, P. & Lu, K.P. The prolyl isomerase Pinl restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784-8 (1999); [11]. Butterfield, D A. et al. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiol Dis 22, 223-32 (2006);
[12]. Ibanez, K., Boullosa, C, Tabares-Seisdedos, R., Baudot, A. & Valencia, A. Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses. PLoS Genet 10, el 004173 (2014); [13]. Lim, J. et al. Pinl has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 118, 1877-89 (2008); [14]. Moore, J.D. & Potter, A. Pinl inhibitors: Pitfalls, progress and cellular pharmacology. Bioorg Med Chem Lett 23, 4283-91 (2013); [15]. Hennig, L. et al. Selective inactivation of parvulin- like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry 37, 5953-60 (1998); [16]. Uchida, T. et al. Pinl and Parl4 peptidyl prolyl isomerase inhibitors block cell proliferation. Chem Biol 10, 15-24 (2003); [17]. Graber, M. et al. Selective targeting of disease-relevant protein binding domains by O-phosphoiylated natural product derivatives. ACS Chem Biol 6, 1008-14 (2011); [18]. Wei, S. et al. Active Pinl is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21, 457-66 (2015); [19]. Wildemann, D. et al. Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pinl from combinatorial peptide libraries. J Med Chem 49, 2147-50 (2006); [20]. Zhang, Y. et al. Structural basis for high-affinity peptide inhibition of human Pinl . ACS Chem Biol 2, 320-8 (2007); [21]. Guo, C. et al. Structure-based design of novel human Pinl inhibitors (I). Bioorg Med Chem Lett 19, 5613-6 (2009); [22]. Dong, L. et al. Structure-based design of novel human Pinl inhibitors (II). Bioorg Med Chem Lett 20, 2210-4 (2010); [23]. Potter, A. et al. Discovery of cell-active phenyl-imidazole Pinl inhibitors by structure-guided fragment evolution. Bioorg Med Chem Lett 20, 6483-8 (2010); [24]. Nussbaumer, P., Grassberger, M. & Schulz, G. C9- imino and ClO-amino derivatives of ascomycin (21-ethyl-FK 506). Tetrahedron Letters 33, 3845- 3846 (1992); [25]. Ham, Y.-B. & Koo, Y.-M. Identification of an 18-Methyl Derivative of
Tacrolimus API in Streptomyces clavuligerus CKD-1119. Bulletin of the Korean Chemical Society 32, 109-112 (2011).
[0511] Example 2 - Modification of FK506/Rapamycin Natural Products.
[0512] Synthetic schemes for FK-NH2 (13) and compound (14) follow:
Figure imgf000142_0001
[0513] Example 3— General Synthetic Scheme.
[0514] A general synthetic scheme for compounds FK-NH2 (13) and (15) follows:
Figure imgf000142_0002
FK506 (1 ) FK-NH2 (13) (15) [0515] Example 4 - Representative Synthetic Scheme
[0516] A representative synthetic scheme for compounds disclosed herein follows.
Figure imgf000143_0001
[0517] 1) To a solution of FK506/rapamycin (25mg, 0.031 mmol, leq) is added ethanol (2.14 mL) and 7M ammonia in methanol 0.857 to a final concentration of 2M ammonia. The solution is stirred for 3hrs and the solvent is removed by evaporation.
[0518] 2) Generally, the crude product from (1) (25mg, 0.03 lmmol, leq) was carried forward and dissolved in 3mL dichloromethane followed by addition of dimethylaminopyridine (0.4mg, 0.003mmol, O. leq) and diisopropylethylamine (12mg, 0.093mmol, 3eq). The reactant (a, b, c, or d) was added and the reaction was stirred overnight. After completion, solvent was evaporated and the product was purified by HPLC. Legend: a) Chlorosulfonic acid; b) Acetic anhydride; c) Succinic anhydride; d) Any suitable anhydride, acyl halide, alkyl halide, alkyl tosylate, alkyl triflate [0519] References.
[0520] [1]. Skytte, D.M., Frydenvang, K., Hansen, L., Nielsen, P.G. & Jaroszewski, J.W.
Synthesis and characterization of an epimer of tacrolimus, an immunosuppressive drug. Journal of natural products 73, 776-779 (2010); [2]. Marinec, P.S., et al. Synthesis of orthogonally reactive FK506 derivatives via olefin cross metathesis. Bioorganic & medicinal chemistry 17, 5763-5768 (2009); [3]. Guo, Z.-F., Zhang, R. & Liang, F.-S. Facile functionalization of FK506 for biological studies by the thiol-ene 'click' reaction. RSC Advances 4, 11400-11403 (2014); [4]. Bayle, J.H., et al. Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chemistry & biology 13, 99-107 (2006); [5]. Ruan, B., et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proceedings of the National Academy of Sciences of the United States of America 105, 33-38 (2008); [6]. Sedrani, R., Thai, B., France, J. & Cottens, S. Dihydroxylation of the Triene Subunit of Rapamycin. The Journal of Organic Chemistry 63, 10069-10073 (1998); [7]. Karanam, B.V., et al. Disposition of L-732,531, a potent immunosuppressant, in rats and baboons. Drug metabolism and disposition: the biological fate of chemicals 26, 949-957 (1998); [8]. Zimmer, R., et al. Synthetic Modifications of Ascomycin. V.* Access to Novel Ascomycin Derivatives by Replacement of the Cyclohexylvinylidene Subunit. Croat. Chem. Acta 78, 17-27 (2005); [9]. Gupta, A.K. & Chow, M. Pimecrolimus: a review. Journal of the European Academy of Dermatology and Venereology : JEADV 17, 493-503 (2003); [10]. Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nature reviews. Drug discovery 5, 671-688 (2006); [11]. Sedrani, R., Cottens, S., Kallen, J. & Schuler, W. Chemical modification of rapamycin: the discovery of SDZ RAD. Transplantation proceedings 30, 2192-2194 (1998); [12]. Rivera, V.M., et al. Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Molecular cancer therapeutics 10, 1059-1071 (2011).
