EP3140274A1 - Naphthaquinone methyltransferase inhibitors and uses thereof - Google Patents

Naphthaquinone methyltransferase inhibitors and uses thereof

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Publication number
EP3140274A1
EP3140274A1 EP15788940.3A EP15788940A EP3140274A1 EP 3140274 A1 EP3140274 A1 EP 3140274A1 EP 15788940 A EP15788940 A EP 15788940A EP 3140274 A1 EP3140274 A1 EP 3140274A1
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EP
European Patent Office
Prior art keywords
optionally substituted
hydrogen
alkyl
compound
hydrocarbyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15788940.3A
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German (de)
French (fr)
Inventor
Minkui LUO
Glorymar Ibanez SANCHEZ
Gil Joseph BLUM
Li Yang
Fabio Pittella Silva
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memorial Sloan Kettering Cancer Center
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Sloan Kettering Institute for Cancer Research
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Publication of EP3140274A1 publication Critical patent/EP3140274A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
    • C07C50/12—Naphthoquinones, i.e. C10H6O2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
    • C07C50/14—Quinones the quinoid structure being part of a condensed ring system containing two rings with unsaturation outside the ring system, e.g. vitamin K1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B13/00—Oxyketone dyes
    • C09B13/02—Oxyketone dyes of the naphthalene series, e.g. naphthazarin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to chemical compounds having SET8 inhibitory activity and their use in the treatment of diseases and conditions associated with inappropriate methyltransferase activity.
  • Epigenetics is inheritable information not encoded in DNA manifested through control of gene expression, thereby controlling a range of cellular activity, including determining cell fate, stem cell fate and regulating proliferation.
  • Epigenetic control over gene expression is accomplished in at least four ways: (1) covalent histone modification, (2) covalent DNA modification, (3) histone variation, and (4) nucleosome structure and
  • DNA/histone contact points Epigenetic control through one mechanism can influence others suggesting a combinatorial regulation, as evidenced by the methylation of histones being implicated in the modulation of DNA methylation.
  • Covalent histone modifications a key mechanism involved in epigenetic control, include: (1) lysine acetylation, (2) lysine and arginine methylation, (3) serine and threonine phosphorylation, (4) ADP-ribosylation, (5) ubiquitination, and (6) SUMOylation.
  • Specific enzymatic activities are associated with these modifications and in the case of histone methylation, methyltransferases catalyze the transfer of a methyl group from cofactor S-adenosylmethionine to a lysine or arginine, producing S-adenosylhomocysteine as a byproduct.
  • Methyltransferases can also modify residues in other cellular proteins, e.g., the tumor suppressor p53.
  • PKMTs protein lysine methyltransferases
  • SETD8/SET8/Pr-SET7/KMT5A exchangeable names
  • H4K20mel histone H4 lysine 20
  • SETD8 Disruption of endogenous SETD8, accompanied with ablation of H4K20 monomethylation, leads to cell cycle defects, chromatin decondensation, and enlarged nuclei, indicating the essential role(s) of SETD8 in DNA replication.
  • SETD8 also methylates nonhistone targets such as proliferating cell nuclear antigen (PCNA), the tumor suppressor p53, and a p53- stabilizing factor Numb. Methylation of p53 or Numb results in the downregulation of apoptosis either by antagonizing p53 acetylation, which is required for p53-mediated transcriptional activation, or promoting p53 ubiquitination for degradation.
  • PCNA proliferating cell nuclear antigen
  • Numb a p53- stabilizing factor
  • SETD8 has been further implicated in cancer invasiveness and metastasis through its interaction with TWIST, a master regulator of epithelial-mesenchymal transition (EMT).
  • EMT epithelial-mesenchymal transition
  • SETD8 actas as an epigenetic modifier on the promoters of TWIST target genes, via methylation of H4K20. See, e.g., Yang et al, The EMBO Journal (2012) 31, 110-123.
  • SET8 promotes EMT and thus promotes metastatis as demonstrated in Yang et al. for lung and breast carcinomas.
  • the invention relates to compounds of Formula (I):
  • the compounds are naphthaquinone and azanaphthaquinone derivatives or analogs, which are inhibitors of methyltransferases.
  • Compounds presented herein may inhibit the protein lysine methyltransferase SET8. Inhibition of SET8 may disrupt transcriptional regulation, DNA replication, and/or DNA damage response, and ultimately lead to cell cycle defects or apoptosis. Inhibition of SET8 may adversely affect epithelial- mesenchymal transition (EMT) (e.g., by modulatin the interaction of SET8 with the EMT regulator, TWIST), and reduce the ability of cancer cells to metastasize.
  • EMT epithelial- mesenchymal transition
  • the invention provides compounds of Formula (III):
  • the invention provides pharmaceutical compoistions and kits of a compound described herein (e.g. , a compound of Formula (I), (II), or (III)).
  • Pharmaceutical compositions comprise one ore more optional excipients and may comprise a therapeutically or prophylactically effective amount of a compound described herein.
  • Pharmaceutical compoistions and kits may also comprise additional pharmaceutical agents (e.g. , anti-cancer agents).
  • the invention provides methods of treating a proliferative disease by administering a compound as described herein (e.g. , a compound of Formula (I), (II), or (III)).
  • the proliferative disease may be cancer or a metastatic cancer.
  • the cancer is leukemia, breast cancer, triple negative breast cancer (TBNC), or melanoma.
  • the cancer is a metastatic cancer, such as metastatic breast cancer or metastatic melanoma.
  • the invention provides methods for inhibiting the activity of
  • SET8 in a subject by administering to the subject a compound as described herein.
  • the activity of SET8 in a biological sample may also be inhibited by contacting a biological sample, such as a cell or tumor, with a compound as described herein.
  • the invention provides methods for labelling SET8 or another methyltransferase.
  • the compound may be labelled (e.g. , with a radioisotope) and then contacted to SET8, in vivo by administering the labelled compound to a subject, or in vitro by administering the labelled compound ot a biological sample.
  • Figure 1 Western blot assays for SETD8, H4K20me, and H3 after treatment of HeLa, HeK293, MDA-MB-213, MDA-MB-231 (TGL), K562, and MCF7 cell lines with SPECS21 at various concentrations.
  • FIG. 1 Western blot assays for SETD8, H4K20me, and H3 after treatment of MDA-MB-213, MDA-MB-231 (TGL), and MCF7 cell lines with SGSS05-NS at various concentrations.
  • Figure 3 Western blot assays for SETD8, H4K20me, MCM5, and H3 after treatment of HeLa, HeK293, MDA-MB-213, MDA-MB-231 (TGL), and MCF7 cell lines with SGSS05-NS at various concentrations.
  • Figure 4 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SPECS21 for 24 hours.
  • Figure 5 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-05NS for 24 hours.
  • FIG. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-15NS for 24, 48, and 72 hours.
  • Figure 7 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-04NS for 24, 48, and 72 hours.
  • Figure 8 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-16NS for 24 and 48 hours.
  • Figure 9 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-19NS for 24 and 48 hours.
  • Figure 10 Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-22NS for 24 and 48 hours.
  • FIG. 11 Graph of mice weights from maximum tolerated dose experiments on Athymic female 5-6 week old mice. Compounds SPECS21, SGSS05-N, and SGSS05-NS were administered in DMSO, salt, and nano encapsulated forms.
  • FIG. 12 Graph of mice weights from maximum tolerated dose experiments on Athymic female 5-6 week old mice. Compounds SPECS21, SGSS05-N, and SGSS05-NS were administered at doses between 5 mg/kg and 75 mg/kg. [0029] Figure 13. Preparation of MDA-MB-231-LM2 cell lines with constitutive expression of luciferase for mouse xenograft experiments.
  • Figure 14 Graph of tumor volume over five weeks of treatment with
  • LM2 mouse xenograft model control and treated group, over 4 weeks of treatment with SGSS05-NS.
  • Figure 17 Assessment of metastasis by bioluminescence in luciferase expressing MDA-MB-231-LM2 mouse xenograft model, control and treated group, after four and five weeks of treatment with SGSS05-NS.
  • Z 1 is O or NR Z1 ;
  • R is hydrogen or optionally substituted alkyl
  • R L is hydrogen, optionally substituted alkyl, or optionally substituted acyl
  • V is CR 2b or N
  • W is CR 2a or N
  • Y is CR Y or N
  • X is CR X or N
  • each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
  • Z is O or NR Z ;
  • R is hydrogen or optionally substituted alkyl
  • each of R 2a and R 2b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R 2a and R 2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
  • R J is hydrogen, NR Ja R Jb , optionally substituted hydrocarbyl, or of formula:
  • n 1 or 2;
  • R J3 is hydrogen or optionally substituted hydrocarbyl
  • R Ja and R Jb are joined to form an optionally substituted 6-membered heterocyclic ring
  • R Jc is optionally substituted hydrocarbyl
  • R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ;
  • R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
  • R J is a non-hydrogen group.
  • R K is a non-hydrogen group. In certain embodiments, each of R J and R K is a non-hydrogen group. In certain embodiments, each of R J and R K is not methyl. In certain embodiments, each of R J and R K is not methyl or butyl. In certain embodiments, a compound of Formula (I) is not of formula:
  • a compound of Formula (I) is a compound of
  • Z 1 is O or NR Z1 ;
  • R is hydrogen or optionally substituted alkyl
  • R L is hydrogen, optionally substituted alkyl, or optionally substituted acyl
  • V is CR 2b or N
  • W is CR 2a or N
  • Y is CR Y or N
  • X is CR X or N
  • each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
  • Z is O or NR Z ;
  • R is hydrogen or methyl
  • each of R 2a and R 2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R 2a and R 2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
  • R J is NR Ja R Jb , optionally substituted hydrocarbyl, or of formula:
  • n 1 or 2;
  • R J3 is hydrogen or optionally substituted hydrocarbyl
  • R Jc is optionally substituted hydrocarbyl
  • R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ;
  • R is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl; provided R J is not -CH 3 .
  • a compound of Formula (II) is not of formula:
  • a compound of Formula (II) is a compound of
  • a compound of Formula (II) is a compound of
  • a compound of Formula (II) is a compound of
  • the compound is present in a mixture of compounds
  • substituents when present, need not be the same.
  • a (C 1 -C 12 )hydrocarbyl may be substituted with one nitro group, with two methyl groups, or with one fluoro group and one methyl group.
  • X is N. In other embodiments, X is CR X .
  • R x is hydrogen. In other embodiments, R x is hydroxyl.
  • R X is (C 1 -C 4 )alkoxy. In other embodiments, R X is halogen. In some embodiments, R X is (C X
  • R is (C 1 -C 6 )haloalkyl.
  • R X is cyano.
  • R X is nitro.
  • RX is optionally substituted acyl.
  • R is optionally substituted amino.
  • R is mono substituted amino, wherein the substituent optionally substituted acyl.
  • R is unsubstituted amino.
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • Y is N. In other embodiments, Y is CR .
  • R Y is hydrogen. In other embodiments, R Y is hydroxyl.
  • R is (C 1 -C 4 )alkoxy. In other embodiments, R is halogen. In some
  • R is (C 1 -C 6 )alkyl. In other embodiments, R is (C 1 -C 6 )haloalkyl. In still other
  • R is cyano. In yet other embodiments, R is nitro. In some embodiments, R
  • R is optionally substituted acyl.
  • R is optionally substituted amino.
  • R is mono substituted amino, wherein the substituent optionally substituted acyl.
  • R is unsubstituted amino.
  • R is optionally substituted sulfonyl.
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or
  • optionally substituted heteroaryl or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • X is CR X and Y is CR Y . In some of these
  • R and R are each selected from hydrogen and hydroxyl.
  • R and R are each hydrogen. In some embodiments, either of X or Y is N. In some embodiments, X is N and Y is N.
  • Z is O. In other embodiments, Z is NR Z .
  • R Zl is optionally substituted (CrC 6 ) alkyl. In other embodiments, R Zl is methyl.
  • G is -N(R L )-.
  • R L is hydrogen.
  • R L is optionally substituted (C 1 -C 1 2)hydrocarbyl.
  • R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • W is N. In other embodiments, W is CR 2a .
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R 2a is optionally substituted amino. In some embodiments, R 2a is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R a is unsubstituted amino. In some embodiments, R 2a is optionally substituted sulfonyl. In some embodiments, R 2a is
  • R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
  • R 2a is
  • R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R 2a is
  • each R E is independently optionally substituted hydrocarbyl
  • optionally substituted heterocyclyl or optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • V is N. In other embodiments, V is CR 2b .
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R 2b is optionally substituted amino. In some embodiments, R 2b is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R 2b is unsubstituted amino. In some embodiments, R 2b is optionally substituted sulfonyl. In some embodiments, R 2b is
  • R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
  • R 2b is
  • R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • each R is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
  • W is CR 2a and V is CR 2b . In some of these
  • R 2a and R 2b are each selected from hydrogen and hydroxyl. In still other embodiments, R 2a and R 2b are each hydrogen. In some embodiments, either of W or V is N.
  • R 2a and R 2b are each independently selected from the group consisting of hydrogen, halogen, (C 1 -Cg)alkyl, (C 1 -C 6 )haloalkyl, hydroxyl, (C - C 6 )alkoxy, cyano, and nitro.
  • R 2a and R 2b are both hydrogen.
  • R 2a and R 2b together with the carbons to which they are attached, R 2a and R 2b form a 5- or 6-membered ring (e.g., carbocyclic, heterocyclic, aryl, heteroaryl).
  • R and R 2b together with the carbons to which they are attached, form a phenyl ring.
  • R 2a and R 2b are joined to form a ring of formula:
  • the ring is optionally substituted at one or more carbon or nitrogen atoms as valency permits, the substituents being selected from the group consisting of halogen, optionally substituted (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, hydroxyl, cyano, nitro, optionally substituted amino and optionally substituted acyl.
  • R J is hydrogen. In certain embodiments, R J is a non- hydrogen group.
  • R J is (C 1 -C 12 )hydrocarbyl.
  • R K is chloro and R is (C 1 -C 12 )hydrocarbyl.
  • R is -SR and R is (C - C 12 )hydrocarbyl.
  • the (C 1 -C 12 )hydrocarbyl is unsubstituted.
  • the (Ci-C 12 )hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C 6 )alkoxy, halogen, (C Cs kyl, (CrCs ⁇ aloalkyl, cyano, nitro, and amino.
  • R J is (C 2 -C 12 )hydrocarbyl.
  • R K is chloro and R is (C 2 -C 12 )hydrocarbyl.
  • R is -SR and R is (C 2 - C 12 )hydrocarbyl.
  • the ⁇ -C ⁇ hydrocarbyl is unsubstituted.
  • the ⁇ -C ⁇ hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, (Q-C ⁇ haloalkyl, cyano, nitro, and amino.
  • R J is unsubstituted (C 1 -Cg)alkyl. In some embodiments,
  • R is chloro and R is unsubstituted (C 1 -Cg)alkyl.
  • R is -SR and R is unsubstituted (C 1 -Cg)alkyl.
  • R J is (Q-Cg) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (Ci-Cg)alkyl, (C 1 -Cg)haloalkyl, cyano, nitro, and amino.
  • R J is methyl.
  • R J is unsubstituted (C 2 -Cg)alkyl. In some embodiments,
  • R is chloro and R is unsubstituted (C 2 -Cg)alkyl.
  • R is -SR and R is unsubstituted (C 2 -Cg)alkyl.
  • R J is (C 2 -C 8 ) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (Ci-C 6 )alkoxy, halogen, (Ci-Cg)alkyl, (C 1 -Cg)haloalkyl, cyano, nitro, and amino.
  • R J is methyl.
  • R J is NR a R b .
  • R Ja is hydrogen. In other embodiments, R Ja is (Q-
  • R Jb is hydrogen. In other embodiments, R Jb is (Q-
  • R Jc is (C 1 -C 8 )hydrocarbyl. In some embodiments, the
  • (C 1 -C 8 )hydrocarbyl is unsubstituted.
  • the (C 1 -Cg)hydrocarbyl is substituted with one or more groups selected from hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C - Cg)alkyl, (C 1 -Cg)haloalkyl, cyano, nitro, and amino.
  • R c is optionally substituted alkyl, phenyl, or benzyl.
  • R Jc is methyl.
  • R Ja and R Jb are each independently selected from (Cr
  • R Ja and R Jb are each independently selected from methyl and ethyl.
  • R Ja and R Jb together with the nitrogen to which they are attached, form a piperidine or morpholine.
  • R Ja and R Jb together with the nitrogen to which they are attached, form a piperazine or a diazepane.
  • the formed piperazine or diazepane may be optionally substituted on the second nitrogen (i.e., the nitrogen not directly attached to the quinone) with (C 1 -C2o)hydrocarbyl.
  • the (C 1 -C 2 o)hydrocarbyl is methyl, ethyl, or benzyl.
  • the (C 1 -C 2 o)hydrocarbyl may be optionally substituted with hydroxy, (C 1 -C 6 )alkoxy, carboxy, acyl, or halogen.
  • R Ja and R Jb together with the nitrogen to which they are attached, form a piperazine substituted by methyl.
  • R J is of formula:
  • R J is of formula:
  • n is 1, forming a piperazine. In other embodiments, n is
  • R J3 is optionally substituted (C 1 -C 2 o)hydrocarbyl. In some embodiments, R J3 is methyl. In some embodiments, R J3 is ethyl. In some embodiments,
  • R J3 is benzyl. In some embodiments, R J3 is optionally substituted methyl. In some
  • R J3 is optionally substituted ethyl. In some embodiments, R J3 is optionally substituted benzyl.
  • the optional substituents on the (C 1 -C 2 o)hydrocarbyl are selected form hydroxy, (Ci-C 6 )alkoxy, carboxy, acyl, and halogen.
  • R J3 is of formula:
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl
  • E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
  • R K is hydrogen. In some embodiments, R K is a non- hydrogen group. In some embodiments, R is halogen. In some embodiments, R is chloro. In other embodiments, R is fluoro. In some embodiments, R is optionally substituted (C - C 12 )hydrocarbyl. In still other embodiments, the (Ci-C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, cyano, nitro, and optionally substituted amino. In some embodiments, R is optionally substituted (C 1 -Cg)alkyl.
  • R is methyl. In some embodiments, R is ethyl. In some embodiments, R is optionally substituted aralkyl. In some embodiments, R is benzyl. In still other embodiments, R is -SR .
  • R Ka is optionally substituted (C 1 -C 12 )hydrocarbyl.
  • the (C 1 -C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C 6 )alkoxy, halogen, (C Cs kyl, (Cr C8)haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino.
  • R is optionally substituted (C - Cg)alkyl.
  • R is methyl.
  • R is ethyl.
  • R is optionally substituted aryl.
  • R is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted aryl, (C 1 -C 6 )alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino.
  • R is phenyl.
  • R is substituted phenyl.
  • R is para-substituted phenyl.
  • R is ortho- or meta- substituted phenyl.
  • R a is naphthyl.
  • R a is optionally substituted heteroaryl.
  • R is a monocyclic heteroaromatic ring.
  • R Ka is:
  • R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
  • heterocyclyl or optionally substituted heteroaryl.
  • R Ka is:
  • R K is -SR Ka
  • R Ka is phenyl
  • R J is of formula:
  • a compound of Formula (I) is of Formula (III):
  • Z 1 is O or NR Z1 ;
  • R is hydrogen or optionally substituted alkyl
  • R L is hydrogen, optionally substituted alkyl, or optionally substituted acyl; V is CR /B or N;
  • W is CR 2a or N
  • Y is CR Y or N
  • X is CR X or N
  • each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
  • Z is O or NR Z ;
  • R is hydrogen or methyl
  • each of R 2a and R 2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R 2a and R 2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
  • n 1 or 2;
  • U is N, O, or CH 2 , wherein if U is O or CH 2 R is absent;
  • R is hydrogen or optionally substituted hydrocarbyl
  • R 4 is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR 4a ;
  • R 4a is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl.
  • a compound of Formula (III) is of Formula (Ilia):
  • a compound of Formula (III) is of Formula (Ilia'):
  • a compound of Formula (III) is of Formula (Illb),
  • the compound is present in a mixture of compounds
  • R 3 is optionally substituted (C 1 -C 2 o)hydrocarbyl.
  • R is methyl. In some embodiments, R is ethyl. In some embodiments,
  • R is benzyl. In some embodiments, R is optionally substituted methyl. In some
  • R is optionally substituted ethyl. In some embodiments, R is optionally substituted benzyl.
  • the optional substituents on the (C 1 -C 2 o)hydrocarbyl are selected form hydroxy, (Ci-C6)alkoxy, carboxy, acyl, and halogen.
  • R is of formula:
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl
  • E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
  • R 4 is hydrogen. In some embodiments, R 4 is a non- hydrogen group. In some embodiments, R 4 is halogen. In some embodiments, R 4 is chloro. In other embodiments, R 4 is fluoro. In some embodiments, R 4 is optionally substituted (Q- C 12 )hydrocarbyl. In still other embodiments, the (C 1 -C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C 6 )alkoxy, halogen, (Ci-C 8 )alkyl, (C 1 -C 8 )haloalkyl, cyano, nitro, and optionally substituted amino.
  • R 4 is optionally substituted (C 1 -Cg)alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is optionally substituted aralkyl. In some embodiments, R 4 is benzyl. In still other embodiments, R 4 is -SR 4a .
  • R 4a is optionally substituted (C 1 -C 12 )hydrocarbyl.
  • the (C 1 -C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, (C - C 8 )haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino.
  • R 4a is optionally substituted (Q- Cg)alkyl.
  • R 4a is methyl.
