WO2023070120A1 - Ketoamides for treating malignancy - Google Patents

Ketoamides for treating malignancy Download PDF

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Publication number
WO2023070120A1
WO2023070120A1 PCT/US2022/078566 US2022078566W WO2023070120A1 WO 2023070120 A1 WO2023070120 A1 WO 2023070120A1 US 2022078566 W US2022078566 W US 2022078566W WO 2023070120 A1 WO2023070120 A1 WO 2023070120A1
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Prior art keywords
methyl
dioxopiperidin
oxoacetamide
phenyl
certain embodiments
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PCT/US2022/078566
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French (fr)
Inventor
Aparajita Hoskote Chourasia
Kyle W.H. Chan
Dung Zung THAI
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Biotheryx, Inc.
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Publication of WO2023070120A1 publication Critical patent/WO2023070120A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Definitions

  • G1 to S phase transition 1 is a translation termination factor that mediates stop codon recognition and release of new protein from the ribosome. Hoshino et al., J. Biol. Chem. 1998, 273, 22254-9; Hoshino et al., Apoptosis 2012, 17, 1287-99. GSPT1 is also involved in several critical cellular processes, such as cell cycle regulation, cytoskeleton organization, and apoptosis. Brito et al., Carcinogenesis 2005, 26, 2046-9; Jean-Jean et al., Mol. Cell. Bio. 2007, 27, 5619-29.
  • GSPT1 has been implicated as an oncogenic driver in many malignancies, including breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer. Id. Wright and Lange, Rev. Urol. 2007, 9, 207-13; Brito et al., Cancer Genet. Cytogenet. 2009, 195, 132-42; Tavassoli et al., Med. Oncol. 2011, 29, 1581-5; Liu et. al., PLOS One 2014, 9, e86371. Depletion of GSPT1 has been reported to induce apoptosis of rapidly dividing cells. Matykiela et al., Nature 2016, 535, 252-7; Uy et al., Blood 2019, 134 (Supplement 1) , 232.
  • a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a GSPT1 inhibitor.
  • Also provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a GSPT1 degrader.
  • a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • R 1 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -OR la , -OC(O)R la , -OC(O)OR la , -OC(O)NR lb R lc , -OC(O)SR la , -OC(NR la )NR lb R lc ,
  • R 3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl;
  • R E1 is hydrogen, deuterium, halo, or C1-6 alkyl
  • R E2 is hydrogen or C1-6 alkyl; each R E4 is independently hydrogen or R E5 ; each R E5 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -OR la , -OC(O)R la , -OC(O)OR la , -OC
  • a method of inhibiting the growth of a malignant cell comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing apoptosis in a malignant cell comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of a GSPT1 in a malignant cell comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of downregulating a MYC in a malignant cell comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • FIG. 1 shows the anticancer effects of compounds A5 and gemcitabine in a xenograft mouse model for NSCLC (NCI-H1155 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 14 days and gemcitabine (40 mg/kg) was administered IP once every four days (Q4D) for 14 days.
  • FIG. 2 shows the anticancer effects of compounds A5 and docetaxel in a xenograft mouse model for SCLC (NCI-H526 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 3 weeks and docetaxel (15 mg/kg) was administered IP once a week (QW) for 3 weeks.
  • FIG. 3 shows the anticancer effects of compounds A5 and fulvestrant in a xenograft mouse model for breast cancer (T47D cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 4 weeks and fulvestrant (3 mg/dose) was administered SC once a week (QW) for 4 weeks.
  • FIG. 4 shows the anticancer effects of compounds A5 and gemcitabine in a xenograft mouse model for ovarian cancer (A2780 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 3 weeks and gemcitabine (30 mg/kg) was administered IP once every 3 days (Q3D) for 3 weeks.
  • FIG. 5 shows the anticancer effects of compounds A5 and rituximab in a xenograft mouse model for lymphoma (SU-DHL-2 cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD) from Day 0 to Day 9 and then at 5 mg/kg from Day 10 to Day 28; and rituximab (3 mg/kg) was administered IV once a week (QW) for 4 weeks.
  • FIG. 6 shows the anticancer effects of compounds A5 and cyclophosphamide in a xenograft mouse model for lymphoma (DOHH2 cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD); and cyclophosphamide (100 mg/kg) was administered IP once a day (QD).
  • FIG. 7 shows the anticancer effects of compounds A5 and cyclophosphamide in a xenograft mouse model for lymphoma (Daudi cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD); and cyclophosphamide (100 mg/kg) was administered IP once a day (QD).
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • patient e.g., cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
  • the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • the terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition.
  • the terms can also refer to reducing adverse effects associated with an active ingredient.
  • the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • contacting or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo.
  • a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule.
  • a therapeutic agent is contacted with a cell in cell culture (in vitro to determine the effect of the therapeutic agent on the cell.
  • the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
  • terapéuticaally effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • ICso or “ECso” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g, //-propyl and isopropyl), butyl (including all isomeric forms, e.g., //-butyl, isobutyl, ec-butyl, and /-butyl), pentyl (including all isomeric forms, e.g., //-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g, //-hexyl, isohexyl, and sec-hexyl).
  • heteroalkyl refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N.
  • the heteroalkyl is optionally substituted with one or more substituents Q as described herein.
  • C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.”
  • heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCEE, -CH2NHCH2CH3, and -NHCH2CH2CH3.
  • substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH 2 CH 3 .
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenyl is optionally substituted with one or more substituents Q as described herein.
  • alkenyl embraces radicals having a “c/ ” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen- 1-yl, propen-2 -yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond.
  • the alkynyl is optionally substituted with one or more substituents Q as described herein.
  • C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.
  • ethynyl ethynyl
  • propynyl including all isomeric forms, e.g., 1-propynyl (-OCCEE) and propargyl
  • cycloalkyl refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group.
  • the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic.
  • the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]- octyl, decalinyl, and adamantyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohe
  • cycloalkylene and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
  • the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane-l,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1,1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclo- pentane- 1,2-diyl, and cyclopentane-l,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane- 1,1 cycl
  • aryl refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (Ce-is), or from 6 to 10 (Ce-io) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl is monocyclic.
  • the aryl is bicyclic.
  • the aryl is tricyclic.
  • the aryl is polycyclic.
  • the aryl is optionally substituted with one or more substituents Q as described herein.
  • aralkyl or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms.
  • aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1 -phenylethyl and 2-phenyl- ethyl), and phenylpropyl (including all isomeric forms, e.g., 1 -phenylpropyl, 2-phenylpropyl, and 3 -phenylpropyl).
  • the aralkyl is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring.
  • heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl is monocyclic.
  • heteroaryl groups examples include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • the heteroaryl is bicyclic.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-Z>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-Z>]-pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-Z>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-a]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl),
  • the heteroaryl is tricyclic.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzo-furanyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phen- anthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl is optionally substituted with one or more substituents Q as described herein.
  • heterocyclyl refers to a monovalent monocyclic nonaromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodi oxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[ ][l,3]oxazinyl, 3,4- dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydro
  • heterocyclylene refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. If a heterocyclylene group containing a nonaromatic heterocyclic ring also contains a heteroaromatic ring, the heterocyclylene group does not have a linkage to the rest of a molecule via its heteroaromatic ring.
  • the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclylene groups include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., l,4-dihydrobenzo[ ][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[d][l,2]oxazindiyl), dihydrobenzo- thiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydr
  • halogen refers to fluoro, chloro, bromo, and/or iodo.
  • each Q a is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -
  • optically active and ’’enantiomerically active refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
  • the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the compound, R and S.
  • isotopically enriched refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon- 11 ( U C), carbon- 12 ( 12 C), carbon- 13 ( 13 C), carbon- 14 ( 14 C), nitrogen- 13 ( 13 N), nitrogen- 14 ( 14 N), nitrogen- 15 ( 15 N), oxygen- 14 ( 14 O), oxygen- 15 ( 15 O), oxygen- 16 ( 16 O), oxygen- 17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S
  • an isotopically enriched compound is in a stable form, that is, non-radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon- 12 ( 12 C), carbon- 13 ( 13 C), nitrogen- 14 ( 14 N), nitrogen- 15 ( 15 N), oxygen- 16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur- 33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 C1), chlorine-37 ( 37 C1), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( 127 I).
  • an isotopically enriched compound is in an unstable form, that is, radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon- 11 ( n C), carbon- 14 ( 14 C), nitrogen- 13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine- 131 ( 131 I).
  • any hydrogen can be 2 H, as example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, or any oxygen can be 18 O, as example, where feasible according to the judgment of one of ordinary skill in the art.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope e.g., 4 H for protium or hydrogen-1) of the element.
  • a less prevalent isotope e.g., D for deuterium or hydrogen-2
  • a more prevalent isotope e.g., 4 H for protium or hydrogen-1
  • isotopic enrichment factor refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
  • hydrogen refers to the composition of naturally occurring hydrogen isotopes, which include protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H), in their natural abundances.
  • Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%.
  • Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
  • carbon or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 ( 12 C) and carbon- 13 ( 13 C) in their natural abundances.
  • Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%.
  • Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
  • carbon-13 enrichment or “ 13 C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon.
  • carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon- 13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average.
  • when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
  • substantially pure and substantially homogeneous mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods.
  • a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound.
  • a deuterated compound that has an atom at a particular position designated as deuterium a compound that contains a protium at the same position is an impurity.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, ⁇ -propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate.
  • hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • a divalent group described herein no orientation is implied by the direction in which the divalent group is presented.
  • the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.