[0521] Example 5 - Binding of a Modified FK506 Derivative to Pinl.
[0522] FK-NH2 substituted with chlorosulfonic acid to generate a sulfamic containing derivative (reaction 2a of Example above) binds to the peptidyl-prolyl isomerase Pinl . Pinl binds to a fluorescent peptide which is then competed away by compound 2a. See FIG.18B. Unmodified FK506 has no affinity for Pinl and is not capable of inhibiting the binding interaction with the fluorescent peptide. Compound 2a is capable of competing the fluorescent peptide away from the wild type protein as well as just the isolated peptidyl-prolyl isomerase domain.
[0523] For wild type shown in FIG. 18B, IC50 and Span are 7.065 and 104.0, respectively. For PPIase domain, IC50 and Span are 15.25 and 47.49, respectively.
[0524] Example 6— Binding of a Modified FK506 Derivative to FKBP12.
[0525] The parent compound, FK506 binds to its native target FKBP12 with high affinity.
Modification of FK506 to FK-NH2, followed by substitution with chlorosulfonic acid to generate a sulfamic containing derivative (reaction 2a above) has significantly weaker binding to FKBP12. See FIG. 21. Similar to the Pinl binding assay, the peptidyl-prolyl isomerase FKBP12 binds to a fluorescent ligand which is then competed away by FK506 and only weakly competed by the modified compound 2a. This suggests that compound 2a may be selective for Pinl over the original target, FKBP12.
EMBODIMENTS
Embodiment 1. A peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
(Pin 1) inhibitor compound, or a pharmaceutically acceptable salt thereof, comprising a macrolide with a pipecolyl moiety.
Embodiment 2. The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, covalently bound to a nitrogen-containing functional group at the C-10 position.
Embodiment 3. The compound of embodiment 2, wherein the nitrogen- containing functional group is an amino group.
Embodiment 4. The compound of embodiment 2, wherein the nitrogen- containing functional group is a primary amino group.
Embodiment 5. The compound of embodiment 2, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an
electronegative group.
Embodiment 6. The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
Embodiment 7. The compound of embodiment 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
Embodiment 8. The compound of embodiment 7, wherein the linker is covalently bound to an electronegative group.
Embodiment 9. The compound of embodiment 5, 6 or 8, wherein the electronegative group is a phosphate isostere. Embodiment 10. The compound of embodiment 5, 6, 8 or 9, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 11. The compound of any one of embodiments 1-10, wherein the FK-506 compound is an ascomycin derivative or variant.
Embodiment 12. The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
Embodiment 13. The compound of embodiment 12, wherein the nitrogen- containing functional group is an amino group.
Embodiment 14. The compound of embodiment 12, wherein the nitrogen- containing functional group is a primary amino group.
Embodiment 15. The compound of embodiment 12, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an electronegative group.
Embodiment 16. The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
Embodiment 17. The compound of embodiment 1, wherein the compound a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
Embodiment 18. The compound of embodiment 17, wherein the linker is covalently bound to an electronegative group. Embodiment 19. The compound of embodiment 15, 16 or 18, wherein the electronegative group is a phosphate isostere.
Embodiment 20. The compound of embodiment 15, 16, 18 or 19, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 21. An FK506 binding protein (FKBP) inhibitor compound, or a pharmaceutically acceptable salt thereof, comprising a macrolide with a pipecolyl moiety.
Embodiment 22. The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
Embodiment 23. The compound of embodiment 22, wherein the nitrogen- containing functional group is an amino group.
Embodiment 24. The compound of embodiment 22, wherein the nitrogen- containing functional group is a primary amino group.
Embodiment 25. The compound of embodiment 22, wherein the nitrogen- containing functional group is an electronegative group or is covalently bound to an
electronegative group.
Embodiment 26. The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
Embodiment 27. The compound of embodiment 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position. Embodiment 28. The compound of embodiment 27, wherein the linker is covalently bound to an electronegative group.
Embodiment 29. The compound of embodiment 25, 26 or 28, wherein the electronegative group is a phosphate isostere.
Embodiment 30. The compound of embodiment 25, 26, 28 or 29, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 31. A macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506 or a pharmaceutically acceptable salt thereof.