  • R 4a is ethyl. In some embodiments, R 4a is optionally substituted aryl. In some embodiments, R 4a is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (Ci-C 6 )alkyl, optionally substituted aryl, (Ci-C 6 )alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino. In some embodiments, R 4a is phenyl. In other embodiments, R 4a is substituted phenyl. In still other embodiments, R 4a is para- substituted phenyl. In still other embodiments, R 4a is ortho- or meta- substituted phenyl. In some embodiments R 4a is naphthyl. In some embodiments, R 4a is optionally substituted heteroaryl. In some embodiments, R 4a is a monocyclic hetero aromatic ring.
  • R 4a is:
  • R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
  • heterocyclyl or optionally substituted heteroaryl.
  • R 4a is:
  • R 4 is -SR 4a , R 4a is phenyl; R J is of formula:
  • a compound of Formula (I) is of Formula (IV):
  • n 1 or 2;
  • R is optionally substituted (C 1 -C 2 o)hydrocarbyl, wherein said (Ci-C 2 o)hydrocarbyl is optionally substituted one or more substituents selected from the group consisting of halogen,
  • R 4 is -F, -CI, or -SR 4a ;
  • R 4a is phenyl or monocyclic heteroaryl.
  • a compound of Formula (I) is of Formula (V):
  • each of R 1 and R 2 is independently (C 1 -C 6 )alkyl;
  • R 1 and R 2" are joined to form a piperazine or diazepane, wherein the nitrogen not directly attached to the quinone is optionally substituted with (C 1 -C 2 o)hydrocarbyl optionally substituted with one or more substituents selected from the group consisting of halogen, (Q-
  • R 4 is -F, -CI, or -SR 4a ;
  • R 4a is phenyl or monocyclic heteroaryl.
  • n is 1, forming a piperazine. In other embodiments, n is
  • R 3 is optionally substituted (C 1 -C 2 o)hydrocarbyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments,
  • R 3 is benzyl. In some embodiments, R 3 is optionally substituted methyl. In some
  • R 3 is optionally substituted ethyl. In some embodiments, R 3 is optionally substituted benzyl.
  • the optional substituents on the (C 1 -C 2 o)hydrocarbyl are selected form hydroxy, (Ci-C 6 )alkoxy, carboxy, acyl, and halogen.
  • R is of formula:
  • R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl
  • E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
  • R 4 is hydrogen. In some embodiments, R 4 is a non- hydrogen group. In some embodiments, R 4 is halogen. In some embodiments, R 4 is chloro. In other embodiments, R 4 is fluoro. In some embodiments, R 4 is optionally substituted (Cr C 12 )hydrocarbyl. In still other embodiments, the (Ci-C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, cyano, nitro, and optionally substituted amino.
  • R 4 is optionally substituted (C 1 -Cg)alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is optionally substituted aralkyl. In some embodiments, R 4 is benzyl. In still other embodiments, R 4 is -SR 4a .
  • R 4a is optionally substituted (C 1 -C 1 2)hydrocarbyl.
  • the (C 1 -C 12 )hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, (C - C8)haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino.
  • R 4a is optionally substituted (Q- Cg)alkyl. In some embodiments, R 4a is methyl.
  • R 4a is ethyl. In some embodiments, R 4a is optionally substituted aryl. In some embodiments, R 4a is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (Ci-C 6 )alkyl, optionally substituted aryl, (Ci-C 6 )alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino. In some embodiments, R 4a is phenyl. In other embodiments, R 4a is substituted phenyl. In still other embodiments, R 4a is para- substituted phenyl. In still other embodiments, R 4a is ortho- or meta- substituted phenyl. In some embodiments R 4a is naphthyl. In some embodiments, R 4a is optionally substituted heteroaryl. In some embodiments, R 4a is a monocyclic hetero aromatic ring.
  • R 4a is:
  • R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
  • heterocyclyl or optionally substituted heteroaryl.
  • R 4a is: [0096] In some embodiments, R 4 is -SR 4a , R 4a is phenyl; R J is of formula:
  • R and R are each independently selected from (Cr 1 ).
  • R and R are each independently selected from methyl and
  • R and R together with the nitrogen to which they are attached, form a piperazine or a diazepane.
  • the formed piperazine or diazepane may be optionally substituted on the second nitrogen (i.e. , the nitrogen not directly attached to the quinone) with (C 1 -C 2 o)hydrocarbyl.
  • the (Cr) may be optionally substituted on the second nitrogen (i.e. , the nitrogen not directly attached to the quinone) with (C 1 -C 2 o)hydrocarbyl.
  • the (Cr) i.e. , the nitrogen not directly attached to the quinone
  • C 2 o)hydrocarbyl is methyl, ethyl, or benzyl.
  • the (C 1 -C 2 o)hydrocarbyl may be optionally substituted with hydroxy, (C 1 -C 6 )alkoxy, carboxy, acyl, or halogen.
  • hydroxy, (C 1 -C 6 )alkoxy, carboxy, acyl, or halogen In some embodiments,
  • a compound of Formula (I) is of Formula (Via):
  • X is CR X or N
  • Y is CR Y or N
  • each of R and R is independently hydrogen, halogen, (Ci-C 6 )alkyl, (C Ce ⁇ aloalkyl, (C -
  • Z is O or NR Z ;
  • R is hydrogen or methyl
  • each of R 2a and R 2b is independently hydrogen, halogen, (C 1 -Cg)alkyl, (C Ce ⁇ aloalkyl, (Cr C 6 )alkoxy, hydroxyl, cyano, or nitro, or R 2a and R 2b are joined to form a 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring.
  • R 9 is NR 9a R 9b or optionally substituted (C 1 -C 12 )hydrocarbyl, wherein said (Q- C 12 )hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (C 1 -Cg)alkyl, (C 1 -C 6 )alkoxy, hydroxyl, amino, cyano, and nitro;
  • R 9a is hydro gen or optionally substituted (C 1 -C 12 )hydrocarbyl, wherein said (Cr
  • C 12 )hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (C 1 -C 6 )alkoxy, hydroxyl, amino, cyano, and nitro;
  • R 9c is optionally substituted (Ci-Cg)hydrocarbyl, wherein said (Ci-Cg)hydrocarbyl is optionally substituted with one or more substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (C 1 -Cg)haloalkyl, (C 1 -C 6 )alkoxy, hydroxyl, amino, cyano, and nitro.
  • a compound of Formula (I) is of Formula (VIb):
  • X is CR X or N
  • Y is CR Y or N
  • each of R and R is independently hydrogen, halogen, (Ci-C 6 )alkyl, (C Ce ⁇ aloalkyl, (C
  • Z is O or NR Z ;
  • R is hydrogen or methyl
  • each of R 2a and R 2b is independently hydrogen, halogen, (Ci-Cg)alkyl, (C Ce ⁇ aloalkyl, (Cr C 6 )alkoxy, hydroxyl, cyano, or nitro, or R 2a and R 2b are joined to form a 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring.
  • R 10 is optionally substituted (C 2 -Cg)alkyl, wherein said (C 2 -Cg) alkyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (Cr Cg)haloalkyl, (C 1 -C 6 )alkoxy, hydroxyl, amino, cyano, and nitro;
  • R 11 is optionally substituted (CrC ⁇ hydrocarbyl, wherein said (Ci-C ⁇ hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (Ci-C 6 )alkoxy, hydroxyl, amino, cyano, and nitro; provided R 10 is not butyl.
  • the compound is of Formula (Via).
  • R 9 is (Q-C ⁇ hydrocarbyl.
  • the (C 1 -C 12 )hydrocarbyl is unsubstituted.
  • the (Ci-C 12 )hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C 6 )alkoxy, halogen, (C 1 -C 8 )alkyl, (Cr
  • R 9 is (C 2 - C 12 )hydrocarbyl.
  • the (C 2 -C 12 )hydrocarbyl is unsubstituted.
  • the (C 2 -C 12 )hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C 6 )alkoxy, halogen, cyano, nitro, and amino.
  • R 9 is NR a R b .
  • R a is hydrogen. In other embodiments, R a is (Q-
  • C 12 )hydrocarbyl In some embodiments, the (Ci-C 12 )hydrocarbyl is unsubstituted. In other embodiments, the (C 1 -C 12 )hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, (C 1 -Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, R a is optionally substituted cyclic (Cs-6)hydrocarbyl. In other substituents, R a is optionally substituted benzyl.
  • R c is (C 1 -Cg)hydrocarbyl. In some embodiments, the
  • (Ci-C 8 )hydrocarbyl is unsubstituted.
  • the is substituted with one or more groups selected from hydroxyl, (Ci-C 6 )alkoxy, halogen, (Cr Cg)alkyl, (C 1 -Cg)haloalkyl, cyano, nitro, and amino.
  • R c is optionally substituted alkyl, phenyl, or benzyl. In other embodiments, R c is methyl.
  • the compound is of Formula (VIb).
  • R 10 is unsubstituted (C 2 -C 8 )alkyl.
  • R 10 is (C 2 -C 8 ) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, cyano, nitro, and amino.
  • R 11 is (Ci-C ⁇ hydrocarbyl.
  • the (Ci-C 12 )hydrocarbyl is substituted with one or two substituents selected from the group consisting of hydroxyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -Cg)alkyl, cyano, nitro, and amino.
  • R 11 is unsubstituted phenyl.
  • R 11 is substituted phenyl.
  • R 11 is ortho- or meta- substituted phenyl.
  • the compound, compound used in a pharmaceutical composition, or compound used in a method is a compound listed in Table El, Table E2, or Table E3. [00108] In certain embodiments, the compound, compound used in a pharmaceutical composition, or compound used in a method is of formula:
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • a plurality of molecules of a single structure may include at least one atom that occurs in an isotopic ratio that is different from the isotopic ratio found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include H, 3 H, n C, 13 C, 14 C, 15 N, 35 S, 18 F, 36 C1, 125 I, 124 I and 13 l l respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared when making the compounds of the invention by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • Quantum dots, fluorescent dyes, colorimetric dyes, or luminescent compounds are often used as label reagents. Any label that is suitable for a diagnostic test and that may be attached to a compound of the invention may be used in vitro.
  • the invention relates to a method of labeling SET8.
  • the method includes exposing SET8 to a compound described herein
  • the method includes exposing SET8 to a compound described herein containing a label.
  • a pharmaceutical composition described herein comprises a compound of Formula (I). In certain embodiments, a pharmaceutical
  • composition described herein comprises a compound of Formula (II). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (III). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (IV). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (V). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (Via). In certain
  • a pharmaceutical composition described herein comprises a compound of Formula (VIb).
  • a compound is presented as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition comprising a compound described herein together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compositions may be formulated for oral, topical or parenteral administration. For example, they may be given intravenously, intraarterially, subcutaneously, and directly into the CNS - either intrathecally or intracerebroventricularly.
  • Formulations include those suitable for oral, parenteral (including
  • the compounds are preferably administered orally or by injection (intravenous or subcutaneous).
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, and optionally a
  • the pharmaceutical composition described herein comprises a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • the effective amount is an amount effective for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • the effective amount is an amount effective for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • the effective amount is an amount effective for inhibiting SET8 in vivo in a subject.
  • the effective amount is an amount effective for inhibiting SET8 in vitro in a biological sample.
  • the effective amount is an amount effective for inhibiting SET8 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting SET8 by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for a range of inhibition between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • compositions described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers
  • colloidal clays e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)
  • long chain amino acid derivatives high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxy
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a liquid suspension of crystalline or amorphous material with poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and g
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents examples include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in- water and/or water-in- oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [00152] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a volatile oil
  • a buffering agent such as a a surface active agent
  • a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein.
  • a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
  • Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting SET8), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • additional pharmaceutical agents e.g., therapeutically and/or prophylactically active agents.
  • additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • peptides proteins
  • carbohydrates monosaccharides
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., infectious disease, proliferative disease, hematological disease, or painful condition).
  • a disease e.g., infectious disease, proliferative disease, hematological disease, or painful condition.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, antidiabetic agents, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, antiinflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-allergic agents, contraceptive agents, and pain-relieving agents.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or
  • immunodulatory agents e.g., IL- 1, 2, 4, 6, or 12
  • immune cell growth factors e.g., GM- CSF
  • antibodies e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
  • chemotherapeutic agents include, but are not limited to, anti- estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.
  • anti- estrogens e.g. tamoxifen, raloxifene, and megestrol
  • LHRH agonists e.g. goscrclin and leuprolide
  • anti-androgens e.g. flutamide and bicalutamide
  • photodynamic therapies e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer
  • cyclophosphamide ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
  • nitrosoureas e.g. carmustine (BCNU) and lomustine (CCNU)
  • alkylsulphonates e.g. busulfan and treosulfan
  • triazenes e.g.
  • dacarbazine, temozolomide platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor- activated pro-drug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate;
  • a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxe
  • docetaxel, taxol epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), antimetabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.
  • uracil analogs e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine
  • cytosine analogs e.g. cytarabine (ara C), cytosine arabinoside, and
  • fludarabine purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g.
  • purine analogs e.g. mercaptopurine and Thioguanine
  • Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
  • isoprenylation inhibitors e.g. lovastatin
  • dopaminergic neurotoxins e.g
  • daunorubicin doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone
  • MDR inhibitors e.g. verapamil
  • Ca 2+ ATPase inhibitors e.g.
  • thapsigargin imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
  • TASIGNA® semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTEVIA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab
  • CAMPATH® gemtuzumab ozogamicin
  • MYLOTARG® gemtuzumab ozogamicin
  • TORISEL® temsirolimus
  • ENMD-2076 PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (V ARGATEF® ) , AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL- 184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)),
  • the additional pharmaceutical agent is an anti-cancer agent for breast cancer.
  • anti-cancer agents for the treatment or prevention (or both) of breast cancer include, but are not limited to: ABITREXATE® (Methotrexate), ABRAXANE® (Paclitaxel Albumin- stabilized Nanoparticle Formulation), AC, AC-T, ADRIAMYCIN PFS® (Doxorubicin Hydrochloride), ADRIAMYCIN RDF® (Doxorubicin Hydrochloride), ADRUCIL® (Fluorouracil), AFINITOR® (Everolimus), AFINITOR DISPERZ® (Everolimus), AREDIA® (Pamidronate Disodium), ARIMIDEX®
  • the additional pharmaceutical agent is an anti-cancer agent for melanoma.
  • anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: DTIC-DOME® (Dacarbazine), INTRON A® (Recombinant Interferon Alfa-2b), KEYTRUDA® (Pembrolizumab), MEKINIST®
  • the additional pharmaceutical agent is an anti-cancer agent for leukemia.
  • anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: ABITREXATE® (methotrexate), ADE®,
  • ADRIAMYCIN RDF® doxorubicin hydrochloride
  • AMBOCHLORIN® chlorambucil
  • ARRANON® nelarabine
  • ARZERRA® ironatumumab
  • BOSULIF® bisutinib
  • BUSULFEX® busulfan
  • CAMPATH® alemtuzumab
  • CERUBIDINE® unorubicin hydrochloride
  • CLAFEN® cyclophosphamide
  • CLOFAREX® clofarabine
  • CLOLAR® clofarabine
  • CVP® CYTOSAR-U®
  • CYTOXAN® cyclophosphamide
  • ERWINAZE® Asparaginase Erwinia Chrysanthemi
  • FLUDARA® fludarabine phosphate
  • FOLEX® methotrexate
  • FOLEX PFS® metalhotrexate
  • GAZYVA® bisnutuzumab
  • GLEEVEC imatinib mesylate
  • HYPER-CVAD® ICLUSIG® (ponatinib hydrochloride)
  • IMBRUVICA® ibrutinib
  • LEUKERAN® chlorambucil
  • SPRYCE®L (dasatinib), SYNRIBO® (omacetaxine mepesuccinate), TARABINE PFS® (cytarabine), TASIGNA® (nilotinib), TREANDA® (bendamustine hydrochloride),
  • TRISENOX® arsenic trioxide
  • VINCASAR PFS® vinylcristine sulfate
  • ZYDELIG® idelalisib
  • kits e.g., pharmaceutical packs.
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • the kits are useful for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • kits are useful for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • the kits are useful for inhibiting SET8 in a subject or in a biological sample.
  • kits described herein further includes instructions for using the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • kits and instructions provide for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • the kits and instructions provide for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof.
  • the kits and instructions provide for inhibiting SET8 in a subject or in a biological sample.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the present invention also provides methods that may be useful for the treatment or prevention of a disease.
  • the disease is a proliferative disease.
  • the proliferative disease is cancer.
  • the proliferative disease is leukemia.
  • the proliferative disease is breast cancer.
  • the proliferative disease is metastatic breast cancer.
  • the proliferative disease is melanoma.
  • the disease is a disease associated with inappropriate methyltransferase activity.
  • the disease is a disease associated with inappropriate SET8 activity.
  • a method described herein comprises use of a compound of Formula (I).
  • a method described herein comprises use of a compound of Formula (II). In certain embodiments, a method described herein comprises use of a compound of Formula (III). In certain embodiments, a method described herein comprises use of a compound of Formula (IV). In certain embodiments, a method described herein comprises use of a compound of Formula (V). In certain embodiments, a method described herein comprises use of a compound of Formula (Via). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (VIb).
  • the compounds described herein may exhibit methyltransferase inhibitory activity, exhibit SET8 inhibitory activity, exhibit a therapeutic or preventative effect in the treatment of cancer (e.g., leukemia, breast cancer, metastatic breast cancer, melanoma), exhibit a therapeutic or preventative effect in the treatment of cancers associated with inappropriate SET8 activity, and/or exhibit a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemo therapeutic agents.
  • cancer e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • a therapeutic profile e.g., optimum safety and curative effect
  • the present invention provides methods that may be useful for the treatment of a proliferative disease (e.g. , cancer (e.g., leukemia, breast cancer, metastatic breast cancer, melanoma) comprising administering a compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical composition thereof, to a subject in need thereof.
  • a proliferative disease e.g., cancer (e.g., leukemia, breast cancer, metastatic breast cancer, melanoma) comprising administering a compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical composition thereof, to a subject in need thereof.
  • the compound is administered as a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
  • the compound is administered as a pharmaceutically acceptable
  • the compound is administered as a specific stereoisomer or mixture of stereoisomers of the compound. In certain embodiments, the compound is administered as a specific tautomer or mixture of tautomers of the compound. In certain embodiments, the compound is administered as a pharmaceutical composition as described herein comprising the compound.
  • the present invention also provides uses of the inventive compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and pharmaceutical compositions thereof, in the manufacture of medicaments for the treatment and prevention of diseases.
  • the disease is a proliferative disease.
  • the proliferative disease is cancer.
  • the proliferative disease is leukemia.
  • the proliferative disease is breast cancer.
  • the proliferative disease is metastatic breast cancer.
  • the proliferative disease is melanoma.
  • the disease is a disease associated with inappropriate methyltransferase activity.
  • the disease is a disease associated with inappropriate SET8 activity.
  • the methods of the invention include administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the invention relates to a method of inhibiting the activity of
  • This method includes bringing SET8 into contact with a compound disclosed herein or a pharmaceutical composition disclosed herein. In some embodiments, this contact occurs in vivo. In some embodiments, this contact occurs in vitro.
  • the present invention provides methods that for inhibiting the activity of SET8 in a subject in need thereof, by administering to the subject a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
  • the present invention provides methods that for inhibiting the activity of SET8 in a biological sample (e.g., cells, tissues, biopsied tissues, purified or partially purified IDE), by contacting the sample with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
  • a biological sample e.g., cells, tissues, biopsied tissues, purified or partially purified IDE
  • the present invention provides methods that for inhibiting methyltransferase activity in a subject in need thereof, by administering to the subject a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
  • the present invention provides methods that for inhibiting methyltransferase activity in a biological sample (e.g., cells, tissues, biopsied tissues, purified or partially purified IDE), by contacting the sample with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
  • a biological sample e.g., cells, tissues, biopsied tissues, purified or partially purified IDE
  • the present invention also provides methods of using a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical compositions thereof, in research studies in the field of disease pathology, biochemistry, cell biology, epigenetics, and other fields associated with proliferative diseases.
  • the compounds of the invention can be used to study the roles of biomolecules (e.g., SET8, SAM, histone H4K20, PCNA, tumor suppressor p53, p53-stabilizing factor Numb).
  • the compounds of the invention can be used to study biological pathways (e.g., histone methylation, apoptosis).
  • the method comprises use of the compound or composition thereof to inhibit SET8.
  • the method comprises determining the concentration of a biomolecule (e.g., SET8, SAM, histone H4K20, PCNA, tumor suppressor p53, p53-stabilizing factor Numb) in a subject or biological sample, for example, by detecting a label (e.g., fluorophore, radioactive isotope).
  • a biomolecule e.g., SET8, SAM, histone H4K20, PCNA, tumor suppressor p53, p53-stabilizing factor Numb
  • a label e.g., fluorophore, radioactive isotope
  • the disease is a cancer selected from: acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelio sarcoma, hemangio sarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.
  • breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC), ER positive breast cancer, ER negative breast cancer, PR positive breast cancer, PR negative breast cancer, ER/PR positive breast cancer, ER/PR negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer
  • brain cancer e.g. , meningioma, glioblastomas, glioma (e.g.
  • astrocytoma oligodendroglioma
  • medulloblastoma bronchus cancer
  • carcinoid tumor e.g. , cervical adenocarcinoma, squamous cell carcinoma of the cervix
  • choriocarcinoma e.g., chordoma
  • craniopharyngioma e.g., colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer;
  • epithelial carcinoma ependymoma
  • endotheliosarcoma e.g., Kaposi' s sarcoma, multiple idiopathic hemorrhagic sarcoma
  • endometrial cancer e.g. , uterine cancer, uterine sarcoma
  • esophageal cancer e.g. , adenocarcinoma of the esophagus, Barrett's adenocarcinoma
  • Ewing's sarcoma e.g. , intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma);
  • GIST gastrointestinal stromal tumor
  • germ cell cancer head and neck cancer (e.g. , head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g. , alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g. , nephroblastoma a.k.a.
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • LMS adenocarcinoma of the lung
  • mastocytosis e.g.