  • an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a diastereomer, a mixture of enantiomers,
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • R 1 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -OR la , -OC(O)R la , -OC(O)OR la , -OC(O)NR lb R lc , -OC(O)SR la , -OC(NR la )NR lb R lc ,
  • R 3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl; or -NR lb R lc ;
  • R E1 is hydrogen, deuterium, halo, or C1-6 alkyl
  • R E2 is hydrogen or C1-6 alkyl; each R E4 is independently hydrogen or R E5 ; each R E5 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R la , -C(O)OR la , -C(O)NR lb R lc , -C(O)SR la , -C(NR la )NR lb R lc , -C(S)R la , -C(S)OR la , -C(S)NR lb R lc , -OR la , -OC(O)R la , -OC(O)OR la ,
  • Z 1 is a bond
  • Z 1 is a bond
  • a compound of Formula (II) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein n is an integer of 0, 1, 2, or 3; and R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, p, and q are each as defined herein.
  • a compound of Formula (III) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (IV) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (V) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (VI) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (VII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (VIII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (IX) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (X) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (XI) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (XII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • a compound of Formula (XIII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R 1 , R 2a , R 2b , R 3 , R E1 , R E2 , R E5 , Z, m, n, p, and q are each as defined herein.
  • R 1 is H or methyl; each R 2a and R 2b is H;
  • R 3 is dimethylamino, phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or cyclohexyl, each of which is optionally substituted with one, two, or three substituents R A , wherein each substituent R A is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl, morpholinylmethyl, isopropyl, ec-butyl, tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido;
  • R E1 is H
  • R E2 is H or D-valyloxymethyl
  • R E5 is fluoro or methyl; m is an integer of 0, 1, or 2; n is an integer of 0, 1, or 2; p is an integer of 0, 1, or 2; and q is an integer of 0, 1, 2, or 3.
  • R 1 is H or methyl; each R 2a and R 2b is H;
  • R 3 is dimethylamino, phenyl, cyanophenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, (l-trifluoromethylethyl)phenyl, trifluoromethylphenyl, dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl, tert-butylphenyl, (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl, (l-methylcyclopropyl)phenyl, (1-trifluoro- methylcyclopropyl)-phenyl, phenylphenyl, (l-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl, dimethylaminophenyl, acetamidophenyl, difluorophenyl, dichlorophenyl
  • R E1 is H
  • R E2 is H or D-valyloxymethyl
  • R E5 is fluoro or methyl; m is an integer of 1 or 2; n is an integer of 0 or 1; p is an integer of 0, 1, or 2; and q is an integer of 0, 1, or 2.
  • R 1 is H or methyl; each R 2a and R 2b is H;
  • R 3 is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(l-trifluoro- methylethyl)phenyl, 4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl, 4-morpholin-4- ylmethylphenyl, 4-isopropylphenyl, 4- ec-butylphenyl, 3 -tert-butyl phenyl, 4-tert-butyl phenyl, 4- (hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl, 4-(l-methylcyclopropyl)phenyl, 4-(l- trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl, 4-(l-methylpipe
  • R E1 is H
  • R E2 is H or D-valyloxymethyl
  • R E5 is fluoro or methyl; m is an integer of 1 or 2; n is an integer of 0 or 1; p is an integer of 1 or 2; and q is an integer of 0, 1, or 2.
  • described herein is compound Al, or a pharmaceutically acceptable salt thereof.
  • compound A2 or a pharmaceutically acceptable salt thereof.
  • compound A3 or a pharmaceutically acceptable salt thereof.
  • compound A4 or a pharmaceutically acceptable salt thereof.
  • compound A5 or a pharmaceutically acceptable salt thereof.
  • compound A6 or a pharmaceutically acceptable salt thereof.
  • compound A7 or a pharmaceutically acceptable salt thereof.
  • compound A8 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A9, or a pharmaceutically acceptable salt thereof.
  • compound A10 or a pharmaceutically acceptable salt thereof.
  • described herein is compound All, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound All, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A13, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A14, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A15, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A16, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A17, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A18, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A19, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A20, or a pharmaceutically acceptable salt thereof.
  • described herein is compound All, or a pharmaceutically acceptable salt thereof.
  • described herein is compound A22, or a pharmaceutically acceptable salt thereof.
  • compound A23 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A24, or a pharmaceutically acceptable salt thereof.
  • compound A25 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A26, or a pharmaceutically acceptable salt thereof.
  • compound A27 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A28, or a pharmaceutically acceptable salt thereof.
  • described herein is compound A29, or a pharmaceutically acceptable salt thereof.
  • described herein is compound A30, or a pharmaceutically acceptable salt thereof.
  • described herein is compound A31, or a pharmaceutically acceptable salt thereof.
  • compound A32 or a pharmaceutically acceptable salt thereof.
  • compound A33 or a pharmaceutically acceptable salt thereof.
  • compound A34 or a pharmaceutically acceptable salt thereof.
  • compound A35 or a pharmaceutically acceptable salt thereof.
  • compound A36 or a pharmaceutically acceptable salt thereof.
  • compound A37 or a pharmaceutically acceptable salt thereof.
  • compound A38 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A39, or a pharmaceutically acceptable salt thereof.
  • compound A40 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A51, or a pharmaceutically acceptable salt thereof.
  • compound A52 or a pharmaceutically acceptable salt thereof.
  • compound A53 or a pharmaceutically acceptable salt thereof.
  • compound A54 or a pharmaceutically acceptable salt thereof.
  • compound A55 or a pharmaceutically acceptable salt thereof.
  • compound A56 or a pharmaceutically acceptable salt thereof.
  • compound A57 or a pharmaceutically acceptable salt thereof.
  • compound A58 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A59, or a pharmaceutically acceptable salt thereof.
  • compound A60 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A61, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A62, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A63, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A64, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A65, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A66, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A67, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A68, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A69, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A70, or a pharmaceutically acceptable salt thereof.
  • described herein is compound A71, or a pharmaceutically acceptable salt thereof.
  • compound A72 or a pharmaceutically acceptable salt thereof.
  • compound A73 or a pharmaceutically acceptable salt thereof.
  • compound A74 or a pharmaceutically acceptable salt thereof.
  • compound A75 or a pharmaceutically acceptable salt thereof.
  • compound A76 or a pharmaceutically acceptable salt thereof.
  • compound A77 or a pharmaceutically acceptable salt thereof.
  • compound A78 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A79, or a pharmaceutically acceptable salt thereof.
  • compound A80 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A91, or a pharmaceutically acceptable salt thereof.
  • compound A92 or a pharmaceutically acceptable salt thereof.
  • compound A93 or a pharmaceutically acceptable salt thereof.
  • compound A94 or a pharmaceutically acceptable salt thereof.
  • compound A95 or a pharmaceutically acceptable salt thereof.
  • compound A96 or a pharmaceutically acceptable salt thereof.
  • compound A97 or a pharmaceutically acceptable salt thereof.
  • compound A98 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A99, or a pharmaceutically acceptable salt thereof.
  • compound A100 or a pharmaceutically acceptable salt thereof.
  • described herein is compound A101, or a pharmaceutically acceptable salt thereof.
  • compound A102 or a pharmaceutically acceptable salt thereof.
  • compound A103 or a pharmaceutically acceptable salt thereof.
  • compound A104 or a pharmaceutically acceptable salt thereof.
  • compound A105 or a pharmaceutically acceptable salt thereof.
  • compound A106 or a pharmaceutically acceptable salt thereof.
  • a compound described herein is deuterium-enriched. In certain embodiments, a compound described herein is carbon-13 enriched. In certain embodiments, a compound described herein is carbon-14 enriched. In certain embodiments, a compound described herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15 N for nitrogen; 17 O or 18 O for oxygen, and 33 S, 34 S, or 36 S for sulfur.
  • a compound described herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 30, no less than about 40, no less than about 50, no less than about 60, no less than about 70, no less than about 80, no less than about 90, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000.
  • an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope.
  • the maximum isotopic enrichment factor is different for different isotopes.
  • the maximum isotopic enrichment factor is 6410 for deuterium and 90 for carbon-13.
  • a compound described herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99
  • a compound described herein has a carbon- 13 enrichment factor of no less than about 1.8 (about 2% carbon-13 enrichment), no less than about 4.5 (about 5% carbon- 13 enrichment), no less than about 9 (about 10% carbon- 13 enrichment), no less than about 18 (about 20% carbon-13 enrichment), no less than about 45 (about 50% carbon-13 enrichment), no less than about 68 (about 75% carbon- 13 enrichment), no less than about 72 (about 80% carbon- 13 enrichment), no less than about 77 (about 85% carbon- 13 enrichment), no less than about 81 (about 90% carbon- 13 enrichment), no less than about 86 (about 95% carbon- 13 enrichment), no less than about 87 (about 97% carbon- 13 enrichment), no less than about 88 (about 98% carbon- 13 enrichment), no less than about 89 (about 99% carbon- 13 enrichment), or no less than about 90 (about 99.5% carbon-13 enrichment).
  • the carbon-13 enrichment can be determined using conventional analytical methods known to one of ordinary
  • At least one of the atoms of a compound described herein, as specified as isotopically enriched has isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • the atoms of a compound described herein, as specified as isotopically enriched have isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • the isotopic enrichment of the isotopically enriched atom of a compound described herein is no less than the natural abundance of the isotope specified.