Embodiment 32. The compound of embodiment 31, wherein the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative or an ascomycin compound derivative.
Embodiment 33. The compound of embodiment 31, wherein the macrolide compound is capable of inhibiting a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) protein.
Embodiment 34. The compound of embodiment 31, wherein the macrolide compound is capable of inhibiting an FK506 binding protein.
Embodiment 35. The compound of any one of embodiments 31-34, wherein the electronegative group is a phosphate isostere.
Embodiment 36. The compound of any one of embodiments 31-34, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 37. A com ound of structural Formula (I):
Figure imgf000150_0001
(I), or a pharmaceutically acceptable salt thereof, wherein:
nl, n2 and n3 are independently an integer from 0 to 4;
ml, m2, m3, vl, v2 and v3 are independently 1 or 2;
L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(0)-, -C(0)0- -S(0)-, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R1 is hydrogen, halogen, -CX1 .1 -C3,HX1 *2, -CF^X1 -.C1,N, -SOniR1A, -SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C, -NHC(0)NHNR1BR1C, -NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D, -C(0)NR1BR1C, -0R1A, -NR1BS02R1A,
-NR1BC(0)R1D, -NR1BC(0)OR1D, -NR1BOR1D, -OCX1 -OC.H13X, 1 \ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2 .1 -C3,HX2.12, -CH2X2 -C.N1, , -S0ll2R2A,
-SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -OR2A, -NR2BS02R2A,
-NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2 -OC.H13X,2 sub.s1ti2t,uted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, halogen, -CX3,1 3, -CHX3.12, -CH2X3 -CN,.1 -, S0ll3R3A,
-SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A,
-NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 -OC.H13X,3 sub.s1ti2t,uted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
L1L, L2L, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C and R3D, are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1B and R1C, R2B and R2C, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X1 -1, X2 1 and X3 1 are independently -C1, -Br, -I or -F, wherein when L2 is -0-,
L1 is a bond, R1 is or -CH2CH3 and R3 is hydroxyl, then R2 is not hydrogen.
Embodiment 38. The compound of embodiment 37, wherein:
L2 is a bond; and
R2 is NH2.
Embodiment 39. The compound of embodiment 37, wherein L2 is -NR2L.
Embodiment 40. The compound of embodiment 37, wherein L2 is
-NR2LC(0)-, alkylene or heteroalkylene. Embodiment 41. The compound of any one of embodiments 39, 40 or 41, wherein R2 is a phosphate isostere.
Embodiment 42. The compound of any one of embodiments 39, 40 or 41, wherein R2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 43. The compound of any one of embodiments 37-42, wherein: L1 is a bond; and
R1 is (R)-ethyl.
Embodiment 44. The com ound of embodiment 37, wherein the compound
Figure imgf000152_0001
Embodiment 45. The compound of embodiment 37, wherein the compound is
Figure imgf000153_0001
((Ia)(R)) or ((Ib)(S)).
Embodiment 46. A compound of structural Formula (II):
(II), or a pharmaceutically acceptable salt thereof, wherein:
and are independently single bonds or double bonds;
n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4;
m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently
1 or 2;
L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(0)-, -C(0)0- -S(0)-, -S(0)2-, 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;
R4 is hydrogen, halogen, -CX4 .1 -C3,HX4.12, -CH2X4 -C.N1, , -SOn4R4A,
-SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A,
-NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 -OC.H13X,4 sub.s1ti2t,uted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R5 is hydrogen, halogen, -CX5,1 3, -CHX5.12, -CH2X5 -CN,.1 -, SOnsH,
-SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .13, -OCHX5.12, 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;
R6 is hydrogen, halogen, -CX6 1 3, -CHX6 -C.1H32,X6 -C.1N, , -SOn6H,
-SOv6NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m6, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6 .13, -OCHX6.12, 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;
R7 is hydrogen, halogen, -CX7,1 3, -CHX7.12, -CH2X7 -C.1N, , -SOnvH,
-SOvvNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mv, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13, -OCHX7.12, 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;
R8 is hydrogen, halogen, -CX8 1 3, -CHX8.12, -CH2X8 -C.1N, , -SOn8H,
-SOv8NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m8, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8 .13, -OCHX8.12, 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;
R9 is hydrogen, halogen, -CX9 .1 -C3,HX9.12, -CH2X9 -C.N1, , -SO^H,
-SOv9NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m9, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .13, -OCHX9.12, 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;
R10 is hydrogen, halogen, -CX10 1 3, -CHX10 -CH.1 22X,10 1, -CN, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX10 .13, -OCHX10 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R3L, R4A, R4B, R4C and R4D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X4 1, X5 1, X6 1, X7'1, X8 1, X9 1 and X10 1 are independently -C1, -Br, -I or -F, wherein when =^=, and are double bonds, L3 is -O- and R6, R7, R8, R9 and R10 are independently hydrogen, then R4 is not hydrogen.
Embodiment 47. The compound of embodiment 46, wherein L3 is -NR3L or a bond.
Embodiment 48. The compound of embodiment 46, wherein L3 is
-NR3LC(0)-, alkylene or heteroalkylene.