  • systemic mastocytosis muscle cancer; myelodysplasia syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
  • adenocarcinoma adenocarcinoma
  • papillary adenocarcinoma papillary adenocarcinoma
  • pancreatic cancer e.g. , pancreatic
  • IPMN intraductal papillary mucinous neoplasm
  • Islet cell tumors mucinous neoplasm
  • penile cancer e.g., Paget' s disease of the penis and scrotum
  • pinealoma primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms
  • prostate cancer e.g.
  • prostate adenocarcinoma rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g. , appendix cancer); soft tissue sarcoma (e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;
  • SCC squamous cell carcinoma
  • KA keratoacanthoma
  • BCC basal cell carcinoma
  • small bowel cancer e.g. , appendix cancer
  • soft tissue sarcoma e.g. , malignant fibr
  • testicular cancer e.g. , seminoma, testicular embryonal carcinoma
  • thyroid cancer e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
  • urethral cancer e.g. , vaginal cancer
  • vulvar cancer e.g. , Paget' s disease of the vulva
  • the cancer is a metastatic cancer.
  • a metastatic cancer is a cancer that has moved from the site in the body of subject associated with the cancer type to one or more other sites in the body of the subject.
  • metastatic breast cancer may lead to the development of cancerous tumors in the bone, brain, liver, or lungs.
  • the cancer cells in a metastatic cancer are cells of the type of cancer, and not cells of the site at which they are present.
  • Exemplary cancers that may occur as metastatic cancers include, but are not limited to, bladder cancer, breast cancer, colon cancer, rectal cancer, renal cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, uterine cancer, and cervical cancer.
  • the proliferative disease is a disease associated with over-expression of SET8.
  • the proliferative disease is a disease associated with aberrant activity of SET8.
  • Aberrant activity of SET8 may be an elevated or an inappropriate activity of the SET8.
  • SET8 is not over-expressed, and the activity of SET8 is not elevated or inappropriate.
  • SET8 is over-expressed, and the activity of SET8 is elevated or inappropriate.
  • the subject described herein is a human.
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject is a mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal such as a dog or cat.
  • the subject is a livestock animal such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • a rodent e.g., mouse, rat
  • dog e.g., dog
  • pig e.g., dog
  • non-human primate e.g., non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal.
  • the biological sample described herein is one or more cells. In certain embodiments, the biological sample described herein is one or more cancer cells. In certain embodiments, a cell described herein is in vitro. In certain embodiments, a cell described herein is ex vivo. In certain embodiments, a cell described herein is in vivo. In certain embodiments, a cell described herein is a malignant cell. In certain embodiments, a cell In certain embodiments, the biological sample described herein is blood, bone, or tissue. In certain embodiments, the biological sample described herein is bone marrow or lymph node. In certain embodiments, the biological sample described herein is biopsied tissue. In certain embodiments, the biological sample described herein is a tumor.
  • Certain methods described herein may comprise administering one or more additional pharmaceutical agent in combination with the compounds described herein.
  • the additional pharmaceutical agent may be an anti-proliferative agent.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • the additional pharmaceutical agent may also be an inhibitor.
  • the additional pharmaceutical agent is an inhibitor of SET8.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or
  • immunodulatory agents e.g., IL- 1, 2, 4, 6, or 12
  • immune cell growth factors e.g., GM- CSF
  • antibodies e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
  • chemotherapeutic agents include, but are not limited to, anti- estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.
  • anti- estrogens e.g. tamoxifen, raloxifene, and megestrol
  • LHRH agonists e.g. goscrclin and leuprolide
  • anti-androgens e.g. flutamide and bicalutamide
  • photodynamic therapies e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer
  • cyclophosphamide ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
  • nitrosoureas e.g. carmustine (BCNU) and lomustine (CCNU)
  • alkylsulphonates e.g. busulfan and treosulfan
  • triazenes e.g.
  • dacarbazine, temozolomide platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor- activated pro-drug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate;
  • a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxe
  • docetaxel, taxol epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), antimetabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.
  • uracil analogs e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine
  • cytosine analogs e.g. cytarabine (ara C), cytosine arabinoside, and
  • fludarabine purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g.
  • purine analogs e.g. mercaptopurine and Thioguanine
  • Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
  • isoprenylation inhibitors e.g. lovastatin
  • dopaminergic neurotoxins e.g
  • daunorubicin doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone
  • MDR inhibitors e.g. verapamil
  • Ca 2+ ATPase inhibitors e.g.
  • thapsigargin imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
  • TASIGNA® semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTEVIA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab
  • CAMPATH® gemtuzumab ozogamicin
  • MYLOTARG® gemtuzumab ozogamicin
  • TORISEL® temsirolimus
  • ENMD-2076 PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (V ARGATEF® ) , AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL- 184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)),
  • the additional pharmaceutical agent is an anti-cancer agent for breast cancer.
  • anti-cancer agents for the treatment or prevention (or both) of breast cancer include, but are not limited to: ABITREXATE® (Methotrexate), ABRAXANE® (Paclitaxel Albumin- stabilized Nanoparticle Formulation), AC, AC-T, ADRIAMYCIN PFS® (Doxorubicin Hydrochloride), ADRIAMYCIN RDF® (Doxorubicin Hydrochloride), ADRUCIL® (Fluorouracil), AFINITOR® (Everolimus), AFINITOR DISPERZ® (Everolimus), AREDIA® (Pamidronate Disodium), ARIMIDEX®
  • the additional pharmaceutical agent is an anti-cancer agent for melanoma.
  • anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: DTIC-DOME® (Dacarbazine), INTRON A® (Recombinant Interferon Alfa-2b), KEYTRUDA® (Pembrolizumab), MEKINIST®
  • the additional pharmaceutical agent is an anti-cancer agent for leukemia.
  • anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: ABITREXATE® (methotrexate), ADE®,
  • ADRIAMYCIN RDF® doxorubicin hydrochloride
  • AMBOCHLORIN® chlorambucil
  • ARRANON® nelarabine
  • ARZERRA® ironatumumab
  • BOSULIF® bisutinib
  • BUSULFEX® busulfan
  • CAMPATH® alemtuzumab
  • CERUBIDINE® unorubicin hydrochloride
  • CLAFEN® cyclophosphamide
  • CLOFAREX® clofarabine
  • CLOLAR® clofarabine
  • CVP® CYTOSAR-U®
  • CYTOXAN® cyclophosphamide
  • ERWINAZE® Asparaginase Erwinia Chrysanthemi
  • FLUDARA® fludarabine phosphate
  • FOLEX® methotrexate
  • FOLEX PFS® metalhotrexate
  • GAZYVA® bisnutuzumab
  • GLEEVEC imatinib mesylate
  • HYPER-CVAD® ICLUSIG® (ponatinib hydrochloride)
  • IMBRUVICA® ibrutinib
  • LEUKERAN® chlorambucil
  • SPRYCE®L (dasatinib), SYNRIBO® (omacetaxine mepesuccinate), TARABINE PFS® (cytarabine), TASIGNA® (nilotinib), TREANDA® (bendamustine hydrochloride),
  • TRISENOX® arsenic trioxide
  • VINCASAR PFS® vinylcristine sulfate
  • ZYDELIG® idelalisib
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C n-n' group e.g., a C n _ n' hydrocarbyl group
  • a (C n -C n ) group which may also be designated a (C n -C n ) group
  • C n _ n' hydrocarbyl group which may also be designated a (C n -C n ) group
  • C 1-8 is recited, the recitation is intended to be shorthand, as if C 1 ; C 2 , C 3 , C 4 , C 5 , C 6 , C 7> and C 8 were fully set forth.
  • the term C 1-8 is intended to include all subranges therein, including, for example, C 1-6 , C 1-4 , C 1-3 , C 2-6 , etc.
  • C 1-6 alkyl is intended to encompass, Q, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-6, Ci-5, Ci-4, C 1-3 , Ci-2, C 2-6 , C 2- 5, C 2 -4, C 2- 3, C 3 -6, C 3 -5, C 3-4 , C4-6, C4-5, and C5-6 alkyl.
  • hydrocarbyl (“hydrocarbon”) is a generic term encompassing C -
  • C n defines the number (n) of carbon atoms in a group.
  • hydrocarbyl groups include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups.
  • hydrocarbyl groups are those having 1 to 8 carbon atoms, examples including C 1-6 hydrocarbyl groups, such as C 1-4 hydrocarbyl groups (e.g., C 1-3 hydrocarbyl groups or Ci_ 2 hydrocarbyl groups).
  • Specific examples of hydrocarbyl groups include any individual value or combination of values selected from C 1 ; C 2 , C 3 , C 4 , C 5 , C 6 , C 7> C 8 , Cg , and Cio hydrocarbyl groups.
  • the groups -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , benzyl, and phenyl are non-limiting examples of specific hydrocarbyl groups.
  • Hydrocarbyl includes any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“ ⁇ 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("Q.g alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Cis alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom ("Q alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (CO, ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g. , n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.
  • C 1-10 alkyl such as unsubstituted C 1-6 alkyl, e.g., -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.
  • the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., -CF 3 , Bn).
  • Lower alkyl refers to alkyl groups of from 1 to 4 carbon atoms.
  • Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbyl groups.
  • cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the subset of cycloalkyl groups are cycloalkyl groups having from 3 to 8 carbon atoms, particular examples being C 3 _ 6 cycloalkyl groups. Cycloalkyl, if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2- 7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C 2 -5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2- 3 alkenyl”). In some embodiments,
  • an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 - 4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • alkenyl groups include, but are not limited to, ethenyl (vinyl), 1- propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl.
  • alkenyl groups include those having 2 to 8 carbon atoms, particular examples being C 2 -6 alkenyl groups, such as C 2 - 4 alkenyl groups.
  • cycloalkenyl groups include, but are not limited to,
  • cyclopropenyl cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.
  • cycloalkenyl groups those having from 3 to 8 carbon atoms, for example, C 3 _ 6 cycloalkenyl groups.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g. , 1, 2, 3, or 4 triple bonds) ("C 2 -io alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 -g alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms ("C 2- 6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 - 3 alkynyl”). In some
  • an alkynyl group has 2 carbon atoms ("C 2 alkynyl").
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 _ 4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2 _ 6 alkenyl groups include the aforementioned C 2 _ 4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-1 o alkynyl. In certain embodiments, the alkynyl group is a substituted C 2-1 o alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl and
  • 2-propynyl (propargyl) groups within the subset of alkynyl groups are those having 2 to 8 carbon atoms, particular examples being C 2 _ 6 alkynyl groups, such as C 2 _ 4 alkynyl groups.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
  • alkoxy and lower alkoxy include
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _ 14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ("C ⁇ o carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5 -6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”). Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ),
  • Exemplary C 3 _8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ),
  • cyclooctenyl Cg
  • bicyclo[2.2.1]heptanyl C 7
  • bicyclo[2.2.2]octanyl Cg
  • Exemplary C 3-1 o carbocyclyl groups include, without limitation, the aforementioned C 3 _ 8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (C 10 ),
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g. , containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _ 14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _ 14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _ 14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C O cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _ 6 cycloalkyl").
  • a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _ 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 - 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl”). Examples of C 5 - 6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3 _ 6 cycloalkyl groups include the aforementioned C 5 _ 6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 _ 14 cycloalkyl.
  • the cycloalkyl group is a substituted C 3 _ 14 cycloalkyl.
  • heterocyclyl refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g.
  • a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)
  • bicyclic heterocyclyl bicyclic system
  • tricyclic heterocyclyl tricyclic system
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3- 14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5- 10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1
  • heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, n
  • aryl refers to a radical of a monocyclic or polycyclic (e.g. , bicyclic or tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g. , phenyl).
  • an aryl group has 10 ring carbon atoms ("C 10 aryl”; e.g.
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g. , anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5- 14 membered monocyclic or polycyclic (e.g. , bicyclic, tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g. , indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g. , 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • halo or halogen means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms, e.g. , fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms ("Cis haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 haloalkyl").
  • the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 haloalkyl”). Examples of haloalkyl groups include -CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, and the like.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g. , a substituent which upon substitution results in a stable compound, e.g. , a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • present invention contemplates any and all such combinations in order to arrive at a stable
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplary carbon atom substituents include, but are not limited to, halogen,
  • each instance of R ⁇ is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-1 o alkenyl, C 2-1 o alkynyl, heteroCi-io alkyl, heteroC 2 _ 1 oalkenyl, heteroC ⁇ ioalkynyl, C 3-1 o carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa , -N(R CC ) 2 , -CN,
  • each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-1 o alkenyl, C 2-1 o alkynyl, heteroCi-io alkyl, heteroC ⁇ io alkenyl, heteroC ⁇ io alkynyl, C 3-1 o carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi- 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3-1 o carbocyclyl, d-io aryl, 3- 10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R is, independently, selected from hydrogen, d_ 6 alkyl, d_ 6 perhaloalkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, heterod_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 - 6 alkynyl, C 3-1 o carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5- 10 membered heteroaryl, or two ff
  • R groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • present invention contemplates any and all such combinations in order to arrive at a stable
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplary carbon atom substituents include, but are not limited to, halogen,
  • each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-1 o alkenyl, C 2-1 o alkynyl, heteroCi-io alkyl, heteroC 2-1 oalkenyl, heteroC 2-1 oalkynyl, C 3-1 o carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- 14 membered heteroaryl, or two R ⁇ groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R cc is, independently, selected from hydrogen, Ci-w alkyl, Ci-w perhaloalkyl, C 2-1 o alkenyl, C 2-1 o alkynyl, heteroCi-io alkyl, heteroC 2-1 o alkenyl, heteroC 2-1 o alkynyl, C 3-1 o carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- 14 membered heteroaryl, or two R cc groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from d_ 6 alkyl, d_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 -6 alkynyl, heteroCi-6 alkyl, heteroC 2 -6alkenyl, heteroC 2 -6 alkynyl, C3-io carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, Ci_ 6 perhaloalkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, heterod_ 6 alkyl, heteroC 2 - 6 alkenyl, heteroC 2 - 6 alkynyl, C 3-1 o carbocyclyl, 3-10 membered heterocyclyl, d- 10 aryl and 5-10 membered heteroaryl, or two
  • R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • hydroxyl or "hydroxy” refers to the group -OH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino” is a monosubstituted amino or a
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X " ' wherein R bb and X " are as defined herein.
  • sulfonyl refers to a group selected from -S0 2 N(R bb ) 2 , -SOaR ⁇ , and -S0 2 OR aa , wherein R aa and R bb are as defined herein.
  • R is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acy
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6,
  • R is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
  • R XI is hydrogen, optionally substituted alkyl, or optionally substituted acyl.
  • sil refers to the group -Si(R aa )3, wherein R aa is as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • the leaving group is a halogen.
  • the leaving group is I.
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • MDA-MB-231 is a cell line of human breast adenocarcinoma triple-negative epithelial cells derived from a pleural effusion.
  • MDA-MB-231 (TGL) or MDA-MB-231 (Luc) cells are MDA-MB-231 cells that have been plasmid transformed to express luciferase.
  • MCF7 is a cell line of human breast adenocarcinoma triple-positive epithelial cells derived from a metastatic site pleural effusion.
  • K562 is a cell line of human chronic myelogenous leukemia (CML) lymphoblasts.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
  • ethanesulfonate formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (Ci-4 alkyl)4 ⁇ salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non- stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • a hydrate of a compound may be represented, for example, by the general formula R x H 2 0, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)
  • tautomers refers to two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam- to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • enantiomers and those that are non-superimposable mirror images of each other are termed "enantiomers".
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • co-crystal refers to a crystalline structure composed of at least two components.
  • a co-crystal contains a compound of the present invention and one or more other component, including but not limited to, atoms, ions, molecules, or solvent molecules.
  • a co-crystal contains a compound of the present invention and one or more solvent molecules.
  • a co- crystal contains a compound of the present invention and one or more acid or base.
  • a co-crystal contains a compound of the present invention and one or more components related to said compound, including not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment or impurity of said compound.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or
  • Ci-Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds described herein may be preferred.
  • composition and “formulation” are used interchangeably.
  • a "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g. , infant, child, or adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g.
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as chicken, duck, goose, or turkey
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal "Disease,” “disorder,” and “condition” are used interchangeably herein.
  • tissue sample refers to any sample including tissue samples
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix
  • proliferative diseases include cancers (i.e., "malignant neoplasms"), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • cancer refers to a class of diseases characterized by the
  • Exemplary cancers include, but are not limited to, hematological malignancies. Additional exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g.
  • lymphangiosarcoma lymphangioendotheliosarcoma, hemangio sarcoma
  • appendix cancer benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g. , adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC), ER positive breast cancer, ER negative breast cancer, PR positive breast cancer, PR negative breast cancer, ER/PR positive breast cancer, ER/PR negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer); brain cancer (e.g. , meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer;
  • cervical cancer e.g., cervical adenocarcinoma, squamous cell carcinoma of the cervix
  • choriocarcinoma chordoma
  • craniopharyngioma colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma)
  • connective tissue cancer epithelial carcinoma; ependymoma; endotheliosarcoma (e.g.
  • Kaposi's sarcoma multiple idiopathic hemorrhagic sarcoma
  • endometrial cancer e.g., uterine cancer, uterine sarcoma
  • esophageal cancer e.g., adenocarcinoma of the esophagus, Barrett' s adenocarcinoma
  • Ewing' s sarcoma ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia
  • gall bladder cancer gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g.
  • throat cancer e.g. , laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
  • heavy chain disease e.g. , alpha chain disease, gamma chain disease, mu chain disease
  • kidney cancer e.g. , nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer
  • NSCLC adenocarcinoma of the lung
  • LMS leiomyosarcoma
  • MDS mastocytosis
  • muscle cancer myelodysplasia syndrome
  • MDS mesothelioma
  • MPD myeloproliferative disorder
  • PV polycythemia vera
  • ET essential thrombocytosis
  • ALM agnogenic myeloid metaplasia
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g. , neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
  • adenocarcinoma adenocarcinoma
  • papillary adenocarcinoma papillary adenocarcinoma
  • pancreatic cancer e.g. , pancreatic
  • IPMN intraductal papillary mucinous neoplasm
  • Islet cell tumors mucinous neoplasm
  • penile cancer e.g., Paget' s disease of the penis and scrotum
  • pinealoma primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms
  • prostate cancer e.g.
  • prostate adenocarcinoma rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g. , appendix cancer); soft tissue sarcoma (e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;
  • SCC squamous cell carcinoma
  • KA keratoacanthoma
  • BCC basal cell carcinoma
  • small bowel cancer e.g. , appendix cancer
  • soft tissue sarcoma e.g. , malignant fibr
  • testicular cancer e.g. , seminoma, testicular embryonal carcinoma
  • thyroid cancer e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
  • urethral cancer e.g. , vaginal cancer
  • vulvar cancer e.g. , Paget' s disease of the vulva
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease or condition, which reduces the severity of the disease or condition, or retards or slows the progression of the disease or condition (i.e., “therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease or condition (i.e. , "prophylactic treatment”).
  • a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient,
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • an "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • a "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibiting SET8.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting SET8 and for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)).
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • a prophylactically effective amount of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a
  • prophylactically effective amount is an amount sufficient for inhibiting SET8. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)). In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting SET8 and for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)).
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • a proliferative disease e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma
  • the term “inhibit” or “inhibition” in the context of enzymes refers to a reduction in the activity of the enzyme.
  • the term refers to a reduction of the level of enzyme activity, e.g., SET8 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity.
  • the term refers to a reduction of the level of enzyme activity, e.g., SET8 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.
  • SET8 or "histone lysine methyltransferase” refers to an enzyme which methylates histone H4 lysine 20 by catalyzing methyl transfer from S- adenosylmethionine to a lysine, and produces S-adenosylhomocysteine as a by-product.
  • SET8 is alternatively referred to by other names, including SETD8, Pr-SET7, and KMT5A.
  • the term SET8 further includes, in some embodiments, sequence variants and mutations (e.g., naturally occurring or synthetic SET8 sequence variants or mutations), and different SET8 isoforms.
  • the term SET8 includes protein or encoding sequences that are homologous to a SET8 protein or encoding sequence, for example, a protein or encoding sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% sequence identity with a SET8 sequence, for example, with a SET8 sequence provided herein.
  • SET8 protein and encoding gene sequences are well known to those of skill in the art, and exemplary protein sequences include, but are not limited to, the following sequences. Additional SET8 sequences, e.g., SET8 homologues from other bacteria species, will be apparent to those of skill in the art, and the invention is not limited to the exemplary sequences provided herein.
  • the reactions were incubated for a designated period of time and the resulting reaction products were assayed for methylation activity by immobilizing the peptides onto P81 phosphocellulose filter paper, proceeded by washing and finally, quantification with a liquid scintillation counter. Briefly, 6 ⁇ ⁇ of the methylation reaction mixture was spotted onto Whatman P-81 phosphocellulose filter paper (1.2 x 1.2 cm ) to immobilize [ H-methyl] -labeled peptides.
  • Antibodies and their dilution conditions anti-H4K20me antibody (Active Motif, 39175 rabbit polyclonal, 1: 150,000), anti- H4K20me2 (Active Motif, 39173 rabbit polyclonal, 1: 100,000), anti-H4K20me3 (Active Motif, 39180 rabbit polyclonal, 1:30,000), anti-H3K9me (Millipore, 07-450 rabbit polyclonal, 1: 10,000), anti-H4 (Millipore, 07-108 rabbit polyclonal, 1: 100,000) and anti-H3 (Millipore, 06-755 rabbit polyclonal, 1: 100,000). Densitometry analysis was carried out with ImageJ program.
  • Figure 1 shows the effect of various concentrations of compound SPEC21 on SETD8, H4K20me, and histone H3 levels in HEK293 cells, HeLA cells MDA-MB-231 cells, MDA-MB-231/Luc cells, MCF7 cells, and K562 cells.