  • At least one of the atoms of a compound described herein, as specified as deuterium-enriched has deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • the atoms of a compound described herein, as specified as deuterium-enriched have deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • At least one of the atoms of a compound described herein, as specified as 13 C-enriched has carbon- 13 enrichment of no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • the atoms of a compound described herein, as specified as 13 C-enriched have carbon- 13 enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • a compound described herein is isolated or purified. In certain embodiments, a compound described herein has a purity of at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
  • the compounds described herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified.
  • the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers.
  • structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • a compound described herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers.
  • a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form.
  • a pharmaceutically acceptable salt of a compound described herein is a hydrate.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohepton
  • a compound described herein is a hydrochloride salt. In certain embodiments, a compound described herein is a -toluenesulfonate salt. In certain embodiments, a compound described herein is a di- - toluenesulfonate salt.
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A-methyl-glucamine, hydrabamine, UT-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(
  • a compound described herein may also be provided as a prodrug, which is a functional derivative of a compound, for example, of Formula I and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising any one of compounds Al to A106, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
  • a pharmaceutical composition provided herein is formulated in a dosage form for oral administration.
  • a pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration.
  • a pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration.
  • a pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration.
  • a pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration.
  • a pharmaceutical composition provided herein is formulated in a dosage form for topical administration.
  • a pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s).
  • an active ingredient(s) e.g., a compound provided herein
  • Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule.
  • a unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form.
  • Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • a pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.
  • a pharmaceutical composition provided herein comprises a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and sugar beads, talc, and povidone.
  • a pharmaceutical composition provided herein comprises any one of compounds Al to A106, or a pharmaceutically acceptable salt thereof; and sugar beads, talc, and povidone.
  • the pharmaceutical composition provided herein is formulated as a capsule.
  • a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.1 to about 100, from about 0.2 to about 50, from about 0.5 to about 20, or from about 0.5 to about 10 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.1 to about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.2 to about 50 mg per capsule.
  • a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.5 to about 20 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.5 to about 10 mg per capsule. [00102] In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount of about 0.1, about 0.2, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 10, about 15, about 20, about 25, about 50, about 75, or about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount of about 0.1, about 0.2, about 0.5, about 1, about 2, about 2.5, about 5, about 10, about 20, or about 50 mg per capsule.
  • a pharmaceutical composition provided herein is formulated as an immediate-release capsule with a size of, e.g., size 1 or size 000.
  • a method of treating a malignancy in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound described herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the malignancy is advanced. In certain embodiments, the malignancy is incurable. In certain embodiments, the malignancy is metastatic. In certain embodiments, the malignancy is recurrent. In certain embodiments, the malignancy is relapsed. In certain embodiments, the malignancy is refractory. In certain embodiments, the malignancy is refractory to a standard therapy. In certain embodiments, the malignancy is intolerant of a standard therapy. In certain embodiments, the malignancy is drug-resistant.
  • the malignancy is MYC dependent. In certain embodiments, the malignancy harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the malignancy harbors MYC gene translocation. In certain embodiments, the malignancy harbors MYC gene amplification. In certain embodiments, the malignancy harbors MYC mRNA overexpression. In certain embodiments, the malignancy harbors MYC protein overexpression.
  • a MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the malignancy is c-MYC dependent.
  • the malignancy harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the malignancy harbors c-MYC gene translocation.
  • the malignancy harbors c-MYC gene amplification.
  • the malignancy harbors c-MYC mRNA overexpression.
  • the malignancy harbors c-MYC protein overexpression.
  • the malignancy is 1-MYC dependent. In certain embodiments, the malignancy harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the malignancy harbors 1-MYC gene translocation. In certain embodiments, the malignancy harbors 1-MYC gene amplification. In certain embodiments, the malignancy harbors 1-MYC mRNA overexpression. In certain embodiments, the malignancy harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the malignancy is n-MYC dependent.
  • the malignancy harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the malignancy harbors n-MYC gene translocation.
  • the malignancy harbors n-MYC gene amplification.
  • the malignancy harbors n-MYC mRNA overexpression.
  • the malignancy harbors n-MYC protein overexpression.
  • the malignancy is a hematological malignancy. In certain embodiments, the hematological malignancy is advanced. In certain embodiments, the hematological malignancy is incurable. In certain embodiments, the hematological malignancy is metastatic. In certain embodiments, the hematological malignancy is recurrent. In certain embodiments, the hematological malignancy is relapsed. In certain embodiments, the hematological malignancy is refractory. In certain embodiments, the hematological malignancy is refractory to a standard therapy. In certain embodiments, the hematological malignancy is intolerant of a standard therapy. In certain embodiments, the hematological malignancy is drugresistant.
  • the hematological malignancy is MYC dependent. In certain embodiments, the hematological malignancy harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the hematological malignancy harbors MYC gene translocation. In certain embodiments, the hematological malignancy harbors MYC gene amplification. In certain embodiments, the hematological malignancy harbors MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors MYC protein overexpression.
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • MYC gene translocation e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/
  • the hematological malignancy is c-MYC dependent.
  • the hematological malignancy harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the hematological malignancy harbors c-MYC gene translocation.
  • the hematological malignancy harbors c-MYC gene amplification.
  • the hematological malignancy harbors c-MYC mRNA overexpression.
  • the hematological malignancy harbors c-MYC protein overexpression.
  • the hematological malignancy is 1-MYC dependent. In certain embodiments, the hematological malignancy harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the hematological malignancy harbors 1-MYC gene translocation. In certain embodiments, the hematological malignancy harbors 1-MYC gene amplification. In certain embodiments, the hematological malignancy harbors 1-MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the hematological malignancy harbors 1-MYC gene translocation.
  • the hematological malignancy is n-MYC dependent. In certain embodiments, the hematological malignancy harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the hematological malignancy harbors n-MYC gene translocation. In certain embodiments, the hematological malignancy harbors n-MYC gene amplification. In certain embodiments, the hematological malignancy harbors n-MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors n-MYC protein overexpression.
  • a n-MYC aberration e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-
  • the malignancy is a leukemia.
  • the leukemia is advanced. In certain embodiments, the leukemia is incurable. In certain embodiments, the leukemia is metastatic. In certain embodiments, the leukemia is recurrent. In certain embodiments, the leukemia is relapsed. In certain embodiments, the leukemia is refractory. In certain embodiments, the leukemia is refractory to a standard therapy. In certain embodiments, the leukemia is intolerant of a standard therapy. In certain embodiments, the leukemia is drug-resistant.
  • the leukemia is MYC dependent.
  • the leukemia harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the leukemia harbors MYC gene translocation.
  • the leukemia harbors MYC gene amplification.
  • the leukemia harbors MYC mRNA overexpression.
  • the leukemia harbors MYC protein overexpression.
  • the leukemia is c-MYC dependent.
  • the leukemia harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the leukemia harbors c-MYC gene translocation.
  • the leukemia harbors c-MYC gene amplification.
  • the leukemia harbors c- MYC mRNA overexpression.
  • the leukemia harbors c-MYC protein overexpression.
  • the leukemia is 1-MYC dependent. In certain embodiments, the leukemia harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the leukemia harbors 1-MYC gene translocation. In certain embodiments, the leukemia harbors 1-MYC gene amplification. In certain embodiments, the leukemia harbors 1- MYC mRNA overexpression. In certain embodiments, the leukemia harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the leukemia is n-MYC dependent.
  • the leukemia harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the leukemia harbors n-MYC gene translocation.
  • the leukemia harbors n-MYC gene amplification.
  • the leukemia harbors n-MYC mRNA overexpression.
  • the leukemia harbors n-MYC protein overexpression.
  • the malignancy is acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the AML is MYC dependent.
  • the AML harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • MYC gene translocation e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • MYC gene translocation e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • MYC gene translocation e.g., MYC gene trans
  • the AML is c-MYC dependent.
  • the AML harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the AML harbors c-MYC gene translocation.
  • the AML harbors c-MYC gene amplification.
  • the AML harbors c-MYC mRNA overexpression.
  • the AML harbors c-MYC protein overexpression.
  • the AML is 1-MYC dependent.
  • the AML harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1- MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the AML harbors 1-MYC gene translocation.
  • the AML harbors 1-MYC gene amplification.
  • the AML harbors 1-MYC mRNA overexpression.
  • the AML harbors 1-MYC protein overexpression.
  • the AML is n-MYC dependent.
  • the AML harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the AML harbors n-MYC gene translocation.
  • the AML harbors n-MYC gene amplification.
  • the AML harbors n-MYC mRNA overexpression.
  • the AML harbors n-MYC protein overexpression.
  • the AML is advanced. In certain embodiments, the AML is metastatic. In certain embodiments, the AML is recurrent. In certain embodiments, the AML is relapsed or refractory. In certain embodiments, the AML is relapsed. In certain embodiments, the AML is refractory. In certain embodiments, the AML is refractory to a standard therapy. In certain embodiments, the AML is intolerant of a standard therapy. In certain embodiments, the AML is del(5q) AML. In certain embodiments, the AML harbors a cytogenetic abnormality. In certain embodiments, the AML harbors del(5q).
  • the AML is drug-resistant. In certain embodiments, the AML is resistant to arsenic trioxide, cyclophosphamide, cytarabine, daunorubicin, dexamethasone, doxorubicin, enasidenib, gemtuzumab ozogamicin, gilteritinib, glasdegib, idamycin, idarubicin, ivosidenib, midostaurin, mitoxantrone, thioguanine, venetoclax, and/or vincristine.
  • the AML is AML with a translocation between chromosomes 8 and 21 [t(8;21 )] .
  • the AML is AML with a translocation or inversion in chromosome 16 [t(l 6; 16) or inv(16)].
  • the AML is APL with the PML-RARA fusion gene.