Embodiment 49. The compound of any one of embodiments 46, 47 or 48, wherein R4 is a phosphate isostere. Embodiment 50. The compound of any one of embodiments 46, 47 or 48, wherein R4 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
Embodiment 51. The compound of any one of embodiment 46, 47 or 48, wherein R4 is 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.
Embodiment 52. The compound of embodiment 46, wherein L3 is substituted or unsubstituted alkyl ene or substituted or unsubstituted heteroalkylene.
Embodiment 53. The compound of embodiment 46 or 52, wherein the R4 is substituted or unsubstituted aryl.
Embodiment 54. The compound of embodiment P46**?**, wherein the compound is
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Embodiment 56. A pharmaceutical composition, comprising a compound of any one of claims 1 to 55 and a pharmaceutically acceptable excipient.
Embodiment 57. A method of inhibiting Pin 1, comprising contacting Pin 1 with a compound of any one of embodiments 1-20, 31-33 or 35-55.
Embodiment 58. A method of inhibiting an FK506 binding protein (FKBP), comprising contacting the FKBP with a compound of any one of embodiments 20-32, 34-36 or 46-55.
Embodiment 59. The method of embodiment 58, wherein the FKBP is FKBP38, FKBP 51 or FKBP52.
Embodiment 60. The method of embodiment 58, wherein the FKBP is
FKBP 51.
Embodiment 61. A method of treating a Pin 1 -mediated disease or disorder, comprising administering to a patient in need thereof a compound of one of embodiments 1-20, 31-33 or 35-55
Embodiment P62. The method of embodiment 61, wherein the Pin 1 -mediated disease or disorder is cancer.
Embodiment 63. The method of embodiment 62, wherein the cancer is prostate cancer, brain cancer, breast cancer, ovarian cancer cervical cancer or skin cancer. Embodiment 64. The method of embodiment 62 or 63, further comprising administering to the subject a chemotherapeutic agent.
Embodiment 65. A method of treating an FKBP51 -mediated disease or disorder, comprising administering to a patient in need thereof a compound of any one of embodiments 20-32, 34-36 or 46-55.
Embodiment 66. The method of embodiment 65, wherein the disease or disorder is depression or mental illness.
Embodiment 67. The method of embodiment 66, wherein the disease or disorder is depression.
Embodiment 68. The method of embodiment 67, further comprising administering to the subject an anti-depressant.
Embodiment 69 . The method of embodiment 66, wherein the mental illness is schizophrenia.
Embodiment 70 . The method of embodiment 66, wherein the disease or disorder is pain.
Embodiment 71. The method of embodiment 70, wherein the pain is chronic pain or neuropathic pain.
Embodiment 72. A method of preparing a compound of structural Formula (I) of embodiment 37, comprising contacting a compound of structural Formula (Ic) with ammonia:
Figure imgf000160_0001
Embodiment 73. The method of embodiment 72, wherein the compound of
Formula (Ic) is
Figure imgf000160_0002
Embodiment 74. A method of preparing a compound of structural Formula (II) of embodiment 46, comprising contacting a compound of structural Formula (lie) with ammonia:
Figure imgf000160_0003
Embodiment 75. The method of embodiment 74, wherein the compound of Formula (lie) is
Figure imgf000161_0001
FURTHER EMBODIMENTS
N1. A peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) inhibitor compound, comprising a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
N2. The compound of embodiment Nl, wherein the compound is an FK506 derivative, comprising a substituted or unsubstituted amino at the C1 O position in place of the -OH present in FK506.
N3. The compound of embodiment N2, wherein the amino is unsubstituted.
N4. The compound of embodiment N2, wherein the amino is mono-substituted.
N5. The compound of embodiment N2, wherein the substituted or unsubstituted amino is an electronegative moiety.
N6. The compound of embodiment Nl, wherein the compound is an FK506 derivative comprising an electronegative moiety in place of the -OH of FK506 at the C-10 position.
N7. The compound of embodiment Nl, wherein the compound is an FK506 derivative comprising a substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in place of the -OH of FK506 at the C-10 position.
N8. The compound of embodiment N7, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with an electronegative moiety.
N9. The compound of embodiment N5, wherein the electronegative moiety is a phosphate isostere moiety.
N10. The compound of embodiment N5, wherein the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety. N11. The compound of embodiment N2, wherein the FK506 derivative is an ascomycin derivative.
N12. The compound of embodiment Nl, wherein the compound is a rapamycin derivative, comprising a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin.
N13. The compound of embodiment N12, wherein the amino is unsubstituted.
N14. The compound of embodiment N12, wherein the amino is mono-substituted.
N15. The compound of embodiment N12, wherein the substituted or unsubstituted amino is an electronegative moiety.
N76. The compound of embodiment Nl, wherein the compound is a rapamycin comprising an electronegative moiety in place of the -OH of rapamycin at the C-10 position.
N17. The compound of embodiment Nl, wherein the compound is a rapamycin derivative comprising a substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl in place of the -OH of rapamycin at the C-10 position
N18. The compound of embodiment N17, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with an electronegative moiety.