  • Figures 2-3 show the effect of various concentrations of compound SGSS05-NS on SETD8, H4K20me, minichromosome maintenance complex component 5 (MCM5), and histone H3 levels in HEK293 cells, HeLA cells, MDA-MB-231 cells, MDA-MB-231 (TGL)cells, MCF7 cells, and K562.
  • MCM5 minichromosome maintenance complex component 5
  • FIG. 4 Images of cell survival after 24, 48, or 72 hours with various amounts of SET8 inhibitor are shown in the following figures: Figure 4, SPECS21, MDA-MB-231 (TGL); Figure 5, SGSS05-NS, MDA-MB-231 (TGL); Figure 6, SGSS15-NS, MDA-MB-231 (TGL); Figure 7 SGSS04-NS, MDA-MB-231 (TGL); Figure 8 SGSS16-NS, MDA-MB-231 (TGL); Figure 9 SGSS15-NS, MDA-MB-231 (TGL); and Figure 10, SGSS22-NS, MDA-MB-231 (TGL).
  • a Maximum tolerated dose (MTD) experiment was carried out in Athymic females mice of 5-6 weeks old, for compounds SPECS21, SGSS05-N and SGSS05-NS.
  • SPECS21-nano 1 mg/kg, 5mg/kg, lOmg/kg and 20mg/kg i.v.
  • Stock solution is 5 mg/mL SGSS05-N-salt, 15 mg/kg i.p., Stock solution is 10 mg/mL
  • Treatment groups (2 mice/group)
  • Xenograft model was created by implanting 10 million cells with matrigel
  • mice in the mammary fat pad of 5-6 weeks old NOD/SCID females mice.
  • a group of 5 mice were treated 1 week after tumor implantation with SGSS05-NS at 15 mg/kg i.p., QDx5 x 5 weeks.
  • a control group of 5 mice received Vehicle only, i.p., QDx5 x 5 weeks.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

Provided herein are compounds of (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof. Also provided are pharmaceutical compositions and methods involving the inventive compounds for the treatment of proliferative diseases (e.g., cancer (e.g., leukemia, breast cancer, melanoma, metastatic cancer) and diseases associated with inappropriate SET8 activity. Also provided are methods for inhibiting SET8 and methods for labelling SET8.

Description

NAPHTHAQUINONE METHYLTRANSFERASE INHIBITORS AND
USES THEREOF
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional applications, U.S.S.N. 61/990,905, filed May 9, 2014, and U.S.S.N. 62/033,938, filed August 6, 2014, each of which is incorporated herein by reference.
GOVERNMENT SUPPORT
[0002] This invention was made with Government support under grant number
GM096056 awarded by the National Instittues of Health. The Government has certain rights in the invention.
TECHNICAL FIELD
[0003] The invention relates to chemical compounds having SET8 inhibitory activity and their use in the treatment of diseases and conditions associated with inappropriate methyltransferase activity.
BACKGROUND
[0004] Epigenetics is inheritable information not encoded in DNA manifested through control of gene expression, thereby controlling a range of cellular activity, including determining cell fate, stem cell fate and regulating proliferation. Epigenetic control over gene expression is accomplished in at least four ways: (1) covalent histone modification, (2) covalent DNA modification, (3) histone variation, and (4) nucleosome structure and
DNA/histone contact points. Epigenetic control through one mechanism can influence others suggesting a combinatorial regulation, as evidenced by the methylation of histones being implicated in the modulation of DNA methylation.
[0005] Covalent histone modifications, a key mechanism involved in epigenetic control, include: (1) lysine acetylation, (2) lysine and arginine methylation, (3) serine and threonine phosphorylation, (4) ADP-ribosylation, (5) ubiquitination, and (6) SUMOylation. Specific enzymatic activities are associated with these modifications and in the case of histone methylation, methyltransferases catalyze the transfer of a methyl group from cofactor S-adenosylmethionine to a lysine or arginine, producing S-adenosylhomocysteine as a byproduct. Methyltransferases can also modify residues in other cellular proteins, e.g., the tumor suppressor p53. [0006] Among more than 50 protein lysine methyltransferases (PKMTs) encoded by the human genome, SETD8/SET8/Pr-SET7/KMT5A (interchangeable names) is the sole PKMT known for the in vivo monomethylation of histone H4 lysine 20 (H4K20mel).
Disruption of endogenous SETD8, accompanied with ablation of H4K20 monomethylation, leads to cell cycle defects, chromatin decondensation, and enlarged nuclei, indicating the essential role(s) of SETD8 in DNA replication. SETD8 also methylates nonhistone targets such as proliferating cell nuclear antigen (PCNA), the tumor suppressor p53, and a p53- stabilizing factor Numb. Methylation of p53 or Numb results in the downregulation of apoptosis either by antagonizing p53 acetylation, which is required for p53-mediated transcriptional activation, or promoting p53 ubiquitination for degradation. These findings associate the functions of SETD8 with transcriptional regulation and DNA damage response. Inhibition of SETD8 is thus expected to show a proapoptotic phenotype through the depletion of H4K20 monomethylation, which leads to cell cycle arrest, or p53/Numb-mediated methylation, which results in the upregulation of p53 target genes.
[0007] SETD8 has been further implicated in cancer invasiveness and metastasis through its interaction with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). SETD8 actas as an epigenetic modifier on the promoters of TWIST target genes, via methylation of H4K20. See, e.g., Yang et al, The EMBO Journal (2012) 31, 110-123. SET8 promotes EMT and thus promotes metastatis as demonstrated in Yang et al. for lung and breast carcinomas.
[0008] The disruption of the normal functions of methyltransferases has been implicated in human diseases. Inappropriate methyltransf erase activities thus represent attractive targets for therapeutic intervention by small molecule inhibitors.
SUMMA Y
[0009] The invention relates to compounds of Formula (I):
as described herein. The compounds are naphthaquinone and azanaphthaquinone derivatives or analogs, which are inhibitors of methyltransferases. Compounds presented herein may inhibit the protein lysine methyltransferase SET8. Inhibition of SET8 may disrupt transcriptional regulation, DNA replication, and/or DNA damage response, and ultimately lead to cell cycle defects or apoptosis. Inhibition of SET8 may adversely affect epithelial- mesenchymal transition (EMT) (e.g., by modulatin the interaction of SET8 with the EMT regulator, TWIST), and reduce the ability of cancer cells to metastasize.
[0010] In one aspect, the invention provides compounds of Formula (III):
[0011] In one aspect, the invention provides pharmaceutical compoistions and kits of a compound described herein (e.g. , a compound of Formula (I), (II), or (III)). Pharmaceutical compositions comprise one ore more optional excipients and may comprise a therapeutically or prophylactically effective amount of a compound described herein. Pharmaceutical compoistions and kits may also comprise additional pharmaceutical agents (e.g. , anti-cancer agents).
[0012] In one aspect, the invention provides methods of treating a proliferative disease by administering a compound as described herein (e.g. , a compound of Formula (I), (II), or (III)). The proliferative disease may be cancer or a metastatic cancer. In certain embodiments, the cancer is leukemia, breast cancer, triple negative breast cancer (TBNC), or melanoma. In certain embodiments, the cancer is a metastatic cancer, such as metastatic breast cancer or metastatic melanoma.
[0013] In another aspect, the invention provides methods for inhibiting the activity of
SET8 in a subject by administering to the subject a compound as described herein. The activity of SET8 in a biological sample may also be inhibited by contacting a biological sample, such as a cell or tumor, with a compound as described herein.
[0014] In another aspect, the invention provides methods for labelling SET8 or another methyltransferase. The compound may be labelled (e.g. , with a radioisotope) and then contacted to SET8, in vivo by administering the labelled compound to a subject, or in vitro by administering the labelled compound ot a biological sample.
[0015] The details of certain embodiments of the invention are set forth in the
Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
[0017] Figure 1. Western blot assays for SETD8, H4K20me, and H3 after treatment of HeLa, HeK293, MDA-MB-213, MDA-MB-231 (TGL), K562, and MCF7 cell lines with SPECS21 at various concentrations.
[0018] Figure 2. Western blot assays for SETD8, H4K20me, and H3 after treatment of MDA-MB-213, MDA-MB-231 (TGL), and MCF7 cell lines with SGSS05-NS at various concentrations.
[0019] Figure 3. Western blot assays for SETD8, H4K20me, MCM5, and H3 after treatment of HeLa, HeK293, MDA-MB-213, MDA-MB-231 (TGL), and MCF7 cell lines with SGSS05-NS at various concentrations.
[0020] Figure 4. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SPECS21 for 24 hours.
[0021] Figure 5. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-05NS for 24 hours.
[0022] Figure 6. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-15NS for 24, 48, and 72 hours.
[0023] Figure 7. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-04NS for 24, 48, and 72 hours.
[0024] Figure 8. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-16NS for 24 and 48 hours.
[0025] Figure 9. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-19NS for 24 and 48 hours.
[0026] Figure 10. Images of survival study on MDA-MB-231 (TGL) cells incubated with various concentrations of SGSS-22NS for 24 and 48 hours.
[0027] Figure 11. Graph of mice weights from maximum tolerated dose experiments on Athymic female 5-6 week old mice. Compounds SPECS21, SGSS05-N, and SGSS05-NS were administered in DMSO, salt, and nano encapsulated forms.
[0028] Figure 12. Graph of mice weights from maximum tolerated dose experiments on Athymic female 5-6 week old mice. Compounds SPECS21, SGSS05-N, and SGSS05-NS were administered at doses between 5 mg/kg and 75 mg/kg. [0029] Figure 13. Preparation of MDA-MB-231-LM2 cell lines with constitutive expression of luciferase for mouse xenograft experiments.
[0030] Figure 14. Graph of tumor volume over five weeks of treatment with
SGSS05-NS in luciferase expressing MDA-MB-231-LM2 mouse xenograft model, control and treated group.
[0031] Figure 15. Graph of mice weights over five weeks of treatment with SGSS05-
NS in luciferase expressing MDA-MB-231-LM2 mouse xenograft model, control and treated group.
[0032] Figure 16. Bioluminescence images of luciferase expressing MDA-MB-231-
LM2 mouse xenograft model, control and treated group, over 4 weeks of treatment with SGSS05-NS.
[0033] Figure 17. Assessment of metastasis by bioluminescence in luciferase expressing MDA-MB-231-LM2 mouse xenograft model, control and treated group, after four and five weeks of treatment with SGSS05-NS.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0034] The present invention provides compounds of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro; Z is O or NRZ;
R is hydrogen or optionally substituted alkyl;
each of R2a and R2b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is hydrogen, NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
or RJa and RJb are joined to form an optionally substituted 6-membered heterocyclic ring;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
[0035] In certain embodiments, RJ is a non-hydrogen group. In certain embodiments,
R K is a non-hydrogen group. In certain embodiments, each of R J and R K is a non-hydrogen group. In certain embodiments, each of R J and R K is not methyl. In certain embodiments, each of R J and R K is not methyl or butyl. In certain embodiments, a compound of Formula (I) is not of formula:
[0036] In certain embodiments, a compound of Formula (I) is a compound of
Formula (II):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is -C(=0)RJc;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl; provided RJ is not -CH3. [0037] In certain embodiments, a compound of Formula (II) is not of formula:
In certain embodiments, a compound of Formula (II) is a compound of
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof.
[0039] In certain embodiments, a compound of Formula (II) is a compound of
Formula (Ila'):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof.
[0040] In certain embodiments, a compound of Formula (II) is a compound of
Formula (lib), (lie), (lid), or (He):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof. [0041] In certain embodiments, the compound is present in a mixture of compounds
(e.g., a mixture of a compound of Formula (lib) and a compound of Formula (lie), a mixture of a compound of Formula (lid) and a compound of Formula (He).
[0042] Unless otherwise specified, "one or two substituents" (or "one or more substituent"), when present, need not be the same. For instance, a (C1-C12)hydrocarbyl may be substituted with one nitro group, with two methyl groups, or with one fluoro group and one methyl group.
[0043] In some embodiments, X is N. In other embodiments, X is CRX.
[0044] In some embodiments, Rx is hydrogen. In other embodiments, Rx is hydroxyl.
In some embodiments, R X is (C1-C4)alkoxy. In other embodiments, R X is halogen. In some embodiments, R X is (C X
1-C6)alkyl. In other embodiments, R is (C1-C6)haloalkyl. In still other embodiments, R X is cyano. In yet other embodiments, R X is nitro. In some embodiments, RX is optionally substituted acyl. In some embodiments, R X is -C(=0)R E , wherein RE is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -C(=0)OR E , wherein RE is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -C(=0)NHR E , wherein RE is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -C(=0)N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally
p
substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In some embodiments, R is optionally substituted amino. In some embodiments, R is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R is unsubstituted amino. In some embodiments, R X is optionally substituted sulfonyl. In some embodiments, R X is -S(=0)2R E , p
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -S(=0)2OR E , wherein RE is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -S(=0)2NHR E , wherein RE is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R X is -S(=0)2N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or p
optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. [0045] In some embodiments, Y is N. In other embodiments, Y is CR .
[0046] In some embodiments, RY is hydrogen. In other embodiments, RY is hydroxyl.
Y Y
In some embodiments, R is (C1-C4)alkoxy. In other embodiments, R is halogen. In some
Y Y
embodiments, R is (C1-C6)alkyl. In other embodiments, R is (C1-C6)haloalkyl. In still other
Y Y Y
embodiments, R is cyano. In yet other embodiments, R is nitro. In some embodiments, R
Y E E
is optionally substituted acyl. In some embodiments, R is -C(=0)R , wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally
Y E E
substituted heteroaryl. In some embodiments, R is -C(=0)OR , wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally
Y E E
substituted heteroaryl. In some embodiments, R is -C(=0)NHR , wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted
Y E E
heteroaryl. In some embodiments, R is -C(=0)N(R )2, wherein each R is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally
p
substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In some embodiments, R is optionally substituted amino. In some embodiments, R is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R is unsubstituted amino. In some
Y Y E
embodiments, R is optionally substituted sulfonyl. In some embodiments, R is -S(=0)2R , p
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or
Y E E
optionally substituted heteroaryl. In some embodiments, R is -S(=0)2OR , wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or
Y E E
optionally substituted heteroaryl. In some embodiments, R is -S(=0)2NHR , wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally
Y E E
substituted heteroaryl. In some embodiments, R is -S(=0)2N(R )2, wherein each R is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or p
optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
[0047] In some embodiments, X is CRX and Y is CRY. In some of these
X Y
embodiments, R and R are each selected from hydrogen and hydroxyl. In still other
X Y
embodiments, R and R are each hydrogen. In some embodiments, either of X or Y is N. In some embodiments, X is N and Y is N.
[0048] In some embodiments, Z is O. In other embodiments, Z is NRZ.
[0049] In some embodiments, Rz is hydrogen. In other embodiments, Rz is optionally substituted (C -C ) alkyl. In other embodiments, R is methyl. [0050] In certain embodiments, G is -C(=Z1)-. In some embodiments, Z1 is O. In other embodiments, Z is NR Zl . In some embodiments, R Zl is hydrogen. In other
embodiments, R Zl is optionally substituted (CrC6) alkyl. In other embodiments, R Zl is methyl.
[0051] In certain embodiments, G is -N(RL)-. In some embodiments, RL is hydrogen.
In some embodiments, RL is optionally substituted (C1-C12)hydrocarbyl. In some
embodiments, RL is optionally substituted (C1-C6)alkyl. In some embodiments, RL is optionally substituted acyl. In some embodiments, R L is -C(=0)R E , wherein RE is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R L is -C(=0)R E , wherein RE is methyl, benzyl, or butyl. In some embodiments, R L is -C(=0)OR E , wherein RE is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R L is -C(=0)NHR E , wherein RE is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some
embodiments, R L is -C(=0)N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two p
R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
[0052] In some embodiments, W is N. In other embodiments, W is CR2a.
[0053] In some embodiments, R2a is hydrogen. In other embodiments, R2a is hydroxyl. In some embodiments, Rz is (C1-C4)alkoxy. In other embodiments, R2a is halogen. In some embodiments, R2a is (C1-C6)alkyl. In other embodiments, R2a is (C1-C6)haloalkyl. In still other embodiments, R2a is cyano. In yet other embodiments, R2a is nitro. In some embodiments, R2a is optionally substituted acyl. In some embodiments, R2a is -C(=0)RE, p
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2<i is -C(=0)OR E , wherein R E is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2<i is -C(=0)NHR E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2a is -C(=0)N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or p
optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In some embodiments, R2a is optionally substituted amino. In some embodiments, R2a is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R a is unsubstituted amino. In some embodiments, R2a is optionally substituted sulfonyl. In some embodiments, R2a is
-S(=0)2R E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2<i is -S(=0)2OR E , p
wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R2a is
-S(=0)2NHR E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R2a is
-S(=0)2N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl,
p
optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
[0054] In some embodiments, V is N. In other embodiments, V is CR2b.
[0055] In some embodiments, R2b is hydrogen. In other embodiments, R2b is hydroxyl. In some embodiments, R2b is (C1-C4)alkoxy. In other embodiments, R2b is halogen. In some embodiments, R2b is (C1-C6)alkyl. In other embodiments, R2b is (C1-C6)haloalkyl. In still other embodiments, R2b is cyano. In yet other embodiments, R2b is nitro. In some embodiments, R2b is optionally substituted acyl. In some embodiments, R2b is -C(=0)RE, p
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2b is -C(=0)OR E , wherein R E is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2b is -C(=0)NHR E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2b is -C(=0)N(R E )2, wherein each R E is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or p
optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In some embodiments, R2b is optionally substituted amino. In some embodiments, R2b is mono substituted amino, wherein the substituent optionally substituted acyl. In some embodiments, R2b is unsubstituted amino. In some embodiments, R2b is optionally substituted sulfonyl. In some embodiments, R2b is
-S(=0)2R E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 2b is -S(=0)2OR E , p
wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R2b is
-S(=0)2NHR E , wherein R E is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R is
E E
-S(=0)2N(R )2, wherein each R is independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.
[0056] In some embodiments, W is CR2a and V is CR2b. In some of these
embodiments, R2a and R2b are each selected from hydrogen and hydroxyl. In still other embodiments, R2a and R2b are each hydrogen. In some embodiments, either of W or V is N.
[0057] In some embodiments, R2a and R2b are each independently selected from the group consisting of hydrogen, halogen, (C1-Cg)alkyl, (C1-C6)haloalkyl, hydroxyl, (C - C6)alkoxy, cyano, and nitro. In some embodiments, R2a and R2b are both hydrogen. In other embodiments, together with the carbons to which they are attached, R2a and R2b form a 5- or 6-membered ring (e.g., carbocyclic, heterocyclic, aryl, heteroaryl). In other embodiments, R and R2b, together with the carbons to which they are attached, form a phenyl ring. In some embodiments, R2a and R2b are joined to form a ring of formula:
wherein the ring is optionally substituted at one or more carbon or nitrogen atoms as valency permits, the substituents being selected from the group consisting of halogen, optionally substituted (Ci-C6)alkyl, (Ci-C6)alkoxy, hydroxyl, cyano, nitro, optionally substituted amino and optionally substituted acyl.
[0058] In certain embodiments, RJ is hydrogen. In certain embodiments, RJ is a non- hydrogen group.
[0059] In some embodiments, RJ is (C1-C12)hydrocarbyl. In some embodiments, RK is chloro and R is (C1-C12)hydrocarbyl. In some embodiments, R is -SR and R is (C - C12)hydrocarbyl. In some embodiments, the (C1-C12)hydrocarbyl is unsubstituted. In still other embodiments, the (Ci-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C6)alkoxy, halogen, (C Cs kyl, (CrCs^aloalkyl, cyano, nitro, and amino. [0060] In some embodiments, RJ is (C2-C12)hydrocarbyl. In some embodiments, RK is chloro and R is (C2-C12)hydrocarbyl. In some embodiments, R is -SR and R is (C2- C12)hydrocarbyl. In some embodiments, the ^-C^hydrocarbyl is unsubstituted. In still other embodiments, the ^-C^hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, (Q-C^haloalkyl, cyano, nitro, and amino.
[0061] In some embodiments, RJ is unsubstituted (C1-Cg)alkyl. In some embodiments,
R is chloro and R is unsubstituted (C1-Cg)alkyl. In some embodiments, R is -SR and R is unsubstituted (C1-Cg)alkyl. In still other embodiments, RJ is (Q-Cg) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (Ci-Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, RJ is methyl.
[0062] In some embodiments, RJ is unsubstituted (C2-Cg)alkyl. In some embodiments,
R is chloro and R is unsubstituted (C2-Cg)alkyl. In some embodiments, R is -SR and R is unsubstituted (C2-Cg)alkyl. In still other embodiments, RJ is (C2-C8) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (Ci-C6)alkoxy, halogen, (Ci-Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, RJ is methyl.
[0063] In some embodiments, RJ is NRaRb.
[0064] In some embodiments, RJa is hydrogen. In other embodiments, RJa is (Q-
C12)hydrocarbyl. In some embodiments, the (C1-C12)hydrocarbyl is unsubstituted. In other embodiments, the (C1-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C6)alkoxy, halogen, (Ci-Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, RJa is optionally substituted cyclic (Cs-6)hydrocarbyl. In other substituents, RJa is optionally substituted benzyl. In some embodiments, RJa is -C(=0)Rc.
[0065] In some embodiments, RJb is hydrogen. In other embodiments, RJb is (Q-
C12)hydrocarbyl. In some embodiments, the (C1-C12)hydrocarbyl is unsubstituted. In other embodiments, the (C1-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (C1-C6)alkoxy, halogen, (C1-C8)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, RJb is optionally substituted cyclic (C5-6)hydrocarbyl. In other substituents, R^ is optionally substituted benzyl. In some embodiments, RJb is -C(=0)Rc.