  • the AML is AML with a translocation between chromosomes 9 and 11 [t(9; 11)].
  • the AML is AML with a translocation between chromosomes 6 and 9 [t(6:9)].
  • the AML is AML with a translocation or inversion in chromosome 3 [t(3 ;3) or inv(3)]. In certain embodiments, the AML is AML (megakaryoblastic) with a translocation between chromosomes 1 and 22 [t(l :22)]. In certain embodiments, the AML is AML with the BCR-ABL1 (BCR-ABL) fusion gene. In certain embodiments, the AML is AML with mutated NPM1 gene. AML with biallelic mutations of the CEBPA gene (that is, mutations in both copies of the gene). In certain embodiments, the AML is AML with mutated RUNX1 gene.
  • the AML is AML with myelodysplasia-related changes. In certain embodiments, the AML is AML related to previous chemotherapy or radiation. In certain embodiments, the AML is AML with minimal differentiation (FAB M0). In certain embodiments, the AML is AML without maturation (FAB Ml). In certain embodiments, the AML is AML with maturation (FAB M2). In certain embodiments, the AML is AML (FAB M4). In certain embodiments, the AML is acute monoblastic/monocytic leukemia (FAB M5). In certain embodiments, the AML is pure erythroid leukemia (FAB M6). In certain embodiments, the AML is acute megakaryoblastic leukemia (FAB M7). In certain embodiments, the AML is acute basophilic leukemia. In certain embodiments, the AML is acute panmyelosis with fibrosis.
  • the AML is relapsed or refractory, and ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit.
  • the malignancy is a solid tumor.
  • the solid tumor is advanced. In certain embodiments, the solid tumor is unresectable. In certain embodiments, the solid tumor is inoperable. In certain embodiments, the solid tumor is incurable. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is recurrent. In certain embodiments, the solid tumor is relapsed. In certain embodiments, the solid tumor is refractory. In certain embodiments, the solid tumor is refractory to a standard therapy. In certain embodiments, the solid tumor is intolerant of a standard therapy. In certain embodiments, the solid tumor is drug-resistant.
  • the solid tumor is MYC dependent.
  • the solid tumor harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the solid tumor harbors MYC gene translocation.
  • the solid tumor harbors MYC gene amplification.
  • the solid tumor harbors MYC mRNA overexpression.
  • the solid tumor harbors MYC protein overexpression.
  • the solid tumor is c-MYC dependent.
  • the solid tumor harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the solid tumor harbors c-MYC gene translocation.
  • the solid tumor harbors c-MYC gene amplification.
  • the solid tumor harbors c-MYC mRNA overexpression.
  • the solid tumor harbors c-MYC protein overexpression.
  • the solid tumor is 1-MYC dependent.
  • the solid tumor harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the solid tumor harbors 1-MYC gene translocation.
  • the solid tumor harbors 1-MYC gene amplification.
  • the solid tumor harbors 1-MYC mRNA overexpression.
  • the solid tumor harbors 1-MYC protein overexpression.
  • the solid tumor is n-MYC dependent.
  • the solid tumor harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the solid tumor harbors n-MYC gene translocation.
  • the solid tumor harbors n-MYC gene amplification.
  • the solid tumor harbors n-MYC mRNA overexpression.
  • the solid tumor harbors n-MYC protein overexpression.
  • the solid tumor is a histologically or cytologically documented, incurable or metastatic solid tumor. In certain embodiments, the solid tumor is a histologically or cytologically documented, incurable or metastatic solid tumor with MYC genomic amplification/overexpression by tumor- or blood-based analysis. [00135] In certain embodiments, the solid tumor is stage I. In certain embodiments, the solid tumor is stage II. In certain embodiments, the solid tumor is stage III. In certain embodiments, the solid tumor is stage IV. In certain embodiments, the solid tumor is stage II, III, or IV. In certain embodiments, the solid tumor is stage III or IV.
  • the solid tumor is bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioblastoma, head or neck cancer, hepatic cancer, lymphoma, lung cancer, melanoma, mesothelioma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), nonmelanoma skin cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, small cell lung cancer (SCLC), thyroid cancer, or uterine cancer.
  • NSCLC non-small cell lung cancer
  • the solid tumor is bladder cancer, breast cancer, colorectal cancer, lung cancer, melanoma, non-Hodgkin’s lymphoma, oral cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, or uterine cancer.
  • the solid tumor is breast cancer, glioma, lung cancer, lymphoma, or ovarian cancer.
  • the solid tumor is bladder cancer. In certain embodiments, the solid tumor is brain cancer. In certain embodiments, the solid tumor is breast cancer. In certain embodiments, the solid tumor is colorectal cancer. In certain embodiments, the solid tumor is lung cancer. In certain embodiments, the solid tumor is melanoma. In certain embodiments, the solid tumor is oral cancer. In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the solid tumor is pancreatic cancer. In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is renal cancer. In certain embodiments, the solid tumor is thyroid cancer. In certain embodiments, the solid tumor is uterine cancer.
  • the solid tumor is glioma.
  • the glioma is advanced. In certain embodiments, the glioma is unresectable. In certain embodiments, the glioma is inoperable. In certain embodiments, the glioma is incurable. In certain embodiments, the glioma is metastatic. In certain embodiments, the glioma is recurrent. In certain embodiments, the glioma is relapsed. In certain embodiments, the glioma is refractory. In certain embodiments, the glioma is refractory to a standard therapy. In certain embodiments, the glioma is intolerant of a standard therapy. In certain embodiments, the glioma is drugresistant.
  • the glioma is MYC dependent. In certain embodiments, the glioma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the glioma harbors MYC gene translocation. In certain embodiments, the glioma harbors MYC gene amplification. In certain embodiments, the glioma harbors MYC mRNA overexpression. In certain embodiments, the glioma harbors MYC protein overexpression.
  • a MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the glioma is c-MYC dependent. In certain embodiments, the glioma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the glioma harbors c-MYC gene translocation. In certain embodiments, the glioma harbors c-MYC gene amplification. In certain embodiments, the glioma harbors c-MYC mRNA overexpression. In certain embodiments, the glioma harbors c-MYC protein overexpression.
  • a c-MYC aberration e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression.
  • the glioma is 1-MYC dependent. In certain embodiments, the glioma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the glioma harbors 1-MYC gene translocation. In certain embodiments, the glioma harbors 1-MYC gene amplification. In certain embodiments, the glioma harbors 1-MYC mRNA overexpression. In certain embodiments, the glioma harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the glioma harbors 1-MYC gene translocation.
  • the glioma harbors 1-MYC gene a
  • the glioma is n-MYC dependent. In certain embodiments, the glioma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the glioma harbors n-MYC gene translocation. In certain embodiments, the glioma harbors n-MYC gene amplification. In certain embodiments, the glioma harbors n- MYC mRNA overexpression.
  • a n-MYC aberration e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression.
  • the glioma harbors n-MYC gene translocation.
  • the glioma
  • the glioma harbors n-MYC protein overexpression.
  • the solid tumor is lung cancer.
  • the lung cancer is advanced. In certain embodiments, the lung cancer is unresectable. In certain embodiments, the lung cancer is inoperable. In certain embodiments, the lung cancer is incurable. In certain embodiments, the lung cancer is metastatic. In certain embodiments, the lung cancer is recurrent. In certain embodiments, the lung cancer is relapsed. In certain embodiments, the lung cancer is refractory. In certain embodiments, the lung cancer is refractory to a standard therapy. In certain embodiments, the lung cancer is intolerant of a standard therapy. In certain embodiments, the lung cancer is drug-resistant.
  • the lung cancer is MYC dependent.
  • the lung cancer harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the lung cancer harbors MYC gene translocation.
  • the lung cancer harbors MYC gene amplification.
  • the lung cancer harbors MYC mRNA overexpression.
  • the lung cancer harbors MYC protein overexpression.
  • the lung cancer is c-MYC dependent.
  • the lung cancer harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the lung cancer harbors c-MYC gene translocation.
  • the lung cancer harbors c-MYC gene amplification.
  • the lung cancer harbors c-MYC mRNA overexpression.
  • the lung cancer harbors c-MYC protein overexpression.
  • the lung cancer is 1-MYC dependent.
  • the lung cancer harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the lung cancer harbors 1-MYC gene translocation.
  • the lung cancer harbors 1-MYC gene amplification.
  • the lung cancer harbors 1-MYC mRNA overexpression.
  • the lung cancer harbors 1-MYC protein overexpression.
  • the lung cancer is n-MYC dependent.
  • the lung cancer harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • a n-MYC aberration e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression.
  • the lung cancer harbors n-MYC gene translocation.
  • the lung cancer harbors n-MYC gene amplification.
  • the lung cancer harbors n-MYC mRNA overexpression.
  • the lung cancer harbors n-MYC protein overexpression.
  • the lung cancer is a histologically or cytologically documented, incurable or metastatic lung cancer. In certain embodiments, the lung cancer is a histologically or cytologically documented, incurable or metastatic lung cancer with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
  • the lung cancer is stage I. In certain embodiments, the lung cancer is stage II. In certain embodiments, the lung cancer is stage III. In certain embodiments, the lung cancer is stage IV. In certain embodiments, the lung cancer is stage II, III, or IV. In certain embodiments, the lung cancer is stage III or IV.
  • the solid tumor is NSCLC.