N19. The compound of embodiment N15, wherein the electronegative moiety is a phosphate isostere moiety.
N20. The compound of embodiment N15, wherein the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
N21. An FK506 binding protein (FKBP) inhibitor compound, comprising a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof. N22. The compound of embodiment N21, wherein the compound is a rapamycin derivative, comprising a substituted or unsubstituted amino at the C1 O position in place of the -OH present in rapamycin.
N23. The compound of embodiment N22, wherein the amino is unsubstituted.
N24. The compound of embodiment N22, wherein the amino is mono-substituted.
N25. The compound of embodiment N22, wherein the substituted or unsubstituted amino is an electronegative moiety.
N26. The compound of embodiment N21, wherein the compound is a rapamycin comprising an electronegative moiety in place of the -OH of rapamycin at the C-10 position.
N27. The compound of embodiment N21, wherein the compound is a rapamycin derivative comprising a substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl in place of the -OH of rapamycin at the C-10 position.
N28. The compound of embodiment N27, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with an electronegative moiety.
N29. The compound of embodiment N25, wherein the electronegative moiety is a phosphate isostere moiety.
N30. The compound of embodiment N25, wherein the electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moietyp.
N31. A macrolide comprising an electronegative moiety at a position equivalent to C1 O of FK506 or a pharmaceutically acceptable salt thereof.
N32. The compound of embodiment N31, wherein the macrolide is an FK506 derivative, a rapamycin derivative or an ascomycin derivative.
N33. The compound of embodiment N31, wherein the macrolide is capable of inhibiting a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) protein. N34. The compound of embodiment N31, wherein the macrolide is capable of inhibiting an FK506 binding protein.
N35. The compound of embodiment N31, wherein the electronegative moiety is a phosphate isostere moiety.
N36. The compound of embodiment N31, electronegative moiety is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
N37. A compound of structural Formula (I):
Figure imgf000165_0001
(I), or a pharmaceutically acceptable salt thereof, wherein: nl, n2 and n3 are independently an integer from 0 to 4; ml, m2, m3, vl, v2 and v3 are independently 1 or 2; L1 is a bond, -0-, -S- -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(0)-, -C(0)0-, -S(0)-, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1 Λ 3, -CHX1.12, -CH2X1.1, -CN, -SOniR1A, -SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C, -NHC(0)NHNR1BR1C,
-NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D, -C(0)NR1BR1C, -0R1A, -NR1BS02R1A, -NR1BC(0)R1D, -NR1BC(0)OR1D, -NR1BOR1D, -OCX1 -OCHX.113, substit.u1t2e,d or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CXZ1 3, -CHX2 1 2, -CH2X2 Λ, -CN, -SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC (0)NHNR2BR2C,
-NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -OR2A, -NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2 -OCHX.123.1,2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, halogen, -CX3 J 3, -CHX3.12, -CH2X3 Λ, -CN, -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C,
-NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A, -NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 -OCHX.133.1,2, 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; R1L, R2L, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C and R3D, are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -C13,-COOH, - CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1B and R1C, R2B and R2C, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1 1, X2 1 and
X3 1 are independently -C1, -Br, -I or -F; when L2 is -0-, L1 is a bond, R1 is or -
CH2CH3 and R3 is hydroxyl, then R2 is not hydrogen.
N38. The compound of embodiment N37, wherein: L2 is a bond; and R2 is -NH2.
N39. The compound of embodiment N37, wherein L2 is -NR2L-.
N40. The compound of embodiment N37, wherein L2 is -NR2LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
N41. The compound of embodiment N39, wherein R2 is a phosphate isostere moiety. N42. The compound of embodiment N39, wherein R2 is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
N43. The compound of embodiment N37, whereiniL1 is a bond; and R1 is (R)-ethyl. N44. The compound of embodiment N37, wherein the compound is
Figure imgf000167_0001
N45. The com ound of embodiment N37, wherein the compound is:
Figure imgf000168_0001
(II), or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000168_0002
, are independently single bonds or double bonds; n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4; m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently 1 or 2; L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(0)-, -C(0)0- -S(0)-, -S(0)2- 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;R4 is hydrogen, halogen, -CX4 Λ 3,
-CHX4.12, -CH2X4 .1, -CN, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C,
-NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A, -NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D,
-OCX4.13, -OCHX4 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R5 is hydrogen, halogen, -CX5 . -1C3,HX5 .1 -3C,H2X5 . -1,CN, -SOnsH, -SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .13 -,OCHX5 .12, 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; R6 is hydrogen, halogen, -CX6 1 3, -CHX6 1 2, -CH2X6 Λ, -CN, -SOn6H, -SOv6NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m6, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6.13, -OCHX6 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7 . -1C3,HX7.12, -CH2X7 . -1,CN, -SOnvH, -SOvvNH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)mv, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13 -,OCHX7 .12 s,ubstituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8 1 3, -CHX8 1 2, -CH2X8 Λ, -CN, -SOnsH, -SOv8NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m8, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8.13, -OCHX8 12, 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; R9 is hydrogen, halogen, -CX9 1 3, -CHX9.12, -CH2X9 -C.N1, , -SO^H, -SOv9NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , -NHC(0)NH2, -N(0)m9, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .13 -,OCHX9 .12, 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; R10 is hydrogen, halogen, -CX10 1 3, -CHX10 1 2, -CH2X10 -1, -CN, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC (0)NHNH2, -NHC(0)NH2, -N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX10 Λ3, -OCHX10 .12 s,ubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R3L, R4A R4B^ R4C and R4D are independently hydrogen, halogen, -CF3, -CC13,
-CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X4 1,
X5 1, X6 1, X7·1, X8 1, X9 1 and X10 1 are independently -C1, -Br, -I or -F; wherein when
Figure imgf000170_0001
and are double bonds, L3 is -O- and R6, R7, R8, R9 and R10 are independently hydrogen, then R4 is not hydrogen.