[0066] In some embodiments, RJc is (C1-C8)hydrocarbyl. In some embodiments, the
(C1-C8)hydrocarbyl is unsubstituted. In other embodiments, the (C1-Cg)hydrocarbyl is substituted with one or more groups selected from hydroxyl, (C1-C6)alkoxy, halogen, (C - Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, R c is optionally substituted alkyl, phenyl, or benzyl. In other embodiments, RJc is methyl.
[0067] In some embodiments, RJa and RJb are each independently selected from (Cr
C6)alkyl. In some embodiments, RJa and RJb are each independently selected from methyl and ethyl. In some embodiments, RJa and R^, together with the nitrogen to which they are attached, form an optionally substituted 6-membered heterocyclic ring. In some
embodiments, RJa and RJb, together with the nitrogen to which they are attached, form a piperidine or morpholine. In some embodiments, RJa and RJb, together with the nitrogen to which they are attached, form a piperazine or a diazepane. In these embodiments, the formed piperazine or diazepane may be optionally substituted on the second nitrogen (i.e., the nitrogen not directly attached to the quinone) with (C1-C2o)hydrocarbyl. In some
embodiments, the (C1-C2o)hydrocarbyl is methyl, ethyl, or benzyl. The (C1-C2o)hydrocarbyl may be optionally substituted with hydroxy, (C1-C6)alkoxy, carboxy, acyl, or halogen. In some embodiments, RJa and RJb, together with the nitrogen to which they are attached, form a piperazine substituted by methyl.
[0068] In certain embodiments, RJ is of formula:
[0069] In certain embodiments, RJ is of formula:
[0070] In some embodiments, n is 1, forming a piperazine. In other embodiments, n is
2, forming a diazepane.
[0071] In some embodiments, RJ3 is optionally substituted (C1-C2o)hydrocarbyl. In some embodiments, R J3 is methyl. In some embodiments, R J3 is ethyl. In some embodiments,
R J3 is benzyl. In some embodiments, R J3 is optionally substituted methyl. In some
embodiments, R J3 is optionally substituted ethyl. In some embodiments, R J3 is optionally substituted benzyl. The optional substituents on the (C1-C2o)hydrocarbyl are selected form hydroxy, (Ci-C6)alkoxy, carboxy, acyl, and halogen.
In some embodiments, R J3 is of formula:
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
[0072] In some embodiments, RK is hydrogen. In some embodiments, RK is a non- hydrogen group. In some embodiments, R is halogen. In some embodiments, R is chloro. In other embodiments, R is fluoro. In some embodiments, R is optionally substituted (C - C12)hydrocarbyl. In still other embodiments, the (Ci-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C6)alkoxy, halogen, (C1-Cg)alkyl, cyano, nitro, and optionally substituted amino. In some embodiments, R is optionally substituted (C1-Cg)alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is optionally substituted aralkyl. In some embodiments, R is benzyl. In still other embodiments, R is -SR .
[0073] In some embodiments, RKa is optionally substituted (C1-C12)hydrocarbyl. In still other embodiments, the (C1-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C6)alkoxy, halogen, (C Cs kyl, (Cr C8)haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino. In some embodiments, R is optionally substituted (C - Cg)alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is optionally substituted aryl. In some embodiments, R is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (C1-C6)alkyl, optionally substituted aryl, (C1-C6)alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino. In some embodiments, R is phenyl. In other embodiments, R is substituted phenyl. In still other embodiments, R is para-substituted phenyl. In still other embodiments, R is ortho- or meta- substituted phenyl. In some embodiments R a is naphthyl. In some embodiments, R a is optionally substituted heteroaryl. In some embodiments, R is a monocyclic heteroaromatic ring.
[0074] In some embodiments, RKa is:
wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
heterocyclyl, or optionally substituted heteroaryl.
[0075] In some embodiments, RKa is:
[0076] In some embodiments, RK is -SRKa, RKa is phenyl; RJ is of formula:
n is 1 ; and R is methyl, ethyl, or benzyl.
[0077] In certain embodiments, a compound of Formula (I) is of Formula (III):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
G is -C{=Z1)- or -N(RL)-;
Z1 is O or NRZ1 ;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl; V is CR/B or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
n is 1 or 2;
U is N, O, or CH2, wherein if U is O or CH2 R is absent;
R is hydrogen or optionally substituted hydrocarbyl;
R4 is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR4a; and
R4a is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl.
[0078] In certain embodiments, a compound of Formula (III) is of Formula (Ilia):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof.
[0079] In certain embodiments, a compound of Formula (III) is of Formula (Ilia'):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof. [0080] In certain embodiments, a compound of Formula (III) is of Formula (Illb),
(IIIc), (Hid), or (Hie):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof.
[0081] In certain embodiments, the compound is present in a mixture of compounds
(e.g. , a mixture of a compound of Formula (Illb) and a compound of Formula (IIIc), a mixture of a compound of Formula (Hid) and a compound of Formula (Hie).
[0082] In some embodiments, R3 is optionally substituted (C1-C2o)hydrocarbyl. In
3 3
some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments,
3 3
R is benzyl. In some embodiments, R is optionally substituted methyl. In some
3 3 embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted benzyl. The optional substituents on the (C1-C2o)hydrocarbyl are selected form hydroxy, (Ci-C6)alkoxy, carboxy, acyl, and halogen.
In some embodiments, R is of formula:
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
[0083] In some embodiments, R4 is hydrogen. In some embodiments, R4 is a non- hydrogen group. In some embodiments, R4 is halogen. In some embodiments, R4 is chloro. In other embodiments, R4 is fluoro. In some embodiments, R4 is optionally substituted (Q- C12)hydrocarbyl. In still other embodiments, the (C1-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (Ci-C6)alkoxy, halogen, (Ci-C8)alkyl, (C1-C8)haloalkyl, cyano, nitro, and optionally substituted amino. In some embodiments, R4 is optionally substituted (C1-Cg)alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is optionally substituted aralkyl. In some embodiments, R4 is benzyl. In still other embodiments, R4 is -SR4a.
[0084] In some embodiments, R4a is optionally substituted (C1-C12)hydrocarbyl. In still other embodiments, the (C1-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, (C - C8)haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino. In some embodiments, R4a is optionally substituted (Q- Cg)alkyl. In some embodiments, R4a is methyl. In some embodiments, R4a is ethyl. In some embodiments, R4a is optionally substituted aryl. In some embodiments, R4a is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (Ci-C6)alkyl, optionally substituted aryl, (Ci-C6)alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino. In some embodiments, R4a is phenyl. In other embodiments, R4a is substituted phenyl. In still other embodiments, R4a is para- substituted phenyl. In still other embodiments, R4a is ortho- or meta- substituted phenyl. In some embodiments R4a is naphthyl. In some embodiments, R4a is optionally substituted heteroaryl. In some embodiments, R4a is a monocyclic hetero aromatic ring.
[0085] In some embodiments, R4a is:
wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
heterocyclyl, or optionally substituted heteroaryl.
[0086] In some embodiments, R4a is:
[0087] In some embodiments, R4 is -SR4a, R4a is phenyl; RJ is of formula:
n is 1; and R is methyl, ethyl, or benzyl.
[0088] In certain embodiments, a compound of Formula (I) is of Formula (IV):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
n is 1 or 2;
R is optionally substituted (C1-C2o)hydrocarbyl, wherein said (Ci-C2o)hydrocarbyl is optionally substituted one or more substituents selected from the group consisting of halogen,
(C1-C6)alkoxy, hydroxyl, carboxy, and acyl;
R4 is -F, -CI, or -SR4a; and
R4a is phenyl or monocyclic heteroaryl.
[0089] In certain embodiments, a compound of Formula (I) is of Formula (V):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein: each of R 1 and R 2 is independently (C1-C6)alkyl;
or R 1 and R 2" are joined to form a piperazine or diazepane, wherein the nitrogen not directly attached to the quinone is optionally substituted with (C1-C2o)hydrocarbyl optionally substituted with one or more substituents selected from the group consisting of halogen, (Q-
C6)alkoxy, hydroxyl, carboxy, and acyl;
R4 is -F, -CI, or -SR4a; and
R4a is phenyl or monocyclic heteroaryl.
[0090] In some embodiments, n is 1, forming a piperazine. In other embodiments, n is
2, forming a diazepane.
[0091] In some embodiments, R3 is optionally substituted (C1-C2o)hydrocarbyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments,
R 3 is benzyl. In some embodiments, R 3 is optionally substituted methyl. In some
embodiments, R 3 is optionally substituted ethyl. In some embodiments, R 3 is optionally substituted benzyl. The optional substituents on the (C1-C2o)hydrocarbyl are selected form hydroxy, (Ci-C6)alkoxy, carboxy, acyl, and halogen.
In some embodiments, R is of formula:
wherein R is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and E is an optionally substituted aryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted heteroaryl ring.
[0092] In some embodiments, R4 is hydrogen. In some embodiments, R4 is a non- hydrogen group. In some embodiments, R4 is halogen. In some embodiments, R4 is chloro. In other embodiments, R4 is fluoro. In some embodiments, R4 is optionally substituted (Cr C12)hydrocarbyl. In still other embodiments, the (Ci-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, cyano, nitro, and optionally substituted amino. In some embodiments, R4 is optionally substituted (C1-Cg)alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is optionally substituted aralkyl. In some embodiments, R4 is benzyl. In still other embodiments, R4 is -SR4a.
[0093] In some embodiments, R4a is optionally substituted (C1-C12)hydrocarbyl. In still other embodiments, the (C1-C12)hydrocarbyl is substituted with one or more substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, (C - C8)haloalkyl, cyano, nitro, optionally substituted acyl, optionally substituted sulfonyl, and optionally substituted amino. In some embodiments, R4a is optionally substituted (Q- Cg)alkyl. In some embodiments, R4a is methyl. In some embodiments, R4a is ethyl. In some embodiments, R4a is optionally substituted aryl. In some embodiments, R4a is phenyl substituted with one or more substituents selected from the group consisting of halogen, optionally substituted (Ci-C6)alkyl, optionally substituted aryl, (Ci-C6)alkoxy, hydroxyl, cyano, nitro, or optionally substituted amino. In some embodiments, R4a is phenyl. In other embodiments, R4a is substituted phenyl. In still other embodiments, R4a is para- substituted phenyl. In still other embodiments, R4a is ortho- or meta- substituted phenyl. In some embodiments R4a is naphthyl. In some embodiments, R4a is optionally substituted heteroaryl. In some embodiments, R4a is a monocyclic hetero aromatic ring.
[0094] In some embodiments, R4a is:
wherein R is hydrogen, optionally substituted hydrocarbyl, optionally substituted
heterocyclyl, or optionally substituted heteroaryl.
[0095] In some embodiments, R4a is: [0096] In some embodiments, R4 is -SR4a, R4a is phenyl; RJ is of formula:
n is 1; and R is methyl, ethyl, or benzyl.
[0097] 1 2
In some embodiments R and R are each independently selected from (Cr
1 2
C6)alkyl. In some embodiments, R and R are each independently selected from methyl and
1 2
ethyl. In some embodiments, R and R , together with the nitrogen to which they are attached, form a piperazine or a diazepane. In these embodiments, the formed piperazine or diazepane may be optionally substituted on the second nitrogen (i.e. , the nitrogen not directly attached to the quinone) with (C1-C2o)hydrocarbyl. In some embodiments, the (Cr
C2o)hydrocarbyl is methyl, ethyl, or benzyl. The (C1-C2o)hydrocarbyl may be optionally substituted with hydroxy, (C1-C6)alkoxy, carboxy, acyl, or halogen. In some embodiments,
1 2
R and R , together with the nitrogen to which they are attached, form a piperazine substituted by methyl.
[0098] In certain embodiments, a compound of Formula (I) is of Formula (Via):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
X is CRX or N;
Y is CRY or N;
each of R and R is independently hydrogen, halogen, (Ci-C6)alkyl, (C Ce^aloalkyl, (C -
C4)alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently hydrogen, halogen, (C1-Cg)alkyl, (C Ce^aloalkyl, (Cr C6)alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form a 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring.
R9 is NR9aR9b or optionally substituted (C1-C12)hydrocarbyl, wherein said (Q- C12)hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (C1-Cg)alkyl, (C1-C6)alkoxy, hydroxyl, amino, cyano, and nitro;
R9a is hydro gen or optionally substituted (C1-C12)hydrocarbyl, wherein said (Cr
C12)hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (C1-C6)alkoxy, hydroxyl, amino, cyano, and nitro;
R9b is -C(=0)R9c;
R9c is optionally substituted (Ci-Cg)hydrocarbyl, wherein said (Ci-Cg)hydrocarbyl is optionally substituted with one or more substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (C1-Cg)haloalkyl, (C1-C6)alkoxy, hydroxyl, amino, cyano, and nitro.
[0099] In certain embodiments, a compound of Formula (I) is of Formula (VIb):
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, stereoisomer, tautomer, pro-drug, or isotopically labeled derivative thereof, wherein:
X is CRX or N;
Y is CRY or N;
each of R and R is independently hydrogen, halogen, (Ci-C6)alkyl, (C Ce^aloalkyl, (C
C4)alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently hydrogen, halogen, (Ci-Cg)alkyl, (C Ce^aloalkyl, (Cr C6)alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form a 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring.
R10 is optionally substituted (C2-Cg)alkyl, wherein said (C2-Cg) alkyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (Cr Cg)haloalkyl, (C1-C6)alkoxy, hydroxyl, amino, cyano, and nitro;
R11 is optionally substituted (CrC^hydrocarbyl, wherein said (Ci-C^hydrocarbyl is optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Cg)alkyl, (Ci-C6)alkoxy, hydroxyl, amino, cyano, and nitro; provided R10 is not butyl. [00100] In some embodiments, the compound is of Formula (Via). In some of these embodiments, R9 is (Q-C^hydrocarbyl. In some embodiments, the (C1-C12)hydrocarbyl is unsubstituted. In still other embodiments, the (Ci-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C6)alkoxy, halogen, (C1-C8)alkyl, (Cr
Cg)haloalkyl, cyano, nitro, and amino. In some of these embodiments, R9 is (C2- C12)hydrocarbyl. In some embodiments, the (C2-C12)hydrocarbyl is unsubstituted. In still other embodiments, the (C2-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (Ci-C6)alkoxy, halogen, cyano, nitro, and amino.
[00101] In some embodiments, R9 is NRaRb.
[00102] In some embodiments, Ra is hydrogen. In other embodiments, Ra is (Q-
C12)hydrocarbyl. In some embodiments, the (Ci-C12)hydrocarbyl is unsubstituted. In other embodiments, the (C1-C12)hydrocarbyl is substituted with one or two substituents selected from hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, Ra is optionally substituted cyclic (Cs-6)hydrocarbyl. In other substituents, Ra is optionally substituted benzyl.
[00103] In some embodiments, Rb is -C(=0)Rc.
[00104] In some embodiments, Rc is (C1-Cg)hydrocarbyl. In some embodiments, the
(Ci-C8)hydrocarbyl is unsubstituted. In other embodiments, the is substituted with one or more groups selected from hydroxyl, (Ci-C6)alkoxy, halogen, (Cr Cg)alkyl, (C1-Cg)haloalkyl, cyano, nitro, and amino. In some embodiments, Rc is optionally substituted alkyl, phenyl, or benzyl. In other embodiments, Rc is methyl.
[00105] In some embodiments, the compound is of Formula (VIb). In other embodiments, R10 is unsubstituted (C2-C8)alkyl. In still other embodiments, R10 is (C2-C8) alkyl substituted with one or two substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, cyano, nitro, and amino.
[00106] In some embodiments, R11 is (Ci-C^hydrocarbyl. In still other embodiments, the (Ci-C12)hydrocarbyl is substituted with one or two substituents selected from the group consisting of hydroxyl, (C1-C6)alkoxy, halogen, (C1-Cg)alkyl, cyano, nitro, and amino. In some embodiments, R11 is unsubstituted phenyl. In other embodiments, R11 is substituted phenyl. In still other embodiments, R11 is ortho- or meta- substituted phenyl.
[00107] In certain embodiments, the compound, compound used in a pharmaceutical composition, or compound used in a method is a compound listed in Table El, Table E2, or Table E3. [00108] In certain embodiments, the compound, compound used in a pharmaceutical composition, or compound used in a method is of formula:

[00111] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Alternatively, a plurality of molecules of a single structure may include at least one atom that occurs in an isotopic ratio that is different from the isotopic ratio found in nature.
Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include H, 3H, nC, 13C, 14C, 15N, 35S, 18F, 36C1, 125I, 124I and 13 ll respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes UC, 13N, 150,
124 I and 18 F are well suited for positron emission tomography. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared when making the compounds of the invention by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
[00112] Other labeling techniques may be used for in vitro assays. For instance, fluorescence, luminescence, or colorimetric tests are also used in detection and/or
diagnostics. Quantum dots, fluorescent dyes, colorimetric dyes, or luminescent compounds are often used as label reagents. Any label that is suitable for a diagnostic test and that may be attached to a compound of the invention may be used in vitro.
[00113] In one aspect, the invention relates to a method of labeling SET8. In some embodiments, the method includes exposing SET8 to a compound described herein
containing a label. In some embodiments, the method includes exposing SET8 to a compound described herein containing a label.
[00114] Persons of skill will readily appreciate that compounds described herein, when appropriately labeled as described above, can be employed in a method of identifying (i.e. labeling) specific methyltransferase enzymes in the presence of other enzymes, including other methyltransferase enzymes, for which their affinity is lower. Usually two orders of magnitude difference in affinity will be sufficient to distinguish between enzymes. Using methods well known to persons of skill in the art, specific methyltransferase enzymes can be localized in tissues, cells and organelles. A further aspect of the invention described herein is thus a method of identifying and/or localizing specific methyltransferase enzymes.
Pharmaceutical Compositions and Administration
[00115] In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (I). In certain embodiments, a pharmaceutical
composition described herein comprises a compound of Formula (II). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (III). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (IV). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (V). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (Via). In certain
embodiments, a pharmaceutical composition described herein comprises a compound of Formula (VIb).
[00116] While it may be possible for the compounds described herein to be
administered as the raw chemical, in some instances, a compound is presented as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound described herein together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions may be formulated for oral, topical or parenteral administration. For example, they may be given intravenously, intraarterially, subcutaneously, and directly into the CNS - either intrathecally or intracerebroventricularly.
[00117] Formulations include those suitable for oral, parenteral (including
subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The compounds are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
[00118] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [00119] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
[00120] The present invention thus provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, and optionally a
pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
[00121] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting SET8 in vivo in a subject. In certain embodiments, the effective amount is an amount effective for inhibiting SET8 in vitro in a biological sample.
[00122] In certain embodiments, the effective amount is an amount effective for inhibiting SET8 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting SET8 by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for a range of inhibition between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
[00123] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
[00124] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
[00125] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
[00126] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
[00127] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
[00128] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
[00129] Exemplary surface active agents and/or emulsifiers include natural emulsifiers
(e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
[00130] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. [00131] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.
[00132] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
[00133] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
[00134] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
[00135] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[00136] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
[00137] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.
[00138] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.
[00139] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[00140] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
[00141] Liquid dosage forms for oral and parenteral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
[00142] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00143] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00144] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be
accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
[00145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.
[00146] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[00147] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of encapsulating agents which can be used include polymeric substances and waxes.
[00148] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
[00149] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in- water and/or water-in- oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
[00150] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for
administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
[00151] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [00152] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
[00153] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
[00154] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
[00155] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
[00156] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
[00157] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
[00158] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct
administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
[00159] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
[00160] In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
[00161] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
[00162] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting SET8), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
[00163] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents.
Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., infectious disease, proliferative disease, hematological disease, or painful condition). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
[00164] The additional pharmaceutical agents include, but are not limited to, antidiabetic agents, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, antiinflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-allergic agents, contraceptive agents, and pain-relieving agents.
[00165] In one aspect, the additional pharmaceutical agent is an anti-cancer agent.
Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
[00166] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or
immunodulatory agents (e.g., IL- 1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM- CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
[00167] Exemplary chemotherapeutic agents include, but are not limited to, anti- estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g.
dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor- activated pro-drug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate;
docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), antimetabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and
fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
(TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTEVIA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab
(CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (V ARGATEF® ) , AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL- 184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, caraiinomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine.
[00168] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for breast cancer. Exemplary anti-cancer agents for the treatment or prevention (or both) of breast cancer include, but are not limited to: ABITREXATE® (Methotrexate), ABRAXANE® (Paclitaxel Albumin- stabilized Nanoparticle Formulation), AC, AC-T, ADRIAMYCIN PFS® (Doxorubicin Hydrochloride), ADRIAMYCIN RDF® (Doxorubicin Hydrochloride), ADRUCIL® (Fluorouracil), AFINITOR® (Everolimus), AFINITOR DISPERZ® (Everolimus), AREDIA® (Pamidronate Disodium), ARIMIDEX®
(Anastrozole), AROMASIN® (Exemestane), CAF, CLAFEN® (Cyclophosphamide), CMF, CYTOXAN® (Cyclophosphamide), Doxorubicin Hydrochloride, EFUDEX® (Fluorouracil), ELLENCE® (Epirubicin Hydrochloride), FARESTON® (Toremifene), FASLODEX® (Fulvestrant), FEC, FEMARA® (Letrozole), Fluoroplex® (Fluorouracil), FOLEX®
(Methotrexate), FOLEX PFS® (Methotrexate), GEMZAR® (Gemcitabine Hydrochloride), HERCEPTIN® (Trastuzumab), IXEMPRA® (Ixabepilone), KADCYLA® (Ado- Trastuzumab Emtansine), MEG ACE® (Megestrol Acetate), METHOTREXATE LPF® (Methotrexate), MEXATE® (Methotrexate), MEXATE-AQ® (Methotrexate), NEOSAR® (Cyclophosphamide), NOLVADEX® (Tamoxifen Citrate), PERJETA® (Pertuzumab), TAC, TAXOL® (Paclitaxel), TAXOTERE® (Docetaxel), TYKERB® (Lapatinib Ditosylate), XELODA® (Capecitabine), and ZOLADEX® (Goserelin Acetate).