  • the NSCLC is advanced. In certain embodiments, the NSCLC is unresectable. In certain embodiments, the NSCLC is inoperable. In certain embodiments, the NSCLC is incurable. In certain embodiments, the NSCLC is metastatic. In certain embodiments, the NSCLC is recurrent. In certain embodiments, the NSCLC is relapsed. In certain embodiments, the NSCLC is refractory. In certain embodiments, the NSCLC is refractory to a standard therapy. In certain embodiments, the NSCLC is intolerant of a standard therapy. In certain embodiments, the NSCLC is drug-resistant.
  • the NSCLC is MYC dependent.
  • the NSCLC harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the NSCLC harbors MYC gene translocation.
  • the NSCLC harbors MYC gene amplification.
  • the NSCLC harbors MYC mRNA overexpression.
  • the NSCLC harbors MYC protein overexpression.
  • the NSCLC is c-MYC dependent.
  • the NSCLC harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • a c-MYC aberration e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression.
  • the NSCLC harbors c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the NSCLC harbors c-MYC gene translocation.
  • the NSCLC harbors c-MYC gene amplification.
  • the NSCLC harbors c- MYC mRNA
  • the NSCLC is 1-MYC dependent.
  • the NSCLC harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the NSCLC harbors 1-MYC gene translocation.
  • the NSCLC harbors 1-MYC gene amplification.
  • the NSCLC harbors 1- MYC mRNA overexpression.
  • the NSCLC harbors 1-MYC protein overexpression.
  • the NSCLC is n-MYC dependent.
  • the NSCLC harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the NSCLC harbors n-MYC gene translocation.
  • the NSCLC harbors n-MYC gene amplification.
  • the NSCLC harbors n- MYC mRNA overexpression.
  • the NSCLC harbors n-MYC protein overexpression.
  • the NSCLC is a histologically or cytologically documented, incurable or metastatic NSCLC. In certain embodiments, the NSCLC is a histologically or cytologically documented, incurable or metastatic NSCLC with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
  • the NSCLC is stage I. In certain embodiments, the NSCLC is stage II. In certain embodiments, the NSCLC is stage III. In certain embodiments, the NSCLC is stage IV. In certain embodiments, the NSCLC is stage II, III, or IV. In certain embodiments, the NSCLC is stage III or IV.
  • the solid tumor is SCLC. In certain embodiments, the SCLC is advanced. In certain embodiments, the SCLC is unresectable. In certain embodiments, the SCLC is inoperable. In certain embodiments, the SCLC is incurable. In certain embodiments, the SCLC is metastatic. In certain embodiments, the SCLC is recurrent.
  • the SCLC is relapsed. In certain embodiments, the SCLC is refractory. In certain embodiments, the SCLC is refractory to a standard therapy. In certain embodiments, the SCLC is intolerant of a standard therapy. In certain embodiments, the SCLC is drug-resistant.
  • the SCLC is MYC dependent.
  • the SCLC harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the SCLC harbors MYC gene translocation.
  • the SCLC harbors MYC gene amplification.
  • the SCLC harbors MYC mRNA overexpression.
  • the SCLC harbors MYC protein overexpression.
  • the SCLC is c-MYC dependent.
  • the SCLC harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the SCLC harbors c-MYC gene translocation.
  • the SCLC harbors c-MYC gene amplification.
  • the SCLC harbors c-MYC mRNA overexpression.
  • the SCLC harbors c-MYC protein overexpression.
  • the SCLC is 1-MYC dependent.
  • the SCLC harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the SCLC harbors 1-MYC gene translocation.
  • the SCLC harbors 1-MYC gene amplification.
  • the SCLC harbors 1-MYC mRNA overexpression.
  • the SCLC harbors 1-MYC protein overexpression.
  • the SCLC is n-MYC dependent.
  • the SCLC harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the SCLC harbors n-MYC gene translocation.
  • the SCLC harbors n-MYC gene amplification.
  • the SCLC harbors n-MYC mRNA overexpression.
  • the SCLC harbors n-MYC protein overexpression.
  • the SCLC is a histologically or cytologically documented, incurable or metastatic SCLC. In certain embodiments, the SCLC is a histologically or cytologically documented, incurable or metastatic SCLC with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
  • the SCLC is stage I. In certain embodiments, the SCLC is stage II. In certain embodiments, the SCLC is stage III. In certain embodiments, the SCLC is stage IV. In certain embodiments, the SCLC is stage II, III, or IV. In certain embodiments, the SCLC is stage III or IV.
  • the malignancy is lymphoma.
  • the lymphoma is advanced. In certain embodiments, the lymphoma is unresectable. In certain embodiments, the lymphoma is inoperable. In certain embodiments, the lymphoma is incurable In certain embodiments, the lymphoma is metastatic. In certain embodiments, the lymphoma is recurrent. In certain embodiments, the lymphoma is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the lymphoma is refractory to a standard therapy. In certain embodiments, the lymphoma is intolerant of a standard therapy. In certain embodiments, the lymphoma is drug-resistant.
  • the lymphoma is MYC dependent. In certain embodiments, the lymphoma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the lymphoma harbors MYC gene translocation. In certain embodiments, the lymphoma harbors MYC gene amplification. In certain embodiments, the lymphoma harbors MYC mRNA overexpression. In certain embodiments, the lymphoma harbors MYC protein overexpression.
  • a MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the lymphoma is c-MYC dependent. In certain embodiments, the lymphoma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the lymphoma harbors c-MYC gene translocation. In certain embodiments, the lymphoma harbors c-MYC gene amplification. In certain embodiments, the lymphoma harbors c-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors c-MYC protein overexpression.
  • a c-MYC aberration e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression.
  • the lymphoma harbors c
  • the lymphoma is 1-MYC dependent. In certain embodiments, the lymphoma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the lymphoma harbors 1-MYC gene translocation. In certain embodiments, the lymphoma harbors 1-MYC gene amplification. In certain embodiments, the lymphoma harbors 1-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the lymphoma is n-MYC dependent. In certain embodiments, the lymphoma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the lymphoma harbors n-MYC gene translocation. In certain embodiments, the lymphoma harbors n-MYC gene amplification. In certain embodiments, the lymphoma harbors n-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors n-MYC protein overexpression.
  • a n-MYC aberration e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression.
  • the lymphoma harbors n
  • the lymphoma is stage I. In certain embodiments, the lymphoma is stage II. In certain embodiments, the lymphoma is stage III. In certain embodiments, the lymphoma is stage IV. In certain embodiments, the lymphoma is stage II, III, or IV. In certain embodiments, the lymphoma is stage III or IV.
  • the malignancy is non-Hodgkin’s lymphoma (NHL).
  • the NHL is advanced. In certain embodiments, the NHL is unresectable. In certain embodiments, the NHL is inoperable. In certain embodiments, the NHL is incurable. In certain embodiments, the NHL is metastatic. In certain embodiments, the NHL is recurrent. In certain embodiments, the NHL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the NHL is refractory to a standard therapy. In certain embodiments, the NHL is intolerant of a standard therapy. In certain embodiments, the NHL is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
  • the NHL is MYC dependent.
  • the NHL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the NHL harbors MYC gene translocation.
  • the NHL harbors MYC gene amplification.
  • the NHL harbors MYC mRNA overexpression.
  • the NHL harbors MYC protein overexpression.
  • the NHL is c-MYC dependent.
  • the NHL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the NHL harbors c-MYC gene translocation.
  • the NHL harbors c-MYC gene amplification.
  • the NHL harbors c-MYC mRNA overexpression.
  • the NHL harbors c-MYC protein overexpression.
  • the NHL is LMYC dependent.
  • the NHL harbors a l-MYC aberration (e.g., l-MYC gene translocation, LMYC gene amplification, 1- MYC mRNA overexpression, and/or l-MYC protein overexpression).
  • the NHL harbors l-MYC gene translocation.
  • the NHL harbors l-MYC gene amplification.
  • the NHL harbors l-MYC mRNA overexpression.
  • the NHL harbors l-MYC protein overexpression.
  • the NHL is n-MYC dependent.
  • the NHL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the NHL harbors n-MYC gene translocation.
  • the NHL harbors n-MYC gene amplification.
  • the NHL harbors n-MYC mRNA overexpression.
  • the NHL harbors n-MYC protein overexpression.
  • the NHL is stage I. In certain embodiments, the NHL is stage II. In certain embodiments, the NHL is stage III. In certain embodiments, the NHL is stage IV. In certain embodiments, the NHL is stage II, III, or IV. In certain embodiments, the NHL is stage III or IV.
  • the NHL is B-cell NHL.
  • the B-cell NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, or Burkitt lymphoma.
  • the NHL is T-cell NHL.
  • the NHL is NK-cell NHL.
  • the malignancy is B-cell NHL.
  • the B-cell NHL is advanced. In certain embodiments, the B-cell NHL is unresectable. In certain embodiments, the B-cell NHL is inoperable. In certain embodiments, the B-cell NHL is incurable. In certain embodiments, the B-cell NHL is metastatic. In certain embodiments, the B-cell NHL is recurrent. In certain embodiments, the B-cell NHL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the B-cell NHL is refractory to a standard therapy. In certain embodiments, the B-cell NHL is intolerant of a standard therapy. In certain embodiments, the B-cell NHL is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
  • the B-cell NHL is MYC dependent.
  • the B-cell NHL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the B-cell NHL harbors MYC gene translocation.
  • the B- cell NHL harbors MYC gene amplification.
  • the B-cell NHL harbors MYC mRNA overexpression.
  • the B-cell NHL harbors MYC protein overexpression.
  • the B-cell NHL is c-MYC dependent.
  • the B-cell NHL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the B-cell NHL harbors c-MYC gene translocation.
  • the B-cell NHL harbors c-MYC gene amplification.
  • the B-cell NHL harbors c-MYC mRNA overexpression.