N47. The compound of embodiment N46, wherein L3 is -NR3L- or a bond.
N48. The compound of embodiment N46, wherein L3 is -NR3LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
N49. The compound of embodiment N46, wherein R4 is a phosphate isostere moiety.
N50. The compound of embodiment N46, wherein R4 is a tetrazole moiety, a triazole moiety, a carboxylic acid moiety, a phosphonate moiety, a boranophosphate moiety, a sulfate moiety, a sulfamic acid moiety, a sulphonate moiety, a nitro moiety, a thiazolidinone moiety, a squaric acid moiety, a hydroxyl moiety or a boronic acid moiety.
N51. The compound of embodiment N46, wherein R4 is 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.
N52. The compound of embodiment N46, wherein L3 is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
Figure imgf000172_0001
N56. A pharmaceutical composition, comprising a compound of embodiment N1 and a pharmaceutically acceptable excipient.
N57. A method of inhibiting Pin 1, comprising contacting Pin 1 with a compound of embodiment N1.
N58. A method of inhibiting an FK506 binding protein (FKBP), comprising contacting the FKBP with a compound of embodiment N1.
N59. The method of embodiment N58, wherein the FKBP is FKBP38, FKBP 51 or
FKBP52.
N60. The method of embodiment N58, wherein the FKBP is FKBP 51.
N61. A method of treating a Pin 1-mediated disease or disorder, comprising administering to a patient in need thereof a compound of embodiment N1.
N62. The method of embodiment N61, wherein the Pin 1-mediated disease or disorder is cancer.
N63. The method of embodiment N62, wherein the cancer is prostate cancer, brain cancer, breast cancer, ovarian cancer cervical cancer or skin cancer.
N64. The method of embodiment N62, further comprising administering to the subject a chemotherapeutic agent.
N65. A method of treating an FKBP51-mediated disease or disorder, comprising administering to a patient in need thereof a compound of embodiment N1.
N66. The method of embodiment N65, wherein the disease or disorder is depression or mental illness.
N67. The method of embodiment N66, wherein the disease or disorder is depression.
N68. The method of embodiment N67, further comprising administering to the subject an anti-depressant.
N69. The method of embodiment N66, wherein the mental illness is schizophrenia.
N70. The method of embodiment N65, wherein the disease or disorder is pain. N71. The method of embodiment N70, wherein the pain is chronic pain or neuropathic pain. N72. A method of preparing a compound of embodiment N37 comprising contacting a
compound of structural Formula (Ic) with ammonia:
Figure imgf000174_0001
N73. The method of embodiment N72, wherein the compound of Formula (Ic)
Figure imgf000174_0002
N74. A method of preparing a compound of embodiment N46, comprising contacting a compound of structural Formula (lie) with ammonia:
Figure imgf000175_0001

Claims

WHAT IS CLAIMED IS:
1. A peptidyl-prolyl cis-trans isomerase NEVIA-interacting 1 (Pin 1) inhibitor compound, comprising a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound is an FK506 compound, covalently bound to a nitrogen-containing functional group at the C-10 position, or a derivative thereof.
3. The compound of claim 2, wherein the nitrogen-containing functional group is an amino group.
4. The compound of claim 2, wherein the nitrogen-containing functional group is a primary amino group.
5. The compound of claim 2, wherein the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
6. The compound of claim 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
7. The compound of claim 1, wherein the compound is an FK506 compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene,
heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
8. The compound of claim 7, wherein the linker is covalently bound to an electronegative group.
9. The compound of claim 5, wherein the electronegative group is a phosphate isostere group.
10. The compound of claim 5, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
11. The compound of claim 1, wherein the FK506 compound is an ascomycin derivative or variant.
12. The compound of claim 1, wherein the compound is a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
13. The compound of claim 12, wherein the nitrogen-containing functional group is an amino group.
14. The compound of claim 12, wherein the nitrogen-containing functional group is a primary amino group.
15. The compound of claim 12, wherein the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
16. The compound of claim 1, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
17. The compound of claim 1, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
18. The compound of claim 17, wherein the linker is covalently bound to an electronegative group.
19. The compound of claim 15, wherein the electronegative group is a phosphate isostere group.
20. The compound of claim 15, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
21. An FK506 binding protein (FKBP) inhibitor compound, comprising a macrolide with a pipecolyl moiety, or a pharmaceutically acceptable salt thereof.