[00169] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for melanoma. Exemplary anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: DTIC-DOME® (Dacarbazine), INTRON A® (Recombinant Interferon Alfa-2b), KEYTRUDA® (Pembrolizumab), MEKINIST®
(Trametinib), PROLEUKIN® (Aldesleukin), SYLATRON® (Peginterferon Alfa-2b), PEG- INTRON® (Peginterferon Alfa-2b), TAFINLAR® (Dabrafenib), YERVOY® (Ipilimumab), and ZELBORAF® (Vemurafenib).
[00170] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for leukemia. Exemplary anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: ABITREXATE® (methotrexate), ADE®,
ADRIAMYCIN RDF® (doxorubicin hydrochloride), AMBOCHLORIN® (chlorambucil), ARRANON® (nelarabine), ARZERRA® (ofatumumab), BOSULIF® (bosutinib),
BUSULFEX® (busulfan), CAMPATH® (alemtuzumab), CERUBIDINE® (daunorubicin hydrochloride), CLAFEN® (cyclophosphamide), CLOFAREX® (clofarabine), CLOLAR® (clofarabine), CVP®, CYTOSAR-U® (cytarabine), CYTOXAN® (cyclophosphamide), ERWINAZE® (Asparaginase Erwinia Chrysanthemi), FLUDARA® (fludarabine phosphate), FOLEX® (methotrexate), FOLEX PFS® (methotrexate), GAZYVA® (obinutuzumab), GLEEVEC (imatinib mesylate), HYPER-CVAD®, ICLUSIG® (ponatinib hydrochloride), IMBRUVICA® (ibrutinib), LEUKERAN® (chlorambucil), LINFOLIZIN® (chlorambucil), MARQIBO® (vincristine sulfate liposome), METHOTREXATE LPF® (methorexate), MEXATE® (methotrexate), MEXATE-AQ® (methotrexate), mitoxantrone hydrochloride, MUSTARGEN® (mechlorethamine hydrochloride), MYLERAN® (busulfan), NEOSAR® (cyclophosphamide), ONCASPAR® (Pegaspargase), PURINETHOL® (mercaptopurine), PURIXAN® (mercaptopurine), RUBIDOMYCIN® (daunorubicin hydrochloride),
SPRYCE®L (dasatinib), SYNRIBO® (omacetaxine mepesuccinate), TARABINE PFS® (cytarabine), TASIGNA® (nilotinib), TREANDA® (bendamustine hydrochloride),
TRISENOX® (arsenic trioxide), VINCASAR PFS® (vincristine sulfate), and ZYDELIG® (idelalisib).
[00171] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form. [00172] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting SET8 in a subject or in a biological sample.
[00173] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain
embodiments, the kits and instructions provide for preventing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting SET8 in a subject or in a biological sample. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
Methods of Treatment and Uses
[00174] The present invention also provides methods that may be useful for the treatment or prevention of a disease. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is leukemia. In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is metastatic breast cancer. In certain embodiments, the proliferative disease is melanoma. In certain embodiments, the disease is a disease associated with inappropriate methyltransferase activity. In certain embodiments, the disease is a disease associated with inappropriate SET8 activity. [00175] In certain embodiments, a method described herein comprises use of a compound of Formula (I). In certain embodiments, a method described herein comprises use of a compound of Formula (II). In certain embodiments, a method described herein comprises use of a compound of Formula (III). In certain embodiments, a method described herein comprises use of a compound of Formula (IV). In certain embodiments, a method described herein comprises use of a compound of Formula (V). In certain embodiments, a method described herein comprises use of a compound of Formula (Via). In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (VIb).
[00176] The compounds described herein may exhibit methyltransferase inhibitory activity, exhibit SET8 inhibitory activity, exhibit a therapeutic or preventative effect in the treatment of cancer (e.g., leukemia, breast cancer, metastatic breast cancer, melanoma), exhibit a therapeutic or preventative effect in the treatment of cancers associated with inappropriate SET8 activity, and/or exhibit a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemo therapeutic agents.
[00177] The present invention provides methods that may be useful for the treatment of a proliferative disease (e.g. , cancer (e.g., leukemia, breast cancer, metastatic breast cancer, melanoma) comprising administering a compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical composition thereof, to a subject in need thereof. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt of the compound. In certain embodiments, the compound is administered as a specific stereoisomer or mixture of stereoisomers of the compound. In certain embodiments, the compound is administered as a specific tautomer or mixture of tautomers of the compound. In certain embodiments, the compound is administered as a pharmaceutical composition as described herein comprising the compound.
[00178] The present invention also provides uses of the inventive compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and pharmaceutical compositions thereof, in the manufacture of medicaments for the treatment and prevention of diseases. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is leukemia. In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is metastatic breast cancer. In certain embodiments, the proliferative disease is melanoma. In certain embodiments, the disease is a disease associated with inappropriate methyltransferase activity. In certain embodiments, the disease is a disease associated with inappropriate SET8 activity.
[00179] In certain embodiments, the methods of the invention include administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.
[00180] In another aspect, the invention relates to a method of inhibiting the activity of
SET8. This method includes bringing SET8 into contact with a compound disclosed herein or a pharmaceutical composition disclosed herein. In some embodiments, this contact occurs in vivo. In some embodiments, this contact occurs in vitro.
[00181] In certain embodiments, the present invention provides methods that for inhibiting the activity of SET8 in a subject in need thereof, by administering to the subject a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
[00182] In certain embodiments, the present invention provides methods that for inhibiting the activity of SET8 in a biological sample (e.g., cells, tissues, biopsied tissues, purified or partially purified IDE), by contacting the sample with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
[00183] In certain embodiments, the present invention provides methods that for inhibiting methyltransferase activity in a subject in need thereof, by administering to the subject a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
[00184] In certain embodiments, the present invention provides methods that for inhibiting methyltransferase activity in a biological sample (e.g., cells, tissues, biopsied tissues, purified or partially purified IDE), by contacting the sample with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof.
[00185] The present invention also provides methods of using a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical compositions thereof, in research studies in the field of disease pathology, biochemistry, cell biology, epigenetics, and other fields associated with proliferative diseases. The compounds of the invention can be used to study the roles of biomolecules (e.g., SET8, SAM, histone H4K20, PCNA, tumor suppressor p53, p53-stabilizing factor Numb). The compounds of the invention can be used to study biological pathways (e.g., histone methylation, apoptosis). In certain embodiments, the method comprises use of the compound or composition thereof to inhibit SET8. In certain embodiments, the method comprises determining the concentration of a biomolecule (e.g., SET8, SAM, histone H4K20, PCNA, tumor suppressor p53, p53-stabilizing factor Numb) in a subject or biological sample, for example, by detecting a label (e.g., fluorophore, radioactive isotope).
[00186] For certain embodiments of the methods described herein, the disease is a cancer selected from: acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelio sarcoma, hemangio sarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g. , cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC), ER positive breast cancer, ER negative breast cancer, PR positive breast cancer, PR negative breast cancer, ER/PR positive breast cancer, ER/PR negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer); brain cancer (e.g. , meningioma, glioblastomas, glioma (e.g. , astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g. , cervical adenocarcinoma, squamous cell carcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer;
epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi' s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g. , uterine cancer, uterine sarcoma); esophageal cancer (e.g. , adenocarcinoma of the esophagus, Barrett's adenocarcinoma);
Ewing's sarcoma; ocular cancer (e.g. , intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma);
gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g. , head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g. , alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g. , nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g. , systemic mastocytosis); muscle cancer; myelodysplasia syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g. , neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g. , pancreatic
andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget' s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g. , prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g. , appendix cancer); soft tissue sarcoma (e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;
testicular cancer (e.g. , seminoma, testicular embryonal carcinoma); thyroid cancer (e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g. , Paget' s disease of the vulva).
[00187] In certain embodiments, the cancer is a metastatic cancer. A metastatic cancer is a cancer that has moved from the site in the body of subject associated with the cancer type to one or more other sites in the body of the subject. For example, metastatic breast cancer may lead to the development of cancerous tumors in the bone, brain, liver, or lungs. The cancer cells in a metastatic cancer are cells of the type of cancer, and not cells of the site at which they are present. Exemplary cancers that may occur as metastatic cancers include, but are not limited to, bladder cancer, breast cancer, colon cancer, rectal cancer, renal cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, uterine cancer, and cervical cancer. [00188] In certain embodiments, the proliferative disease is a disease associated with over-expression of SET8. In certain embodiments, the proliferative disease is a disease associated with aberrant activity of SET8. Aberrant activity of SET8 may be an elevated or an inappropriate activity of the SET8. In certain embodiments, SET8 is not over-expressed, and the activity of SET8 is not elevated or inappropriate. In certain other embodiments, SET8 is over-expressed, and the activity of SET8 is elevated or inappropriate.
[00189] In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.
[00190] In certain embodiments, the biological sample described herein is one or more cells. In certain embodiments, the biological sample described herein is one or more cancer cells. In certain embodiments, a cell described herein is in vitro. In certain embodiments, a cell described herein is ex vivo. In certain embodiments, a cell described herein is in vivo. In certain embodiments, a cell described herein is a malignant cell. In certain embodiments, a cell In certain embodiments, the biological sample described herein is blood, bone, or tissue. In certain embodiments, the biological sample described herein is bone marrow or lymph node. In certain embodiments, the biological sample described herein is biopsied tissue. In certain embodiments, the biological sample described herein is a tumor.
[00191] Certain methods described herein, may comprise administering one or more additional pharmaceutical agent in combination with the compounds described herein. In certain embodiments, the additional pharmaceutical agent may be an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. The additional pharmaceutical agent may also be an inhibitor. In certain embodiments, the additional pharmaceutical agent is an inhibitor of SET8.
[00192] In one aspect, the additional pharmaceutical agent is an anti-cancer agent.
Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. [00193] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or
immunodulatory agents (e.g., IL- 1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM- CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
[00194] Exemplary chemotherapeutic agents include, but are not limited to, anti- estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photo sensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g.
dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor- activated pro-drug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate;
docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), antimetabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and
fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
(TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTEVIA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab
(CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (V ARGATEF® ) , AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL- 184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, caraiinomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine.
[00195] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for breast cancer. Exemplary anti-cancer agents for the treatment or prevention (or both) of breast cancer include, but are not limited to: ABITREXATE® (Methotrexate), ABRAXANE® (Paclitaxel Albumin- stabilized Nanoparticle Formulation), AC, AC-T, ADRIAMYCIN PFS® (Doxorubicin Hydrochloride), ADRIAMYCIN RDF® (Doxorubicin Hydrochloride), ADRUCIL® (Fluorouracil), AFINITOR® (Everolimus), AFINITOR DISPERZ® (Everolimus), AREDIA® (Pamidronate Disodium), ARIMIDEX®
(Anastrozole), AROMASIN® (Exemestane), CAF, CLAFEN® (Cyclophosphamide), CMF, CYTOXAN® (Cyclophosphamide), Doxorubicin Hydrochloride, EFUDEX® (Fluorouracil), ELLENCE® (Epirubicin Hydrochloride), FARESTON® (Toremifene), FASLODEX® (Fulvestrant), FEC, FEMARA® (Letrozole), Fluoroplex® (Fluorouracil), FOLEX®
(Methotrexate), FOLEX PFS® (Methotrexate), GEMZAR® (Gemcitabine Hydrochloride), HERCEPTIN® (Trastuzumab), IXEMPRA® (Ixabepilone), KADCYLA® (Ado- Trastuzumab Emtansine), MEG ACE® (Megestrol Acetate), METHOTREXATE LPF® (Methotrexate), MEXATE® (Methotrexate), MEXATE-AQ® (Methotrexate), NEOSAR® (Cyclophosphamide), NOLVADEX® (Tamoxifen Citrate), PERJETA® (Pertuzumab), TAC, TAXOL® (Paclitaxel), TAXOTERE® (Docetaxel), TYKERB® (Lapatinib Ditosylate), XELODA® (Capecitabine), and ZOLADEX® (Goserelin Acetate).
[00196] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for melanoma. Exemplary anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: DTIC-DOME® (Dacarbazine), INTRON A® (Recombinant Interferon Alfa-2b), KEYTRUDA® (Pembrolizumab), MEKINIST®
(Trametinib), PROLEUKIN® (Aldesleukin), SYLATRON® (Peginterferon Alfa-2b), PEG- INTRON® (Peginterferon Alfa-2b), TAFINLAR® (Dabrafenib), YERVOY® (Ipilimumab), and ZELBORAF® (Vemurafenib).
[00197] In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent for leukemia. Exemplary anti-cancer agents for the treatment or prevention (or both) of melanoma include, but are not limited to: ABITREXATE® (methotrexate), ADE®,
ADRIAMYCIN RDF® (doxorubicin hydrochloride), AMBOCHLORIN® (chlorambucil), ARRANON® (nelarabine), ARZERRA® (ofatumumab), BOSULIF® (bosutinib),
BUSULFEX® (busulfan), CAMPATH® (alemtuzumab), CERUBIDINE® (daunorubicin hydrochloride), CLAFEN® (cyclophosphamide), CLOFAREX® (clofarabine), CLOLAR® (clofarabine), CVP®, CYTOSAR-U® (cytarabine), CYTOXAN® (cyclophosphamide), ERWINAZE® (Asparaginase Erwinia Chrysanthemi), FLUDARA® (fludarabine phosphate), FOLEX® (methotrexate), FOLEX PFS® (methotrexate), GAZYVA® (obinutuzumab), GLEEVEC (imatinib mesylate), HYPER-CVAD®, ICLUSIG® (ponatinib hydrochloride), IMBRUVICA® (ibrutinib), LEUKERAN® (chlorambucil), LINFOLIZIN® (chlorambucil), MARQIBO® (vincristine sulfate liposome), METHOTREXATE LPF® (methorexate), MEXATE® (methotrexate), MEXATE-AQ® (methotrexate), mitoxantrone hydrochloride, MUSTARGEN® (mechlorethamine hydrochloride), MYLERAN® (busulfan), NEOSAR® (cyclophosphamide), ONCASPAR® (Pegaspargase), PURINETHOL® (mercaptopurine), PURIXAN® (mercaptopurine), RUBIDOMYCIN® (daunorubicin hydrochloride),
SPRYCE®L (dasatinib), SYNRIBO® (omacetaxine mepesuccinate), TARABINE PFS® (cytarabine), TASIGNA® (nilotinib), TREANDA® (bendamustine hydrochloride),
TRISENOX® (arsenic trioxide), VINCASAR PFS® (vincristine sulfate), and ZYDELIG® (idelalisib).
DEFINITIONS
Chemical terms
[00198] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic
Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.
[00199] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et ah, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical
Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[00200] In a formula, ·™~ is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified,— is absent or a single bond, and = or = is a single or double bond. [00201] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of 12C with 13C or 14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[00202] As used herein, when a Cn-n' group (e.g., a Cn_n'hydrocarbyl group), which may also be designated a (Cn-Cn ) group, is recited, whether on its own or as part of another group (e.g., haloCn_n'hydrocarbyl or (Cn-Cn')haloalkyl), it is intended that the recitation "Cn_n'" includes all numbers and subranges falling within the n-n' range. For example, where C1-8 is recited, the recitation is intended to be shorthand, as if C1 ; C2, C3, C4, C5, C6, C7> and C8 were fully set forth. As further example, the term C1-8 is intended to include all subranges therein, including, for example, C1-6, C1-4, C1-3, C2-6, etc.
[00203] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "C1-6 alkyl" is intended to encompass, Q, C2, C3, C4, C5, C6, Ci-6, Ci-5, Ci-4, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[00204] The term "hydrocarbyl" ("hydrocarbon") is a generic term encompassing C -
Cio aliphatic, alicyclic and aromatic groups having an all-carbon backbone, except where otherwise stated. "Cn" defines the number (n) of carbon atoms in a group. Examples of hydrocarbyl groups include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Within the subset of hydrocarbyl groups are those having 1 to 8 carbon atoms, examples including C1-6 hydrocarbyl groups, such as C1-4 hydrocarbyl groups (e.g., C1-3 hydrocarbyl groups or Ci_2 hydrocarbyl groups). Specific examples of hydrocarbyl groups include any individual value or combination of values selected from C1 ; C2, C3, C4, C5, C6, C7> C8, Cg, and Cio hydrocarbyl groups. The groups -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, benzyl, and phenyl are non-limiting examples of specific hydrocarbyl groups. Hydrocarbyl includes any substituent comprised of hydrogen and carbon as the only elemental constituents.
[00205] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
[00206] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("Ο1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("Q.g alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("Cis alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Q alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (CO, ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g. , n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g. , unsubstituted w-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (w-Bu), unsubstituted iert-butyl or ί-Bu), unsubstituted sec-butyl unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn). Lower alkyl refers to alkyl groups of from 1 to 4 carbon atoms.
[00207] Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbyl groups.
Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the subset of cycloalkyl groups are cycloalkyl groups having from 3 to 8 carbon atoms, particular examples being C3_6 cycloalkyl groups. Cycloalkyl, if not otherwise limited, refers to monocycles, bicycles and polycycles.
[00208] The term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2- 7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some
embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-io alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g. , -CH=CHCH3 or ^~^jSr' ) may ^6 an or ^)- double bond.
[00209] Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1- propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl. Within the subset of alkenyl groups are those having 2 to 8 carbon atoms, particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups.
[00210] Examples of cycloalkenyl groups include, but are not limited to,
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the subset of cycloalkenyl groups are those having from 3 to 8 carbon atoms, for example, C3_6 cycloalkenyl groups.
[00211] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g. , 1, 2, 3, or 4 triple bonds) ("C2-io alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-g alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2- 6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some
embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2_4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2_6 alkenyl groups include the aforementioned C2_4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-1o alkynyl. In certain embodiments, the alkynyl group is a substituted C2-1o alkynyl.
[00212] Examples of alkynyl groups include, but are not limited to, ethynyl and
2-propynyl (propargyl) groups. Within the subset of alkynyl groups are those having 2 to 8 carbon atoms, particular examples being C2_6 alkynyl groups, such as C2_4 alkynyl groups.
[00213] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include
methylenedioxy and ethylenedioxy.
[00214] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3_14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C^o carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3_8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3_7 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3_6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4_6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl"). Exemplary C3_6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4),
cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3_8 carbocyclyl groups include, without limitation, the aforementioned C3_6 carbocyclyl groups as well as cycloheptyl (C7),
cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cg),
cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cg), and the like. Exemplary C3-1o carbocyclyl groups include, without limitation, the aforementioned C3_8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10),
spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g. , containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3_14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3_14 carbocyclyl.
[00215] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3_14 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C O cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3_8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6 cycloalkyl groups include the aforementioned C5_6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3_8 cycloalkyl groups include the aforementioned C3_6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3_14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3_14 cycloalkyl.
[00216] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g. , a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3- 14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
[00217] In some embodiments, a heterocyclyl group is a 5- 10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
[00218] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1
heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b] pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c] pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1 ,2,3,4-tetrahydro- 1 ,6-naphthyridinyl, and the like.
[00219] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g. , bicyclic or tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g. , phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl"; e.g. , naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl"; e.g. , anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.
[00220] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
[00221] The term "heteroaryl" refers to a radical of a 5- 14 membered monocyclic or polycyclic (e.g. , bicyclic, tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g. , indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g. , 5-indolyl).
[00222] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain
embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
[00223] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary
5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary
6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
[00224] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety. [00225] Reference to the formation of a ring by R a, R , and the carbons to which they are attached, shall, unless the context indicates otherwise, include carbocylic, heterocyclic, aryl, and heteroaryl rings.
[00226] The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
[00227] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms, e.g. , fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("Cis haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2 haloalkyl"). Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, -CF2C1, and the like.
[00228] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g. , alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
[00229] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g. , a substituent which upon substitution results in a stable compound, e.g. , a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable
compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.