  • the B-cell NHL harbors c-MYC protein overexpression.
  • the B-cell NHL is 1-MYC dependent. In certain embodiments, the B-cell NHL harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the B-cell NHL harbors 1-MYC gene translocation. In certain embodiments, the B-cell NHL harbors 1-MYC gene amplification. In certain embodiments, the B-cell NHL harbors 1-MYC mRNA overexpression. In certain embodiments, the B-cell NHL harbors 1-MYC protein overexpression.
  • a 1-MYC aberration e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression.
  • the B-cell NHL is n-MYC dependent.
  • the B-cell NHL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the B-cell NHL harbors n-MYC gene translocation.
  • the B-cell NHL harbors n-MYC gene amplification.
  • the B-cell NHL harbors n-MYC mRNA overexpression.
  • the B-cell NHL harbors n-MYC protein overexpression.
  • the B-cell NHL is stage I. In certain embodiments, the B- cell NHL is stage II. In certain embodiments, the B-cell NHL is stage III. In certain embodiments, the B-cell NHL is stage IV. In certain embodiments, the B-cell NHL is stage II, III, or IV. In certain embodiments, the B-cell NHL is stage III or IV.
  • the B-cell NHL is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
  • the malignancy is diffuse large B-cell lymphoma (DLBCL).
  • the DLBCL is advanced. In certain embodiments, the DLBCL is unresectable. In certain embodiments, the DLBCL is inoperable. In certain embodiments, the DLBCL is incurable. In certain embodiments, the DLBCL is metastatic. In certain embodiments, the DLBCL is recurrent. In certain embodiments, the DLBCL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the DLBCL is refractory to a standard therapy. In certain embodiments, the DLBCL is intolerant of a standard therapy. In certain embodiments, the DLBCL is drug-resistant.
  • the lymphoma is drug-resistant.
  • the DLBCL is MYC dependent.
  • the DLBCL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression).
  • MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • the DLBCL harbors MYC gene translocation.
  • the DLBCL harbors MYC gene amplification.
  • the DLBCL harbors MYC mRNA overexpression.
  • the DLBCL harbors MYC protein overexpression.
  • the DLBCL is c-MYC dependent.
  • the DLBCL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression).
  • the DLBCL harbors c-MYC gene translocation.
  • the DLBCL harbors c-MYC gene amplification.
  • the DLBCL harbors c- MYC mRNA overexpression.
  • the DLBCL harbors c-MYC protein overexpression.
  • the DLBCL is 1-MYC dependent.
  • the DLBCL harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the DLBCL harbors 1-MYC gene translocation.
  • the DLBCL harbors 1-MYC gene amplification.
  • the DLBCL harbors 1- MYC mRNA overexpression.
  • the DLBCL harbors 1-MYC protein overexpression.
  • the DLBCL is n-MYC dependent.
  • the DLBCL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression).
  • the DLBCL harbors n-MYC gene translocation.
  • the DLBCL harbors n-MYC gene amplification.
  • the DLBCL harbors n- MYC mRNA overexpression.
  • the DLBCL harbors n-MYC protein overexpression.
  • the DLBCL is stage I. In certain embodiments, the DLBCL is stage II. In certain embodiments, the DLBCL is stage III. In certain embodiments, the DLBCL is stage IV. In certain embodiments, the DLBCL is stage II, III, or IV. In certain embodiments, the DLBCL is stage III or IV.
  • the DLBCL is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
  • the malignancy is Burkitt lymphoma.
  • the Burkitt lymphoma is advanced. In certain embodiments, the Burkitt lymphoma is unresectable. In certain embodiments, the Burkitt lymphoma is inoperable. In certain embodiments, the Burkitt lymphoma is incurable. In certain embodiments, the Burkitt lymphoma is metastatic. In certain embodiments, the Burkitt lymphoma is recurrent. In certain embodiments, the Burkitt lymphoma is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the Burkitt lymphoma is refractory to a standard therapy. In certain embodiments, the Burkitt lymphoma is intolerant of a standard therapy. In certain embodiments, the Burkitt lymphoma is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
  • the Burkitt lymphoma is MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors MYC protein overexpression.
  • a MYC aberration e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression.
  • MYC gene translocation e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression,
  • the Burkitt lymphoma is c-MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors c-MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors c-MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors c-MYC mRNA overexpression.
  • a c-MYC aberration e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression.
  • the Burkitt lymphoma harbors c-MYC
  • the Burkitt lymphoma harbors c-MYC protein overexpression.
  • the Burkitt lymphoma is 1-MYC dependent.
  • the Burkitt lymphoma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression).
  • the Burkitt lymphoma harbors 1-MYC gene translocation.
  • the Burkitt lymphoma harbors 1-MYC gene amplification.
  • the Burkitt lymphoma harbors 1-MYC mRNA overexpression.
  • the Burkitt lymphoma harbors 1-MYC protein overexpression.
  • the Burkitt lymphoma is n-MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors n-MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors n-MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors n-MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors n-MYC protein overexpression.
  • a n-MYC aberration e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-
  • the Burkitt lymphoma is stage I. In certain embodiments, the Burkitt lymphoma is stage II. In certain embodiments, the Burkitt lymphoma is stage III. In certain embodiments, the Burkitt lymphoma is stage IV. In certain embodiments, the Burkitt lymphoma is stage II, III, or IV. In certain embodiments, the Burkitt lymphoma is stage III or IV.
  • the Burkitt lymphoma is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
  • the subject has failed a prior therapy. In certain embodiments, the subject has failed more than one prior therapy.
  • the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. [00200] A method provided herein encompasses treating a subject regardless of patient’s age, although some diseases are more common in certain age groups.
  • the therapeutically effective amount of a ketoamide described herein is ranging from about 0.01 to about 10 mg/kg per day, from about 0.02 to about 5 mg/kg per day, from about 0.05 to about 2 mg/kg per day, or from about 0.1 to about 1 mg/kg per day. In one embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.01 to about 10 mg/kg per day. In another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.02 to about 5 mg/kg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.05 to about 2 mg/kg per day.
  • the therapeutically effective amount of a ketoamide described herein is ranging from about 0.1 to about 1 mg/kg per day. In still another embodiment, the therapeutically effective amount of a ketoamide described herein is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg/kg per day.
  • the therapeutically effective amount of a ketoamide described herein is ranging from about 1 to about 500 mg per day, from about 2 to about 200 mg per day, from about 5 to about 100 mg per day, or from about 10 mg to about 100 mg per day. In one embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 1 to about 500 mg per day. In another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 2 to about 200 mg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 5 to about 100 mg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 10 to about 100 mg per day. In still another embodiment, the therapeutically effective amount of a ketoamide described herein is about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, or about 200 mg per day.
  • the administered dose of a ketoamide described herein can also be expressed in units other than mg/kg every other day.
  • doses for parenteral administration can be expressed as mg/m 2 per day.
  • doses for parenteral administration can be expressed as mg/m 2 per day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg per day to mg/m 2 per day to given either the height or weight of a subject or both.
  • a dose of 1 mg/m 2 per day for a 65 kg human is approximately equal to 58 mg/kg per day.
  • a ketoamide described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant
  • inhalation nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • a ketoamide described herein is administered orally. In another embodiment, a ketoamide described herein is administered parenterally. In yet another embodiment, a ketoamide described herein is administered intravenously. In yet another embodiment, a ketoamide described herein is administered intramuscularly. In yet another embodiment, a ketoamide described herein is administered subcutaneously. In still another embodiment, a ketoamide described herein is administered topically.
  • a ketoamide described herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
  • a ketoamide described herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by a method known in the art such as evaluation of subject’s symptoms, physical examination, visualization of the cancer that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
  • a ketoamide described herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • the administration can be continuous, /. ⁇ ., every day, or intermittently.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of a ketoamide described herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • a ketoamide described herein is cyclically administered to a subject to be treated. Cycling therapy involves the administration of the compound for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • a ketoamide described herein is administered for a cycle of about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, or about ten weeks, with a rest period of about 1 day to about four weeks.
  • a ketoamide described herein is administered for a cycle of three weeks, four weeks, five weeks, or six weeks with a rest period of 1, 3, 5, 7, 9, 12, or 14.
  • the rest period is 7 days.
  • the rest period is 14 days.
  • the rest period is a period that is sufficient for bone marrow recovery. The frequency, number, and length of dosing cycles can be increased or decreased.
  • a ketoamide described herein is administered for three weeks in a 28-day cycle with a 7-day rest period. In one embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered every day for five days of a week. In another embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered on Days 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15, 16, 17, 18, and 19. In one embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered every day for three days of a week.
  • a ketoamide described herein is administered on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19.
  • the subject is treated with a ketoamide described herein from about 1 to about 50, from about 2 to about 20, from about 2 to 10, or from about 4 to about 8 cycles.
  • the subject is treated with a ketoamide described herein from about 1 to about 50 cycles.
  • the subject is treated with a ketoamide described herein from about 2 to about 20 cycles.
  • the subject is treated with a ketoamide described herein from about 2 to 10 cycles.
  • the subject is treated with a ketoamide described herein from about 4 to about 8 cycles.
  • a method of inhibiting the growth of a malignant cell comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound described herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing apoptosis in a malignant cell comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound described herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of a GSPT1 in a malignant cell comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound described herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of downregulating a MYC in a malignant cell comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound described herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the malignant cell is a cell of a malignancy described herein.