22. The compound of claim 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising a nitrogen-containing functional group at the C-10 position.
23. The compound of claim 22, wherein the nitrogen-containing functional group is an amino group.
24. The compound of claim 22, wherein the nitrogen-containing functional group is a primary amino group.
25. The compound of claim 22, wherein the nitrogen-containing functional group is an electronegative group or is covalently bound to an electronegative group.
26. The compound of claim 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an electronegative group at the C-10 position.
27. The compound of claim 21, wherein the compound is a rapamycin compound, or a derivative thereof, comprising an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene linker at the C-10 position.
28. The compound of claim 27, wherein the linker is covalently bound to an electronegative group.
29. The compound of claim 25, wherein the electronegative group is a phosphate isostere group.
30. The compound of claim 25, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
31. A macrolide compound covalently attached to an electronegative group at a position equivalent to C-10 of FK506 or a pharmaceutically acceptable salt thereof.** covers FK506?**
32. The compound of claim 31, wherein the macrolide compound is an FK506 compound derivative, a rapamycin compound derivative or an ascomycin compound derivative.
33. The compound of claim 31, wherein the macrolide compound is capable of inhibiting a peptidyl-prolyl cis-trans isomerase NEVIA-interacting 1 (Pin 1) protein.
34. The compound of claim 31, wherein the macrolide compound is capable of inhibiting an FK506 binding protein.
35. The compound of claim 31, wherein the electronegative group is a phosphate isostere group.
36. The compound of claim 31, wherein the electronegative group is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a
boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
37. A compound of structural Formula (I):
Figure imgf000180_0001
(I), or a pharmaceutically acceptable salt thereof, wherein:
nl, n2 and n3 are independently an integer from 0 to 4;
ml, m2, m3, vl, v2 and v3 are independently 1 or 2;
L1 is a bond, -0-, -S-, -NR1L- -NR1LC(0)-, -C(O)-, -C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L2 is a bond, -0-, -S-, -NR2L- -NR2LC(0)-, -C(0)-, -C(0)0- -S(0)- -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R1 is hydrogen, halogen, -CX1 .1 -C3,HX1.12, -CH2X1 \ -CN, -SOniR1A, -SOviNR1BR1C, -NHNR1BR1C, -0NR1BR1C, -NHC(0)NHNR1BR1C, -NHC(0)NR1BR1C, -N(0)mi, -NR1BR1C, -C(0)R1D, -C(0)OR1D, -C(0)NR1BR1C, -0R1A, -NR1BS02R1A, -NR1BC(0)R1D, -NR1BC(0)OR1D, -NR1BOR1D, -OCX1 -OC.H13X, 1 \ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2 -CN.,1 -, SO„2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(0)NHNR2BR2C, -NHC(0)NR2BR2C, -N(0)m2, -NR2BR2C, -C(0)R2D, -C(0)OR2D, -C(0)NR2BR2C, -0R2A, -NR2BS02R2A, -NR2BC(0)R2D, -NR2BC(0)OR2D, -NR2BOR2D, -OCX2 -OC.H13X,2 \ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, halogen, -CX3 .1 -C3,HX3.12, -CH2X3 -C.N1, , -SO„3R3A,
-SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(0)NHNR3BR3C, -NHC(0)NR3BR3C, -N(0)m3, -NR3BR3C, -C(0)R3D, -C(0)OR3D, -C(0)NR3BR3C, -OR3A, -NR3BS02R3A,
-NR3BC(0)R3D, -NR3BC(0)OR3D, -NR3BOR3D, -OCX3 -OC.H13X,3 sub.s1ti2t,uted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R1L R2L RlA R1B RlC R1D R2A R2B r2C R2D R3A R3B R3C AND R3D ARE independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1B and R1C, R2B and R2C, R3B and R3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X1·1, X2 1 and X3 1 are independently -C1, -Br, -I or -F; wherein when L2 is -0-, L1 is a bond, R1 is or -CH2CH3 and R3 is hydroxyl, then R2 is not hydrogen.
38. The compound of claim 37, wherein:
L2 is a bond; and
R2 is -NH2.
39. The compound of claim 37, wherein L2 is -NR2L-.
40. The compound of claim 37, wherein L2 is -NR2LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
41. The compound of claim 39, wherein R2 is a phosphate isostere group.
42. The compound of claim 39, wherein R2 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
43. The compound of claim 37, wherein:
L1 is a bond; and
R1 is (R)-ethyl.