[00230] Exemplary carbon atom substituents include, but are not limited to, halogen,
-CN, -NO2, -N3, -SO2H, -S03H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X"' -N(ORcc)Rbb, -SH, -SR"*, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, -OC(=0)Raa, -OC02Raa, -C(=0)N(Rbb)2, -OC(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -S02ORaa, -OS02Raa, -S(=0)Raa, -OS(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, -SC(=S)SRaa,
-SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)2Raa, -OP(=0)2Raa, -P(=0)(Raa)2, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)2N(Rbb)2, -OP(=0)2N(Rbb)2, -P(=0)(NRbb)2, -OP(=0)(NRbb)2, -NRbbP(=0)(ORcc)2, -NRbbP(=0)(NRbb)2, -P(RCC)2, -P(RCC)3, -OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), CM0 alkyl, CM0 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC2-1o alkenyl, heteroC2-1o alkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc;
each instance of R^ is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC2_1oalkenyl, heteroC^ioalkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R^ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN,
-C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -SOaR^, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2,
-S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC,
-P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, CM0 alkyl, CM0 perhaloalkyl,
C2-1o alkenyl, C2-1o alkynyl, heteroCi-ioalkyl, heteroC^ioalkenyl, heteroC^ioalkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC^io alkenyl, heteroC^io alkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X"' -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, -OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,
-NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree, -S(=0)Ree, -Si(Ree)3,
-OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)2Ree,
-P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2_6 alkynyl, heteroCi-ealkyl, heteroC2_6alkenyl, heteroC2_6alkynyl, C3-1o carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S;
each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi-6 alkyl, heteroC2_6alkenyl, heteroC2_6 alkynyl, C3-1o carbocyclyl, d-io aryl, 3- 10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
ff
each instance of R is, independently, selected from hydrogen, d_6 alkyl, d_6 perhaloalkyl, C2-6 alkenyl, C2_6 alkynyl, heterod_6alkyl, heteroC2_6alkenyl, heteroC2-6alkynyl, C3-1o carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5- 10 membered heteroaryl, or two ff
R groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -S0 H, -OH, -OCi_6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci_6 alkyl)2, -N(Ci_6 alkyl)3 +X"' -NH(Ci_6 alkyl)2 +X-' -NH2(Ci_6 alkyl) +X"' -NH3 +X"' -N(OCi_6 alkyl)(Ci_6 alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SCi-6 alkyl, -SS(C1-6 alkyl), -C(=0)(C1-6 alkyl), -C02H, -C02(C1-6 alkyl),
-OC(=0)(Ci_6 alkyl), -OC02(Ci_6 alkyl), -C(=0)NH2, -C(=0)N(Ci_6 alkyl)2,
-OC(=0)NH(Ci_6 alkyl), -NHC(=0)( Ci_6 alkyl), -N(Ci_6 alkyl)C(=0)( Ci_6 alkyl),
-NHC02(Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl)2, -NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci-6 alkyl), -OC(=NH)(C1-6 alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(NH)NH(d_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(Ci_6 alkyl)2, -NHC(=NH)NH2, -NHS02(Ci_6 alkyl), -S02N(d_6 alkyl)2, -S02NH(d_6 alkyl), -S02NH2, -S02d_6 alkyl, -S02OC1 6 alkyl, -OS02d-6 alkyl, -SOC1-6 alkyl, -Si(C1-6 alkyl)3, -OSi(C1-6 alkyl)3 -C(=S)N(C1-6 alkyl)2, alkyl), C(=S)NH2, -C(=0)S(C1-6 alkyl), -C(=S)SC1-6 alkyl, -SC(=S)SC1-6 alkyl, -P(=0)2(d_6 alkyl), -P(=0)(d_6 alkyl)2, -OP(=0)(d_6 alkyl)2, -OP(=0)(Od_6 alkyl)2, d_6 alkyl, d_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heterod_6alkyl, heteroC2_ 6alkenyl, heteroC2-6alkynyl, C3-1o carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S;
wherein X~ is a counterion.
[00231] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable
compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.
[00232] Exemplary carbon atom substituents include, but are not limited to, halogen,
-CN, -NO2, -N3, -SO2H, -S03H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X"' -N(ORcc)Rbb, -SH, -SR"*, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, -OC(=0)Raa, -OC02Raa, -C(=0)N(Rbb)2, -OC(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -S02ORaa, -OS02Raa, -S(=0)Raa, -OS(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, -SC(=S)SRaa,
-SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)2Raa, -OP(=0)2Raa, -P(=0)(Raa)2, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)2N(Rbb)2, -OP(=0)2N(Rbb)2, -P(=0)(NRbb)2, -OP(=0)(NRbb)2, -NRbbP(=0)(ORcc)2, -NRbbP(=0)(NRbb)2, -P(RCC)2, -P(RCC)3, -OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), CM0 alkyl, CM0 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC2-1o alkenyl, heteroC2-1o alkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc;
each instance of Raa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC2-1oalkenyl, heteroC2-1oalkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two R^ groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -SOaR^, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -Ρ(=0)^, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, CM0 alkyl, CM0 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-ioalkyl, heteroC2-1oalkenyl, heteroC2-1oalkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Rbb groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, Ci-w alkyl, Ci-w perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-io alkyl, heteroC2-1o alkenyl, heteroC2-1o alkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Rcc groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X"' -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, -OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,
-NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree, -S(=0)Ree, -Si(Ree)3,
-OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)2Ree,
-P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, d_6 alkyl, d_6 perhaloalkyl, C2_6 alkenyl, C2-6 alkynyl, heterod_6alkyl, heteroC2-6alkenyl, heteroC2_6alkynyl, C3-1o carbocyclyl, 3-10 membered heterocyclyl, d-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S;
each instance of Ree is, independently, selected from d_6 alkyl, d_6 perhaloalkyl, C2_6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
each instance of R ff is, independently, selected from hydrogen, C1-6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2_6 alkynyl, heterod_6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-1o carbocyclyl, 3-10 membered heterocyclyl, d-10 aryl and 5-10 membered heteroaryl, or two
R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OCi-6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci_6 alkyl)2, -N(Ci_6 alkyl)3 +X-' -NH(Ci_6 alkyl)2 +X-' -NH2(Ci_6 alkyl) +X"' -NH3 +X"' -N(OCi_6 alkyl)(Ci_6 alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SCi_6 alkyl, -SS(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), -C02H, -C02(Ci_6 alkyl),
-OC(=0)(Ci_6 alkyl), -OC02(Ci_6 alkyl), -C(=0)NH2, -C(=0)N(Ci_6 alkyl)2,
-OC(=0)NH(C1-6 alkyl), -NHC(=0)( C1-6 alkyl), -N(C1-6 alkyl)C(=0)( C1-6 alkyl),
-NHC02(Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl)2, -NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci_6 alkyl), -OC(=NH)(Ci_6 alkyl), -OC(=NH)OCi_6 alkyl, -C(=NH)N(Ci_6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(NH)NH(d_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHS02(C1-6 alkyl), -S02N(d_6 alkyl)2, -S02NH(d_6 alkyl), -S02NH2, -S02d_6 alkyl, -S02OC1 6 alkyl, -OS02Ci_6 alkyl, -SOCi_6 alkyl, -Si(Ci_6 alkyl)3, -OSi(Ci_6 alkyl)3 -C(=S)N(Ci_6 alkyl)2, alkyl), C(=S)NH2, -C(=0)S(C1-6 alkyl), -C(=S)SC1-6 alkyl, -SC(=S)SC1-6 alkyl, -P(=0)2(Ci_6 alkyl), -P(=0)(Ci_6 alkyl)2, -OP(=0)(Ci_6 alkyl)2, -OP(=0)(OCi_6 alkyl)2, d_6 alkyl, d_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heterod_6alkyl, heteroC2_ 6alkenyl, heteroC2_6alkynyl, C3-1o carbocyclyl, -10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S;
wherein X~ is a counterion.
[00233] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term
"substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=0)SRaa, -OC(=0)Raa, -OC02Raa, -OC(=0)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa,
-OC(=NRbb)N(Rbb)2, -OS(=0)Raa, -OSOaR^, -OSi(Raa)3, -OP(Rcc)2, -OP(Rcc)3,
-OP(=0)2Raa, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -OP(=0)2N(Rbb)2, and -OP(=0)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein.
[00234] The term "amino" refers to the group -NH2. The term "substituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a
disubstituted amino group.
[00235] The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=0)Raa, -NHC02Raa, -NHC(=0)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHS02Raa, -NHP(=0)(ORcc)2, and -NHP(=0)(NRbb)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group -NH(Rbb) is not hydrogen.
[00236] The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbb C(=0)Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbS02Raa, -NRbbP(=0)(ORcc)2, and -NRbbP(=0)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
[00237] The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3 and -N(Rbb)3 +X"' wherein Rbb and X" are as defined herein.
[00238] The term "sulfonyl" refers to a group selected from -S02N(Rbb)2, -SOaR^, and -S02ORaa, wherein Raa and Rbb are as defined herein.
[00239] The term "sulfinyl" refers to the group -S(=0)Raa, wherein Raa is as defined herein. [00240] The term "acyl" refers to a group having the general formula -C(=0)R ,
-C(=0)ORxl, -C(=0)-0-C(=0)Rxl, -C(=0)SRxl, -C(=0)N(Rxl)2, -C(=S)RX1,
-C(=S)N(RX1)2, and -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRxl)ORxl, -C(=NRX1)SRX1, and
XI XI XI
-C(=NR )N(R )2, wherein R is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or
XI
di-heteroarylamino; or two R groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-C02H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[00241] In certain embodiments, acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6,
7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.
[00242] The term "carboxy" refers to a group having the general formula
XI XI
-C(=0)OR , wherein R is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino. In certain embodiments R XI is hydrogen, optionally substituted alkyl, or optionally substituted acyl.
[00243] The term "silyl" refers to the group -Si(Raa)3, wherein Raa is as defined herein.
[00244] The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.
[00245] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -SOaR^, -C(=NRbb)Raa, -C(=NRcc)ORaa,
-C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, CM0 alkyl, CM0 perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, heteroCi-ioalkyl, heteroC2_1oalkenyl, heteroC2_ 10alkynyl, C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.
[00246] As used herein, a "leaving group" (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), -ORaa (when the O atom is attached to a carbonyl group, wherein Raa is as defined herein), -0(C=0)R , or -0(SO)2R (e.g., tosyl, mesyl, besyl), wherein RLG is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some cases, the leaving group is a halogen. In some embodiments, the leaving group is I.
[00247] As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
[00248] A "non-hydrogen group" refers to any group that is defined for a particular variable that is not hydrogen.
[00249] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.
[00250] These and other exemplary substituents are described in more detail in the
Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
[00251] MDA-MB-231 is a cell line of human breast adenocarcinoma triple-negative epithelial cells derived from a pleural effusion. MDA-MB-231 (TGL) or MDA-MB-231 (Luc) cells are MDA-MB-231 cells that have been plasmid transformed to express luciferase. MCF7 is a cell line of human breast adenocarcinoma triple-positive epithelial cells derived from a metastatic site pleural effusion. K562 is a cell line of human chronic myelogenous leukemia (CML) lymphoblasts.
[00252] MCM5 is
Other definitions
[00253] As used herein, the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts.
[00254] The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyl)4~ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
[00255] The term "solvate" refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non- stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates.
Representative solvates include hydrates, ethanolates, and methanolates.
[00256] The term "hydrate" refers to a compound that is associated with water.
Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H20, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H20)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H20) and hexahydrates (R-6 H20)).
[00257] The term "tautomers" or "tautomeric" refers to two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam- to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
[00258] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".
[00259] Stereoisomers that are not mirror images of one another are termed
"diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
[00260] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
[00261] The term "co-crystal" refers to a crystalline structure composed of at least two components. In certain embodiments, a co-crystal contains a compound of the present invention and one or more other component, including but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal contains a compound of the present invention and one or more solvent molecules. In certain embodiments, a co- crystal contains a compound of the present invention and one or more acid or base. In certain embodiments, a co-crystal contains a compound of the present invention and one or more components related to said compound, including not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment or impurity of said compound.
[00262] The term "prodrugs" refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.
[00263] The terms "composition" and "formulation" are used interchangeably.
[00264] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g. , infant, child, or adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g. , primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal "Disease," "disorder," and "condition" are used interchangeably herein.
[00265] The term "biological sample" refers to any sample including tissue samples
(such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
[00266] The term "administer," "administering," or "administration" refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
[00267] The terms "condition," "disease," and "disorder" are used interchangeably.
[00268] The term "proliferative disease" refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix
metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., "malignant neoplasms"), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
[00269] The term "cancer" refers to a class of diseases characterized by the
development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematological malignancies. Additional exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g. , lymphangiosarcoma, lymphangioendotheliosarcoma, hemangio sarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g. , adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC), ER positive breast cancer, ER negative breast cancer, PR positive breast cancer, PR negative breast cancer, ER/PR positive breast cancer, ER/PR negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer); brain cancer (e.g. , meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer;
carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma, squamous cell carcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g. , Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett' s adenocarcinoma); Ewing' s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g. , oral squamous cell carcinoma), throat cancer (e.g. , laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g. , alpha chain disease, gamma chain disease, mu chain disease;
hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g. , nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer
(NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g. , systemic mastocytosis); muscle cancer; myelodysplasia syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g. , neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g. , pancreatic
andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget' s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g. , prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g. , appendix cancer); soft tissue sarcoma (e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;
testicular cancer (e.g. , seminoma, testicular embryonal carcinoma); thyroid cancer (e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g. , Paget' s disease of the vulva).
[00270] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease or condition, which reduces the severity of the disease or condition, or retards or slows the progression of the disease or condition (i.e., "therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease or condition (i.e. , "prophylactic treatment"). A therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient,
notwithstanding that the patient may still be afflicted with the underlying disorder. The compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
[00271] An "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.
[00272] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting SET8. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting SET8 and for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)).
[00273] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a
prophylactically effective amount is an amount sufficient for inhibiting SET8. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)). In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting SET8 and for treating a proliferative disease (e.g., cancer, e.g., leukemia, breast cancer, metastatic breast cancer, melanoma)).
[00274] As used herein the term "inhibit" or "inhibition" in the context of enzymes, for example, in the context of SET8, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., SET8 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., SET8 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.
[00275] As used herein the term "SET8" or "histone lysine methyltransferase" refers to an enzyme which methylates histone H4 lysine 20 by catalyzing methyl transfer from S- adenosylmethionine to a lysine, and produces S-adenosylhomocysteine as a by-product. SET8 is alternatively referred to by other names, including SETD8, Pr-SET7, and KMT5A. The term SET8 further includes, in some embodiments, sequence variants and mutations (e.g., naturally occurring or synthetic SET8 sequence variants or mutations), and different SET8 isoforms. In some embodiments, the term SET8 includes protein or encoding sequences that are homologous to a SET8 protein or encoding sequence, for example, a protein or encoding sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% sequence identity with a SET8 sequence, for example, with a SET8 sequence provided herein. SET8 protein and encoding gene sequences are well known to those of skill in the art, and exemplary protein sequences include, but are not limited to, the following sequences. Additional SET8 sequences, e.g., SET8 homologues from other bacteria species, will be apparent to those of skill in the art, and the invention is not limited to the exemplary sequences provided herein.
[00276] >gil45356743lreflNP_065115.31 N-lysine methyltransferase SETD8 [Homo sapiens]
MARGRKMSKPRAVEAAAAAAAVAATAPGPEMVERRGPGRPRTDGENVFTGQSKI YSYMSP NKCSGMRFPLQEE SVTHHEVKCQGKPLAGI YRKREEKRNAGNAVRSAMKSEEQKIKDAR KGPLVPFPNQKSEAAEPPKTPPS SCDSTNAAIAKQALKKP IKGKQAPRKKAQGKTQQNRK LTDFYPVRRS SRKSKAELQSEERKRI DEL IESGKEEGMKI DL I DGKGRGVIATKQFSRGD FWEYHGDL IE I TDAKKREALYAQDPSTGCYMYYFQYLSKTYCVDATRETNRLGRL INHS KCGNCQTKLHDI DGVPHL I L IASRDIAAGEELLYDYGDRSKAS IEAHPWLKH ( SEQ I D NO : 1 ) EXAMPLES
[00277] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
Synthesis of the compounds Naphthoquinones with sulfur substituents
[00278] Various para-naphthoquinones (1 equiv.) were mixed in an
ethanol/isopropanol (55/45) mixture with different thiols (3.5 equiv.) for 24 hours at room temperature {Scheme El). In each example, the reaction mixture was diluted in water and extracted with diethyl ether, followed by washing with CuS04 10% (w/v) and brine. The organic phase was dried on MgS04, concentrated by vacuum and the final products purified on normal phase silica by flash chromatography (EtOAc/Hexanes). Yields of 12 ranged from 5 to 71% {Scheme El).
Scheme El.
Chloro-naphthoquinones with nitrogen substituents
[00279] Dichloro naphthoquinone (1 equiv.) was mixed with a variety of amines (1.1 equiv.) in 1,4 dioxane for 24 hours at room temperature {Scheme E2 (b)). In each example, the resulting mixture was washed with saturated NHCO3 and extracted with ethylacetate. The organic phase was washed with water and brine, dried on sodium sulfate and concentrated by vacuum. The final products (15) were purified on normal phase silica by flash
chromatography (ethylacetate/hexanes; toluene/hexanes; dichloromethane/methanol, depending on product), yields ranged from 10 to 90% {Scheme E2 (b)). Scheme E2.
overnight
Chloro-naphthoquinones with carbon substituents
[00280] Dichloro naphthoquinone (1 equiv.) was mixed with various boronic acids/pinacols (1.2 equiv.) in the presence of CsF (2.4 equiv.), Pd2(dba)3 (0.24 equiv.) catalyst and HP(tBu)3 ligand, in dry 1,4 dioxane at 70 °C overnight (Scheme E2 (c)). In each example, the resulting mixture was washed with saturated NHC03, and extracted with ethylacetate. The organic phase was washed with water and brine, dried on sodium sulfate and concentrated by vacuum. The final products were purified on silica by flash
chromatography (dichloromethane/hexanes; toluene/hexanes, depending on product) and in some cases by an additional reverse phase HPLC step (AcetonitrileAVater, 0.1 % (v/v) TFA). Yields for the different compounds (16) ranged from 20 to 40% (Scheme E2 (c)).
Naphthoquinones functionalized with thiols
[00281] Compound 15 or 16 (1 equiv.) was stirred in MeOH or DMF (depending on the different starting materials) with thiophenol (2 equiv.) in the presence of triethylamine (2 equiv.) at 70 °C overnight (Scheme E3). The resulting mixtures were washed with saturated NHC03, and extracted with ethylacetate. The organic phase was washed with water and brine, dried on sodium sulfate and concentrated by vacuum. Finally, the products were purified on silica by flash chromatography (ethylacetate/hexanes; toluene/hexanes;
dichloromethane/methanol, depending on product). Yields for the different compounds (17 and 18) ranged from 18 to 85% (Scheme E3).
[00282] Characterization data for specific compounds 12 and 15-18 are listed in Table
El . Scheme E3.
Table El. NMR and MS data for exemplary compounds.
1H), 4.19 (s, 2H).
0 SGSS03- :H N MR (500 M Hz, Chloroform-d) δ 356
CS 8.11 (dd, J = 7.5, 1.5 Hz, 1H), 7.95
(dd, J = 7.6, 1.4 Hz, 1H), 7.68 (dtd, J =
(17-iii)
22.6, 7.4, 1.4 Hz, 2H), 7.44 - 7.33 (m,
4H), 7.30 - 7.24 (m, 5H), 7.23 - 7.17
(m, 1H), 5.30 (s, 1H), 4.37 (s, 2H).
SGSS03-N :H N MR (500 M Hz, Chloroform-d) δ 263 (15-xviii) 8.12 - 8.06 (d, J = 7.6, 1H), 7.98 (d, J
= 7.6,1H), 7.73 - 7.56 (m, 2H), 3.57
(qd, J = 7.1, 0.9 Hz, 4H), 1.20 (td, J =
0
7.1, 0.9 Hz, 6H).
SGSS03- :H N MR (500 M Hz, Chloroform-d) δ 337 NS 8.00 (dd, J = 7.3, 1.2 Hz, 1H), 7.91
(dd, J = 7.6, 1.3 Hz, 1H), 7.58 (dtd, J =
(18-xi)
18.4, 7.4, 1.5 Hz, 2H), 7.20 - 7.16 (m,
°ό 2H), 7.16 - 7.09 (m, 2H), 7.08 - 7.03
(m, 1H), 3.41 (q, J = 7.0 Hz, 4H), 0.98
(t, J = 7.0 Hz, 6H).
SGSS04-C :H N MR (500 M Hz, Chloroform-d) δ 260 (16-xi) 8.15 - 8.12 (m, 1H), 8.12 - 8.09 (m,
1H), 7.75 - 7.72 (m, 2H), 5.11 (dddq,
J = 7.3, 5.9, 2.9, 1.4 Hz, 1H), 3.52 (d, J
= 7.2 Hz, 2H), 1.82 (s, 3H), 1.69 (s,
3H).
SGSS04-N :H N MR (500 M Hz, Chloroform-d) δ 275 (15-xix) 8.11 (dd, J = 7.5, 1.5 Hz, 1H), 8.00
(dd, J = 7.5, 1.5 Hz, 1H), 7.66 (dtd, J =
21.1, 7.4, 1.5 Hz, 2H), 3.56 - 3.51 (m,
0
4H), 1.80 - 1.66 (m, 6H).
SGSS06- :H N MR (500 M Hz, Chloroform-d) δ 440
NS 8.11 - 8.05 (m, 1H), 8.05 - 7.98 (m,
1H), 7.75 - 7.62 (m, 2H), 7.34 (m,
(18-xxi)
°ό 4H), 7.30 - 7.00 (m, 6H), 4.16 - 3.18
(m, 6H), 2.60 (brs, 4H).
SGSS07-N :H N MR (500 M Hz, Chloroform-d) δ 287 (15-viii) 8.15 (dd, J = 7.7, 1.3 Hz, 1H), 8.04
(dd, J = 7.7, 1.3 Hz, 1H), 7.73 (td, J =
0 7.6, 1.3 Hz, 1H), 7.63 (td, J = 7.6, 1.3
Hz, 1H), 7.40 (dd, J = 2.0, 0.8 Hz, 1H),
6.37 - 6.32 (m, 2H), 6.20 (s, 1H), 5.05
(d, J = 5.7 Hz, 2H).
SGSS07- :H N MR (500 M Hz, Chloroform-d) δ 361
NS 8.19 (d, J = 1.1 Hz, 1H), 8.12 (d, J =
7.8 Hz, 1H), 7.77 (tt, J = 1.1, 1.2 Hz,
(18-vii)
1H), 7.68 (tt, J = 7.5, 1.2 Hz, 1H), 7.38
(dt, J = 1.8, 0.9 Hz, 1H), 7.29 (d, J =
1.4 Hz, 2H), 7.27 - 7.23 (m, 2H), 7.14
(ddt, J = 7.8, 5.0, 2.4 Hz, 1H), 6.80 (s,
1H), 6.35 - 6.32 (m, 1H), 6.25 - 6.22
(m, 1H), 5.12 (s, 2H).