  • a compound described herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,525,907; 5,052,558; and 5,055,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
  • Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • aqueous vehicles including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection
  • water-miscible vehicles including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Phase la is a dose escalation phase, determining the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the ketoamide in the subjects with advanced AML, solid tumor, or NHL.
  • the ketoamide is administered 3 days per week (Monday /Wednesday /Friday (M/W/F)) orally for a 28-day treatment cycle of 4 weeks.
  • the starting dose of the ketoamide for Cohort 1 is 0.1 mg based on nonclinical pharmacology, toxicology, and pharmacokinetic data.
  • the seven dosing levels in Phase la are summarized in Table 1.
  • a single subject is treated at each dose level. If the subject treated at a given dose level does not experience DLT or two adverse events of Grade 2 or higher that cannot be clearly attributed to disease progression, intercurrent illness, preexisting condition, or concomitant medications, the dose is escalated. If the subject treated at a given dose level experiences DLT, then the dose cohort is expanded to 3 subjects and a standard 3+3 design is utilized to further evaluate the dose level at which the DLT occurred and to evaluate all subsequent cohorts.
  • Dosing Levels in Phase la a. De-escalation in dose, if required in response to DLT, is a mid-dose between the current dose and the previous lower dose with DLT subject incidence of ⁇ 33%. b. Dose level increases are 2-fold or less. c. Cohort size(s) is increased to 3 patients if a DLT or two Grade 2 adverse event(s) occur that are not clearly attributable to disease progression, intercurrent illness, preexisting condition, or concomitant medications. d. Dosing interval may be reduced in response to toxicity (either for a given patient or for a cohort).
  • 3 to 6 subjects are initially exposed to the ketoamide at each dose level. To account for early drop out, up to 6 subjects may be enrolled. If 0 of the 3 initial subjects treated at a given dose level experiences DLT, the dose is escalated, and 3 subjects are enrolled at the next higher dose level. In the event more than 3 subjects are enrolled, all subjects are evaluated for DLT before escalation to the next dose level cohort. If 1 of the 3 initial subjects treated at a given dose level experiences DLT, then 3 additional subjects are enrolled at the same dose level (for a total of 6 subjects). In the event more than 3 subjects are enrolled, if 1 DLT is observed, the dose cohort is expanded to 6.
  • the dose is escalated, and 3 subjects are enrolled at the next higher dose level. If 1 or more of the additional subjects experiences DLT (z.e., DLT observed in 2 or more of the 6 subjects enrolled in the level), it is concluded that the MTD has been exceeded. If 1 or more of the additional subjects experiences DLT (z.e., DLT observed in 2 or more of the 6 subjects enrolled in the level), it is concluded that the MTD has been exceeded. If 2 or more of the initial subjects treated at a given dose level experience DLT, then it is concluded that the MTD has been exceeded. If the MTD has been exceeded, then up to 6 subjects are enrolled at the next lower dose if fewer than 6 subjects are evaluated at the lower dose. The MTD is the highest dose level of the ketoamide at which no more than 1 of 6 subjects experiences DLT.
  • a DLT is a severe or clinically significant adverse event (AE) or abnormal laboratory value (Grade 3 or greater, unless otherwise specified), unless it is clearly related to disease progression, intercurrent illness, preexisting condition, or concomitant medications. Toxicity severity is graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. For purposes of dose escalation, the totality of accrued safety information across all cycles completed at the time of data review by a Dose Escalation Committee (DEC) is taken into consideration.
  • NCI National Cancer Institute
  • CCAE Common Terminology Criteria for Adverse Events
  • Phase lb is a cohort expansion phase, which starts when the RP2D is determined. Up to 41 additional subjects are enrolled in each of two disease cohorts: subjects with AML and subjects with documented MYC genomic amplified/overexpressed tumors. Each subject in this phase is treated for a 28-day treatment cycle of 4 weeks.
  • the DEC reviews cumulative safety and available PK data in subjects treated in Phase lb for DLTs, with DEC reviews scheduled after the 6 th , 12 th , 21 st (interim analysis), 32 nd , and 41 st subjects of each disease cohort complete a treatment cycle with the ketoamide.
  • the Dose Escalation Phase (Phase la) enrolls up to 84 subjects, depending on the dose at which the MTD is determined; additional subjects may be enrolled in the event that a given subject either does not receive the ketoamide or discontinues early for reasons other than safety and is not evaluable for toxicity.
  • Eligible subjects for the Dose-Escalation Phase are > 18 years of age with documented diagnosis of (i) relapsed or refractory AML, according to the World Health Organization (WHO) classification, ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit; (ii) B cell NHL that is refractory to or intolerant of all standard therapy or for which no standard therapy is available; or (iii) histologically or cytologically documented, incurable or metastatic solid tumor.
  • WHO World Health Organization
  • Eligible subjects for the Expansion Phase are > 18 years of age with documented diagnosis of (i) relapsed or refractory AML, according to the World Health Organization (WHO) classification, ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit; or (ii) histologically or cytologically documented, incurable or metastatic solid tumor with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
  • WHO World Health Organization
  • MYC genomic amplification/overexpression by tumor- or blood-based analysis for a solid tumor, each eligible subject must have a measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST vl.l).
  • RECIST vl.l Solid Tumors Version 1.1
  • MRI magnetic resonance imaging
  • Additional inclusion criteria for the eligible subjects include: (i) an Eastern Cooperative Oncology Group (ECOG) performance status of ⁇ 2; (ii) serum AST and serum ALT ⁇ 3.0 x LLN ( ⁇ 5.0 x LLN in subjects with documented liver involvement); (iii) alkaline phosphatase ⁇ 2.5 x LLN ( ⁇ 5.0 x L N in subjects with documented liver involvement or bone metastases); (iv) direct serum bilirubin ⁇ 1.5 x LLN; (v) creatinine clearance of > 50 mL/min; and (vi) international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ⁇ 1.5 x LLN (subjects on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days); if receiving warfarin, the subject must have an INR ⁇ 3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study drug); subjects on low
  • the eligible subjects with a solid tumor or NHL must have: (i) absolute neutrophil count (ANC) > 1000 cells/pL; (ii) white blood cell (WBC) count > 1500/pL; (iii) platelet count > 100,000/pL; and (iv) hemoglobin > 9.0 g/dL.
  • the eligible subjects with AML must have white blood cell (WBC) count ⁇ 25 x 10 9 L at the time of screening (hydroxyurea may be used to bring the WBC count below the threshold; subjects may be retested within the 28-day screening period following treatment).
  • Screening commences with obtaining the subject’s signed informed consent and occurs up to 28 days prior to the first dosing of the ketoamide. Screening procedures include medical history review; physical exam; vital signs; 12 lead electrocardiogram (ECG); ECOG performance status; prior/concomitant medication review; blood collection for pregnancy test (females of childbearing potential); chemistry, hematology, and coagulation; AE assessment; and archival or recent biopsy formalin-fixed paraffin-embedded (FFPE) tissue block collection.
  • ECG electrocardiogram
  • ECOG performance status prior/concomitant medication review
  • blood collection for pregnancy test females of childbearing potential
  • chemistry, hematology, and coagulation AE assessment
  • AE assessment archival or recent biopsy formalin-fixed paraffin-embedded (FFPE) tissue block collection.
  • FFPE formalin-fixed paraffin-embedded
  • Baseline tumor lesions are measured and characterized prior to Cycle 1 Day 1 to assess the subject disease status prior to beginning treatment via bone marrow biopsy/aspirate, PB sample and/or CT/MRI/positron emission tomography-computed tomography (PET-CT) (scans that meet protocol requirements that are obtained as part of standard medical practice up to 6 weeks prior to Cycle 1 Day 1 are acceptable).
  • PET-CT positron emission tomography-computed tomography
  • the ketoamide is supplied as orally administered, immediate-release capsules of 0.1 mg, 0.5 mg, and 2.5 mg each. Subjects who meet eligibility criteria receive the ketoamide orally 3 days per week (M/W/F) for a 28-day treatment cycle of 4 weeks.
  • subjects undergo post-baseline BM biopsy/aspirate patients with AML and non-FDG avid lymphomas), CT/MRI, or PET-CT (as appropriate for FDG-avid lymphomas) scans for tumor response assessment.
  • a subject who does not show evidence of disease progression by clinical assessment or by biopsy/aspirate, CT/MRI, or applicable scan may continue receiving study treatment until disease progression (clinical or radiographic), unacceptable toxicity, withdrawal of consent, or other reasons.
  • a safety follow-up is done by phone 30 days after last dose of the ketoamide.
  • Adverse events > Grade 2 ongoing at the 30-day safety follow-up are followed until the event resolves to ⁇ Grade 1, stabilizes, subject starts alternate therapy, returns to a status that is clinically acceptable, is lost to follow-up, or terminates with the subject’s death.
  • the safety of the ketoamide is evaluated by (i) adverse events (NCI CTCAE Version 5.0); (ii) clinical laboratory testing (hematology, chemistry, and coagulation); (iii) physical examinations; (iv) vital signs (blood pressure, pulse, respiratory rate, body temperature, and weight); and (v) 12 lead ECGs. Dose limiting toxi cities are evaluated for determination of the MTD and/or RP2D. Throughout the study, safety is evaluated by a Dose Escalation Committee (DEC) that includes principal investigator(s), the sponsor’s physician (in consultation with the sponsor’s pharmacologist/pharmacokineticist as needed), and/or independent experts. The DEC reviews all cumulative available data and authorizes plans for the dosing of each subsequent cohort.