44. The compound of claim 37, wherein the compound is
Figure imgf000182_0001
45. The com ound of claim 37 wherein the compound is:
Figure imgf000183_0001
((Ia)(R)) or ((Ib)(S)). A com ound of structural Formula (II):
Figure imgf000183_0002
(II), or a pharmaceutically acceptable salt thereof, wherein:
=^ and are independently single bonds or double bonds;
n4, n5, n6, n7, n8, n9 and nlO are independently an integer from 0 to 4;
m4, m5, m6, m7, m8, m9, mlO, v4, v5, v6, v7, v8, v9 and vlO are independently
1 or 2;
L3 is a bond, -0-, -S-, -NR3L- -NR3LC(0)-, -C(0)-, -C(0)0- -S(0)-, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene; R4 is hydrogen, halogen, -CX4 .1 -C3,HX4.12, -CH2X4 -C.N1, , -SOn4R4A,
-SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(0)NHNR4BR4C, -NHC(0)NR4BR4C, -N(0)m4, -NR4BR4C, -C(0)R4D, -C(0)OR4D, -C(0)NR4BR4C, -OR4A, -NR4BS02R4A,
-NR4BC(0)R4D, -NR4BC(0)OR4D, -NR4BOR4D, -OCX4 -OC.H13X,4 sub.s1ti2t,uted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R5 is hydrogen, halogen, -CX5,1 3, -CHX5.12, -CH2X5 -CN,.1 -, SOnsH,
-SOv5NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m5, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX5 .13, -OCHX5.12, 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;
R6 is hydrogen, halogen, -CX6 1 3, -CHX6.12, -CH2X6 -C.1N, , -SOn6H,
-SOv6NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m6, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX6 .13, -OCHX6.12, 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;
R7 is hydrogen, halogen, -CX7,1 3, -CHX7.12, -CH2X7 -C.1N, , -SOnvH,
-SOvvNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mv, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX7 .13, -OCHX7.12, 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;
R8 is hydrogen, halogen, -CX8 1 3, -CHX8.12, -CH2X8 -C.1N, , -SOn8H,
-SOv8NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m8, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX8 .13, -OCHX8.12, 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; R9 is hydrogen, halogen, -CX9 .1 -C3,HX9.12, -CH2X9 -C.N1, , -SO^H,
-SOv9NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)m9, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX9 .13, -OCHX9.12, 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;
R10 is hydrogen, halogen, -CX10 1 3, -CHX10 -CH.1 22X,10 1, -CN, -SOnioH, -SOvioNH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -N(0)mio, -NH2, -C(0)H, -C(0)OH, -C(0)NH2, -OH, -NHS02H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX10 .13, -OCHX10.12, 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;
R3L, R4A, R4B, R4C and R4D are independently hydrogen, halogen, -CF3, -CC13, -CBr3, -C13,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X4 1, X5 1, X6 1, X7'1, X8 1, X9 1 and X10 1 are independently -C1, -Br, -I or -F; wherein when and are double bonds, L3 is -O- and R6, R7, R8, R9 and R10 are independently hydrogen, then R4 is not hydrogen.
47. The compound of claim 46, wherein L3 is -NR3L- or a bond.
48. The compound of claim 46, wherein L3 is -NR3LC(0)-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
49. The compound of claim 46, wherein R4 is a phosphate isostere group.
50. The compound of claim 46, wherein R4 is a tetrazole group, a triazole group, a carboxylic acid group, a phosphonate group, a boranophosphate group, a sulfate group, a sulfamic acid group, a sulphonate group, a nitro group, a thiazolidinone group, a squaric acid group, a hydroxyl group or a boronic acid group.
51. The compound of claim 46, wherein R4 is 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.
52. The compound of claim 46, wherein L3 is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
53. The compound of claim 46, wherein the R4 is substituted or unsubstituted aryl.
54. The compound of claim 46, wherein the compound is
Figure imgf000186_0001
Figure imgf000187_0001
55. The com ound of claim 46, wherein the compound is:
Figure imgf000187_0002
56. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
57. A method of inhibiting Pin 1, comprising contacting Pin 1 with a compound of claim 1.
58. A method of inhibiting an FK506 binding protein (FKBP), comprising contacting the FKBP with a compound of claim 2.
59. The method of claim 58, wherein the FKBP is FKBP38, FKBP 51 or
FKBP52.
60. The method of claim 58, wherein the FKBP is FKBP 51.
61. A method of treating a Pin 1 -mediated disease or disorder, comprising administering to a patient in need thereof a compound of claim 2.
62. The method of claim 61, wherein the Pin 1 -mediated disease or disorder is cancer.
63. The method of claim 62, wherein the cancer is prostate cancer, brain cancer, breast cancer, ovarian cancer cervical cancer or skin cancer.
64. The method of claim 62, further comprising administering to the subject a chemotherapeutic agent.
65. A method of treating an FKBP51 -mediated disease or disorder, comprising administering to a patient in need thereof a compound of claim 2.
66. The method of claim 65, wherein the disease or disorder is depression or mental illness.
67. The method of claim 66, wherein the disease or disorder is depression.
68. The method of claim 67, further comprising administering to the subject an anti-depressant.
69. The method of claim 66, wherein the mental illness is schizophrenia. The method of claim 65, wherein the disease or disorder is pain.
The method of claim 70, wherein the pain is chronic pain or neuropathic
72. A method of preparing a compound of claim 37, comprising contacting a compound of structural Formula Ic) with ammonia:
Figure imgf000189_0001
73. The method of claim 72, wherein the compound of Formula (Ic) is
Figure imgf000189_0002
74. A method of preparing a compound of claim 46, comprising contacting a compound of structural Formula (lie) with ammonia:
Figure imgf000190_0001
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