0 SGSS08-C :H N MR (500 M Hz, Chloroform-d) δ 248
(16-x) 8.18 - 8.15 (m, 1H), 8.14 - 8.11 (m,
1H), 7.75 (qt, J = 7.2, 3.7 Hz, 2H),
0 2.89 - 2.72 (m, 2H), 1.59 - 1.50 (m,
2H), 1.46 (dt, J = 14.7, 7.2 Hz, 2H),
0.97 (t, J = 7.2 Hz, 3H).
SGSS08- :H N MR (500 M Hz, Chloroform-d) δ 322 CS 8.11 (dd, J = 8.0, 1.3 Hz, 1H), 7.97
(dd, J = 1.1, 1.4 Hz, 1H), 7.69 (dtd, J =
(17-i)
21.9, 7.4, 1.5 Hz, 2H), 7.38 - 7.34 (m,
2H), 7.30 - 7.21 (m, 5H), 3.02 - 2.94
0
(m, 2H), 1.58 - 1.49 (m, 2H), 1.46 (p,
(dtd, J = 7.8, 6.0, 2.8 Hz, 2H).
SGMS06 :H N MR (500 M Hz, Chloroform-d) δ 310
(12-xi) 8.16 - 8.07 (dd, J = 7.5, 1.6 Hz, 1H),
8.04 (dd, J = 7.5, 1.6 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.19 (t, J = 7.9 Hz, 1H),
6.96 - 6.88 (m, 2H), 6.78 (ddd, J =
8.3, 2.4, 1.0 Hz, 1H), 3.77 (s, 3H),
2.36 (s, 3H).
SGMS07 :H N MR (500 M Hz, Chloroform-d) δ 310 (12-xi) 8.10 (dd, J = 7.4, 1.5 Hz, 1H), 8.00
(dd, J = 7.4, 1.6 Hz, 1H), 7.68 (dtd, J =
OCH3 17 A, 7.4, 1.5 Hz, 2H), 7.32 (dd, J =
7.7, 1.7 Hz, 1H), 7.29 - 7.20 (m, 1H),
6.96 - 6.83 (m, 2H), 3.78 (s, 3H), 2.32
(s, 3H).
SGMS08 :H N MR (500 M Hz, Chloroform-d) δ 314 (12-iv) 8.12 (dd, J = 7.3, 1.7 Hz, 1H), 8.01
(dd, J = 7.5, 1.6 Hz, 1H), 7.77 - 7.66
(m, 2H), 7.34 - 7.29 (m, 2H), 7.27- 7.25 (m, 2H), 2.39 (s, 3H).
CI SGMS09 :H N MR (500 M Hz, Chloroform-d) δ 314
(12-v) 8.12 (dd, J = 7.3, 1.6 Hz, 1H), 8.01
(dd, J = 7.5, 1.5 Hz, 1H), 7.76 - 7.65
(m, 2H), 7.39 (ddd, J = 16.5, 7.5, 1.9
Hz, 2H), 7.25 - 7.13 (m, 2H), 2.38 (s,
3H).
SGMS10 :H N MR (500 M Hz, Chloroform-d) δ 314 (12-vi) 8.16 - 8.10 (dd, J = 7.5, 1.6 Hz, 1H),
8.03 (dd, J = 7.5, 1.6 Hz, 1H), 7.77 - CI 7.66 (m, 2H), 7.33 (q, J = 1.1 Hz, 1H),
7.26 - 7.20 (m, 3H), 2.40 (s, 3H).
SGMS11 :H N MR (500 M Hz, Chloroform-d) δ 298 (12-vii) 8.11 (dd, J = 7.6, 1.4 Hz, 1H), 8.00
(dd, J = 7.5, 1.5 Hz, 1H), 7.75 - 7.64
(m, 2H), 7.40 (dd, J = 8.8, 5.1 Hz, 1H),
7.00 (t, J = 8.6 Hz, 1H), 2.38 (s, 3H).
19F N MR (471 MHz, CDCI3) δ -113.39.
Biological activity
IC50 Measurement
[00283] The dose response curves of the high throughput screening hits for SETD8 inhibition were determined by a secondary radioactivity filter paper assay as documented previously (See, e.g., Ibanez et al., "A High Throughput Scintillation Proximity Imaging Assay for Protein Methyltransferases", Comb. Chem. High Throughput Screen. 2012, 15, 359-371.). Various concentrations of the compounds in DMSO stocks were incubated for 10 minutes with 2 μΜ SETD8 in a reaction buffer (50 mM Hepes-HCl (pH = 8.0), Tween-20 0.005% (v/v), 5 μg/mL BSA and 1 mM TCEP) with the final concentrations of 0 to 200 μΜ compound (Mixture A). A 20 μΐ^ methylation reaction was then carried out by mixing 10 μϊ^ of Mixture A with 10 μΐ, of Mixture B containing 50 mM Hepes-HCl (pH = 8.0), Tween-20 0.005% (v/v), 5 μg/mL BSA, 1 mM TCEP, 3 μΜ of peptide substrates, 1.5 μΜ of [3H-Me]- SAM and 20% (v/v) DMSO (this DMSO concentration was shown previously not to affect the methylation reaction). The reactions were incubated for a designated period of time and the resulting reaction products were assayed for methylation activity by immobilizing the peptides onto P81 phosphocellulose filter paper, proceeded by washing and finally, quantification with a liquid scintillation counter. Briefly, 6 μΐ^ of the methylation reaction mixture was spotted onto Whatman P-81 phosphocellulose filter paper (1.2 x 1.2 cm ) to immobilize [ H-methyl] -labeled peptides. After drying in air at ambient temperature (22 °C) for 20 min, filter paper was immersed in 20 mL of 50 mM Na2C03/NaHC03 buffer (pH = 9.2), and shook for 10 min/time, the wash step was repeated 5 times. The filter paper was then transferred to a 10 mL scintillation vial containing 500 μΐ^ of distilled water followed by addition of 5 mL of Ultima Gold scintillation cocktail (PerkinElmer). β-emission of the immobilized peptides was quantified by a Beckman LS6000IC liquid scintillation counter. The CPM values of the β-emission (Partial) were plotted as the percent of inhibition relating to the DMSO control (Full) after subtracting background CPM (Background for CPM of nonenzyme control) according to the following equation:
[00284] The IC50 values were obtained by fitting [%Inhibition] versus the
concentrations of inhibitors with GraphPad Prism6 software. Results for exemplary compounds are listed in Tables E2 and E3. "A" indicates: 5.0 μΜ < IC50 < 50 μΜ, "B" indicates: IC50 < 5.0 μΜ, and "C" indicates IC50 > 50 μΜ.
Table E2. IC50 values of exemplary compounds for inhibition of SETD8.
Table E3. IC50 values of exemplary compounds for inhibition of SETD8.
[00285] Inhibition other protein methyltransferases by the compounds was tested using the conditions listed in Table E4. The determined IC50 values for compounds SGSS05-NS, SGSS05-N, and SPECS21 are listed in Table E5. Table E4. Conditions for IC50 assays of inhibition of various protein methyltransf erases.
Table E5. IC50 values for exemplary compounds for inhibition of various PMTs
Western blot assay and cell survival
[00286] After seeding 105 HEK293T cells/well in 6- well plates for 24 hours, various concentrations of inhibitor or DMSO control were added. At each time interval (24 hours or 48 hours), a whole well of the treated cells were collected and their viability was determined by a standard trypan blue staining assay (triplicate). The remaining cells were subject to Western blot analysis. Briefly, the lysate of approximately 5xl04 HEK293T cells (for each lane of Western blot) was resolved by SDS-PAGE. The proteins were transferred to a PVDF membrane, and then blocked with 5% nonfat milk in TBST buffer at 4 °C for 1 hour, followed by blotting with a corresponding primary antibody overnight. After washing the blotted PVDF membrane with TBST buffer, HRP-conjugated secondary antibodies (Jackson ImmunoResearch; 1: 10,000) in 5% nonfat milk in TBST buffer were incubated for 2 hours at ambient temperature (22 °C). The membrane was then washed with TBST buffer, followed by the addition of ECL Plus (GE Healthcare) for film exposure. Antibodies and their dilution conditions: anti-H4K20me antibody (Active Motif, 39175 rabbit polyclonal, 1: 150,000), anti- H4K20me2 (Active Motif, 39173 rabbit polyclonal, 1: 100,000), anti-H4K20me3 (Active Motif, 39180 rabbit polyclonal, 1:30,000), anti-H3K9me (Millipore, 07-450 rabbit polyclonal, 1: 10,000), anti-H4 (Millipore, 07-108 rabbit polyclonal, 1: 100,000) and anti-H3 (Millipore, 06-755 rabbit polyclonal, 1: 100,000). Densitometry analysis was carried out with ImageJ program.
[00287] A similar procedure was used in the testing of other cell lines, with appropriate antibodies for the desired analytes. Figure 1 shows the effect of various concentrations of compound SPEC21 on SETD8, H4K20me, and histone H3 levels in HEK293 cells, HeLA cells MDA-MB-231 cells, MDA-MB-231/Luc cells, MCF7 cells, and K562 cells. Figures 2-3 show the effect of various concentrations of compound SGSS05-NS on SETD8, H4K20me, minichromosome maintenance complex component 5 (MCM5), and histone H3 levels in HEK293 cells, HeLA cells, MDA-MB-231 cells, MDA-MB-231 (TGL)cells, MCF7 cells, and K562.
[00288] Images of cell survival after 24, 48, or 72 hours with various amounts of SET8 inhibitor are shown in the following figures: Figure 4, SPECS21, MDA-MB-231 (TGL); Figure 5, SGSS05-NS, MDA-MB-231 (TGL); Figure 6, SGSS15-NS, MDA-MB-231 (TGL); Figure 7 SGSS04-NS, MDA-MB-231 (TGL); Figure 8 SGSS16-NS, MDA-MB-231 (TGL); Figure 9 SGSS15-NS, MDA-MB-231 (TGL); and Figure 10, SGSS22-NS, MDA-MB-231 (TGL).
Mouse xenograft experiments
[00289] A Maximum tolerated dose (MTD) experiment was carried out in Athymic females mice of 5-6 weeks old, for compounds SPECS21, SGSS05-N and SGSS05-NS.
[00290] Two different formulations for each compound were tested. A DMSO
(Dimethyl sulfoxide) based formulation for SPECS21 and a salt formulation for SGSS05-N and SGSS-05NS and a "nano" formulation for all compounds, consisting of a fucoidan polysaccharide encapsulation, were used. Mice weights and clinical signs were monitored daily (Figures 11-12).
[00291] Drug formulations:
SPECS21, 7.5 mg/kg i.p., Stock solution is 10 mg/mL in 100% DMSO
SPECS21-nano, 1 mg/kg, 5mg/kg, lOmg/kg and 20mg/kg i.v. Stock solution is 5 mg/mL SGSS05-N-salt, 15 mg/kg i.p., Stock solution is 10 mg/mL
SGSS05-N-nano, 5mg/kg, lOmg/kg and 20mg/kg i.v., Stock solution is 5 mg/mL
SGSS05-NS-salt, 15 mg/kg i.p., Stock solution is 10 mg/mL
SGSS05-NS-nano, 25mg/kg, 50mg/kg and 75mg/kg i.v., Stock solution is 5 mg/mL
[00292] Vehicles:
SPECS21: 100 % DMSO
SPECS21, SGSS05-N, SGSS05-NS-nano: PBS
SGSS05-N, SGSS05-NS-salt: PBS
[00293] Treatment groups: (2 mice/group)
SPECS21, i.p. QDx5 x 2 weeks
SPECS21-nano, i.v. twice/week x 2 weeks
SGSS05-N-salt, i.p. QDx5 x 2 weeks
SGSS05-N-nano, i.v., twice/week x 2 weeks
SGSS05-NS-salt, i.p. QDx5 x 2 weeks
SGSS05-NS-nano, i.v., twice/week x 2 weeks
[00294] Breast Cancer cell line MDA-MB-231 (LM2) cells with constitutive expression of lucif erase were prepared (Figure 13).
[00295] Xenograft model was created by implanting 10 million cells with matrigel
(MFP#4) in the mammary fat pad of 5-6 weeks old NOD/SCID females mice. A group of 5 mice were treated 1 week after tumor implantation with SGSS05-NS at 15 mg/kg i.p., QDx5 x 5 weeks. A control group of 5 mice received Vehicle only, i.p., QDx5 x 5 weeks.
[00296] Mice weights and tumor volumes were monitored 2x/week, see Figures 14-15.
Bioluminescence analysis of lucif erase expressing MDA231-LM2 was performed once a week to access tumor growth (Figure 16). MDA231-LM2 metastatic lung colonization was assessed by bioluminescence analysis on week 4 and 5 of treatment (Figure 7). EQUIVALENTS AND SCOPE
[00297] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[00298] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[00299] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[00300] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

What is claimed is:
1. A compound of Formula (III):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
n is 1 or 2;
U is N, O, or CH2, wherein if U is O or CH2 R is absent;
R is hydrogen or optionally substituted hydrocarbyl;
R4 is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR4a; and
R4a is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl.
2. The compound of claim 1, wherein the compound is of Formula (Ilia'):
O (Ilia')
The compound of claim 1, wherein the compound is of Formula (Illb), (IIIc), (Hid),
4. The compound of claim 1, wherein the compound is of Formula (IV):
wherein:
R is optionally substituted (C1-C2o)hydrocarbyl, wherein said (Ci-C2o)hydrocarbyl is optionally substituted one or more substituents selected from the group consisting of halogen,
(C1-C6)alkoxy, hydroxyl, carboxy, and acyl;
R4 is -F, -CI, or -SR4a; and
R4a is phenyl or monocyclic heteroaryl.
5. The compound of any one of claims 1-4, wherein R4 is -CI.
6. The compound of any one of claims 1-4, wherein R4 is -SR4a.
7. The compound of claim 6, wherein R4a is optionally substituted phenyl.
8. The compound of claim 6, wherein R4a is phenyl.
9. The compound of any one of claims 1-8, wherein, R is optionally substituted (Q- C6)alkyl.
10. The compound of claim 9, wherein R is optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, or optionally substituted benzyl.
11. The compound of claim 9, wherein R is methyl, ethyl, propyl, or benzyl.
12. The compound of claim 9, wherein R is methyl.
13. The compound of any one of claims 1-12, wherein n is 1.
14. The compound of any one of claims 1-12, wherein n is 2.
15. The compound of any one of claims 1-14, wherein Z is O.
16. The com ound of claim 1, wherein the compound is of formula:
122
18. A method of treating a proliferative disease, comprising administering a compound of any one of claims 1-16, or a pharmaceutical composition of claim 17, to a subject in need thereof.
19. The method of claim 18, wherein the proliferative disease is cancer.
20. The method of claim 19, wherein the cancer is leukemia.
21. The method of claim 19, wherein the cancer is breast cancer.
22. The method of claim 19, wherein the cancer is melanoma.
23. The method of claim 19, wherein the cancer is a metastatic cancer.
24. The method of claim 23, wherein the cancer is metastatic breast cancer.
25. The method of claim 23, wherein the cancer is metastatic melanoma.
26. The method of any one of claims 18-25, wherein the subject is a human.
27. A method of inhibiting the activity of SET8 in a subject comprising administering to the subject a compound of any one of claims 1-16, or a pharmaceutical composition of claim 17.
28. A method of inhibiting the activity of SET8 in a biological sample comprising contacting the biological sample with a compound of any one of claims 1-16, or a
pharmaceutical composition of claim 17.
29. A method of labelling SET8 in a subject comprising administering to the subject a labelled compound of any one of claims 1-16, or a pharmaceutical composition of claim 17.
30. A method of labelling SET8 in biological sample comprising contacting the biological sample with a labelled compound of any one of claims 1-16, or a pharmaceutical composition of claim 17.
31. A pharmaceutical composition of Formula (II) :
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and optionally a pharmaceutical excipient, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or methyl;
each of R2a and R2b is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is NRJaRJb, optionally substituted (C1-C2o)hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc; R is optionally substituted hydrocarbyl, or -C(=0)R c;
RJb is -C(=0)RJc;
RJc is optionally substituted hydrocarbyl;
R K is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR Ka ; and
R Ka is hydrogen, optionally substituted hydrocarbyl or optionally substituted heteroaryl; provided:
RJ is not -CH3; and
the compound is not 2-butyl-3-(phenylthio)naphthalene-l,4-dione.
The pharmaceutical composition of claim 31, wherein the compound is of Formula
33. The pharmaceutical composition of claim 31, wherein the compound is of Formula (lib), (lie), (lid), or (He):
34. The pharmaceutical composition of any one of claims 31-33, wherein R is -CI.
35. The pharmaceutical composition of any one of claims 31-33, wherein, R K is -SR Ka
36. The pharmaceutical composition of claim 35, wherein R Ka is optionally substituted phenyl.
37. The pharmaceutical composition of claim 35, wherein R Ka is phenyl.
38. The pharmaceutical composition of any one of claims 31-37, wherein RJ is NRJaRJb.
39. The pharmaceutical composition of claim 38, wherein each of RJa is hydrogen, and RJb is optionally substituted (Ci-C ) alkyl, optionally substituted benzyl, or optionally substituted acyl.
40. The pharmaceutical composition of claim 39, wherein RJb is -C(=0)RJc.
41. The pharmaceutical composition of claim 40, wherein RJc is optionally substituted (C1-C6)alkyl.
42. The pharmaceutical composition of claim 41, wherein RJc is methyl.
43. The pharmaceutical composition of claim 38, wherein each of RJa and RJb is optionally substituted (CrC6) alkyl, optionally substituted benzyl, or optionally substituted acyl.
44. The pharmaceutical composition of claim 39, wherein RJb is -C(=0)RJc.
45. The pharmaceutical composition of claim 40, wherein RJc is optionally substituted (Ci-C6)alkyl.
46. The pharmaceutical composition of claim 41, wherein RJc is methyl.
47. The pharmaceutical composition of any one of claims 31-37, wherein RJ is optionally substituted (C1-C12)hydrocarbyl.
48. The pharmaceutical composition of any one of claims 31-37, wherein RJ is optionally substituted (Q- alkyl
49. The pharmaceutical composition of any one of claims 31-37, wherein RJ is optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, or optionally substituted benzyl.
128
claim 50, or a pharmaceutical composition of any one of claims 31-49, to a subject in need thereof.
52. The method of claim 51, wherein the proliferative disease is cancer.
53. The method of claim 52, wherein the cancer is leukemia.
54. The method of claim 52, wherein the cancer is breast cancer.
55. The method of claim 52, wherein the cancer is melanoma.
56. The method of claim 52, wherein the cancer is a metastatic cancer.
57. The method of claim 56, wherein the cancer is metastatic breast cancer.
58. The method of claim 56, wherein the cancer is metastatic melanoma.
59. The method of any one of claims 51-52, wherein the subject is a human.
60. A method of inhibiting the activity of SET8 in a subject comprising administering to the subject a compound of claim 50, or a pharmaceutical composition of any one of claims 31-49.
61. A method of inhibiting the activity of SET8 in a biological sample comprising contacting the biological sample with a compound of claim 50, or a pharmaceutical composition of any one of claims 31-49.
62. A method of labelling SET8 in a subject comprising administering to the subject a labelled compound of claim 50, or a pharmaceutical composition of any one of claims 31-49 comprising a labelled compound.
63. A method of labelling SET8 in biological sample comprising contacting the biological sample with a labelled compound of claim 50, or a pharmaceutical composition of any one of claims 31-49 comprising a labelled compound.
64. A method of inhibiting the activity of SET8 in a subject comprising administering to the subject a compound of Formula (I):
or a pharmaceutically acceptable, stereoisomer, or tautomer, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NR' zi
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted
V is CR/B or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or optionally substituted alkyl;
each of R2a and R2b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is hydrogen, NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
or RJa and RJb are joined to form an optionally substituted 6-membered heterocyclic ring;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
65. A method of inhibiting the activity of SET8 in a biological sample comprising contacting the biological sample with a compound of Formula (I):
or a pharmaceutically acceptable, stereoisomer, or tautomer, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NR' zi
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted
V is CR/B or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or optionally substituted alkyl;
each of R2a and R2b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R a and R are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is hydrogen, NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
or RJa and RJb are joined to form an optionally substituted 6-membered heterocyclic ring;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
66. A method of labelling SET8 in a subject comprising administering to the subject or a labelled compound of Formula (I):
or a pharmaceutically acceptable, stereoisomer, or tautomer, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R Zl is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro;
Z is O or NRZ;
R is hydrogen or optionally substituted alkyl; each of R a and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is hydrogen, NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
or RJa and RJb are joined to form an optionally substituted 6-membered heterocyclic ring;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
67. A method of labelling SET8 in a biological sample comprising contacting the biological sample with a labelled compound of Formula (I):
or a pharmaceutically acceptable, stereoisomer, or tautomer, wherein:
G is -C(=Z1)- or -N(RL)-;
Z1 is O or NRZ1;
R is hydrogen or optionally substituted alkyl;
RL is hydrogen, optionally substituted alkyl, or optionally substituted acyl;
V is CR2b or N;
W is CR2a or N;
Y is CRY or N;
X is CRX or N;
each of R and R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro; Z is O or NRZ;
R is hydrogen or optionally substituted alkyl;
each of R2a and R2b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted sulfonyl, haloalkyl, alkoxy, hydroxyl, cyano, or nitro, or R2a and R2b are joined to form an optionally substituted 5- or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring;
RJ is hydrogen, NRJaRJb, optionally substituted hydrocarbyl, or of formula:
n is 1 or 2;
R J3 is hydrogen or optionally substituted hydrocarbyl;
RJa is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
RJb is hydrogen, optionally substituted hydrocarbyl, or -C(=0)RJc;
or RJa and RJb are joined to form an optionally substituted 6-membered heterocyclic ring;
RJc is optionally substituted hydrocarbyl;
R is hydrogen, halogen, optionally substituted hydrocarbyl, or -SR ; and
R is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heteroaryl.
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