  • DEC Dose Escalation Committee
  • responses are evaluated every cycle for subjects with AML and every 8 weeks for subjects with NHL or solid tumors at the beginning of each odd numbered cycle (i.e., Cycle 3, 5, 7, etc.). Responses are evaluated based on BM biopsy/aspirate, peripheral blood (PB), CT, MRI, and/or PET-CT as appropriate for the corresponding malignancy.
  • PB peripheral blood
  • CT magnetic resonance
  • MRI magnetic resonance
  • PET-CT PET-CT
  • responses are evaluated using the European LeukemiaNet (ELN) panel 2017 guidelines.
  • Response categories include complete response (CR), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), stable disease, and progressive disease.
  • CR complete response
  • CRi complete remission with incomplete blood count recovery
  • MLFS morphologic leukemia free state
  • PR partial remission
  • stable disease stable disease
  • progressive disease progressive disease.
  • responses are evaluated using the Lugano response criteria.
  • Response categories include CR, PR, stable disease, or progressive disease.
  • responses are evaluated using RECIST vl.l.
  • Response categories include CR, PR, stable disease, or progressive disease.
  • a response based on imaging is confirmed by the same imaging technique no less than 4 weeks after the criteria for response are first met.
  • the preliminary efficacy of the ketoamide is evaluated by the following measures and endpoints: (i) objective response rate (ORR); (ii) best response; (iii) disease control rate (DCR); (iv) duration of response (DOR); (v) progression-free survival (PFS), defined as the time from first enrollment into the study to the earlier of the first documentation of definitive disease progression or death due to any cause (summarized descriptively using the Kaplan Meier method); and (vi) overall survival (OS), defined as the time from first enrollment into the study to death due to any cause (summarized descriptively using the Kaplan Meier method).
  • ORR objective response rate
  • DCR disease control rate
  • DCR duration of response
  • PFS progression-free survival
  • OS overall survival
  • the PK parameters of the ketoamide are determined, including (i) maximum observed plasma concentration (Cmax); (ii) observed time of peak concentration (Tmax); (iii) overall exposure (area under the plasma concentration curve, AUC); and (iv) elimination halflife.
  • PBMC Peripheral blood mononuclear cells
  • PB samples are collected to evaluate markers of pharmacodynamic activity, including GSPT1 levels in CD3+ T cells. Samples are also collected and stored for analysis for possible exploratory association with response or biomarker analyses, including, but not limited to, gene sequencing and gene expression profiling. Cytogenetics and mutation panel include (i) gene expression levels of MYC by digital droplet polymerase chain reaction (PCR); (ii) MYC protein expression levels; and (iii) gene mutation analysis by next generation sequencing.
  • PCR digital droplet polymerase chain reaction
  • Blood samples are obtained for biomarker evaluation from all eligible subjects. Archival tumor tissue samples obtained outside of this study for other purposes are collected from all subjects and used for biomarker evaluation.
  • ABC-1 cells were cultured in EMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. Daudi, DOHH-2, Namalwa, SU-DHL-2, SU-DHL-6, and WSU-DLCL-2 cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. All other cell lines were cultured as per a standard protocol. ABC-1, DOHH-2, and WSU-DLCL-2 cells were seeded at 4,000 cells per well; and Daudi, Namalwa, SU-DHL-2, and SU-DHL-6 cells were seeded at 5,000 cells per well in white walled 96-well plates.
  • ABC-1 cells were cultured in EMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. Daudi and SU-DHL-2 cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin.
  • ABC-1 cells were plated at 1.75 million cells per well in a 12 well plate. Daudi and SU-DHL-2 cells were cultured at approximately 3 x 10 6 cells per well in a 24 well plate and incubated in the presence of DMSO or a compound for 6 h.
  • Whole cell extracts were prepared using an IP lysis buffer according to the manufacturer’s protocol (Pierce). Briefly, 4 x 10 6 cells were washed once in PBS. The cell pellets were then resuspended in the IP lysis buffer and incubated for 15 min on ice. Cells debris was removed by centrifugation and the cleared whole cell lysates were transferred to new tubes for further analysis.
  • anti-eRF3/GSPTl antibody (Abeam), c-MYC rabbit monoclonal antibody (Cell Signaling Technology), n-MYC rabbit monoclonal antibody (Cell Signaling Technology), P-actin mouse monoclonal antibody (Cell Signaling Technology), IRDYE® goat anti-rabbit antibody (LI-COR), and IRDYE® goat anti-mouse antibody (LI-COR).
  • Anti-eRF3/GSPTl antibody Abeam
  • c-MYC rabbit monoclonal antibody Cell Signaling Technology
  • n-MYC rabbit monoclonal antibody Cell Signaling Technology
  • P-actin mouse monoclonal antibody Cell Signaling Technology
  • IRDYE® goat anti-rabbit antibody LI-COR
  • IRDYE® goat anti-mouse antibody LI-COR
  • BALB/c nude mice were inoculated subcutaneously at the flank with A2780 (ovarian cancer), NCI-H526 (SCLC), NCI-H1155 (NSCLC), or T47D (breast cancer) cells in PBS for tumor development.
  • Female CB.17 SCID mice were inoculated subcutaneously at the flank with DOHH-2 (B-cell lymphoma), SU-DHL-2 (large cell lymphoma), or Daudi (Burkitt’s lymphoma) cells in PBS for tumor development. The treatments started when the average tumor volume reached approximately 100-150 mm 3 . Each compound was administered IP daily. The results are shown in FIGS. 1 to 7.
  • BALB/c nude mice are inoculated subcutaneously at the flank with NCI-H526 or NCI-H1155 cells in PBS for tumor development.
  • Female CB.17 SCID mice are inoculated subcutaneously at the flank with SU-DHL-2 or Daudi cells in PBS for tumor development. The treatments start when the average tumor volume reaches approximately 100-150 mm 3 .
  • Compound A5 is administered orally daily.

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Abstract

Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy with a ketoamide, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

Description

KETOAMIDES FOR TREATING MALIGNANCY
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the priority of U.S. Provisional Application Nos. 63/270,732, filed October 22, 2021, and 63/365,409, filed May 26, 2022; the disclosure of each of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy with a ketoamide, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
BACKGROUND
[0003] G1 to S phase transition 1 (GSPT1) is a translation termination factor that mediates stop codon recognition and release of new protein from the ribosome. Hoshino et al., J. Biol. Chem. 1998, 273, 22254-9; Hoshino et al., Apoptosis 2012, 17, 1287-99. GSPT1 is also involved in several critical cellular processes, such as cell cycle regulation, cytoskeleton organization, and apoptosis. Brito et al., Carcinogenesis 2005, 26, 2046-9; Jean-Jean et al., Mol. Cell. Bio. 2007, 27, 5619-29. GSPT1 has been implicated as an oncogenic driver in many malignancies, including breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer. Id. Wright and Lange, Rev. Urol. 2007, 9, 207-13; Brito et al., Cancer Genet. Cytogenet. 2009, 195, 132-42; Tavassoli et al., Med. Oncol. 2011, 29, 1581-5; Liu et. al., PLOS One 2014, 9, e86371. Depletion of GSPT1 has been reported to induce apoptosis of rapidly dividing cells. Matykiela et al., Nature 2016, 535, 252-7; Uy et al., Blood 2019, 134 (Supplement 1) , 232.
[0004] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 1,898,160 new cancer cases diagnosed and 608,570 cancer deaths in the US alone in 2021. Cancer Facts & Figures 2021. Therefore, there is a need for an effective therapy for cancer treatment. SUMMARY OF THE DISCLOSURE
[0005] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a GSPT1 inhibitor.
[0006] Also provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a GSPT1 degrader.
[0007] Additionally, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):
Figure imgf000003_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4)=; or Z1 is a bond, one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4)= or -S-;
R1 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R2a and R2b is independently hydrogen, deuterium, halo, Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R2a and R2b together with the carbon atom to which they are attached form C3-10 cycloalkylene or heterocyclylene;
R3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl;
RE1 is hydrogen, deuterium, halo, or C1-6 alkyl;
RE2 is hydrogen or C1-6 alkyl; each RE4 is independently hydrogen or RE5; each RE5 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -0C(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(0)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, or 2; p is an integer of 0, 1, 2, 3, 4, or 5; and q is an integer of 0, 1, 2, or 3; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rb, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRb)NRfRg, -NReC(S)Rb, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rb, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rb is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0008] Furthermore, provided herein is a method of inhibiting the growth of a malignant cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0009] Provided herein is a method of inducing apoptosis in a malignant cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0010] Provided herein is a method of inducing degradation of a GSPT1 in a malignant cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0011] Provided herein is a method of downregulating a MYC in a malignant cell, comprising contacting the cell with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0001] FIG. 1 shows the anticancer effects of compounds A5 and gemcitabine in a xenograft mouse model for NSCLC (NCI-H1155 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 14 days and gemcitabine (40 mg/kg) was administered IP once every four days (Q4D) for 14 days.
[0002] FIG. 2 shows the anticancer effects of compounds A5 and docetaxel in a xenograft mouse model for SCLC (NCI-H526 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 3 weeks and docetaxel (15 mg/kg) was administered IP once a week (QW) for 3 weeks.
[0003] FIG. 3 shows the anticancer effects of compounds A5 and fulvestrant in a xenograft mouse model for breast cancer (T47D cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 4 weeks and fulvestrant (3 mg/dose) was administered SC once a week (QW) for 4 weeks.
[0004] FIG. 4 shows the anticancer effects of compounds A5 and gemcitabine in a xenograft mouse model for ovarian cancer (A2780 cells), where compound A5 (25 mg /kg) was administered IP once a day (QD) for 3 weeks and gemcitabine (30 mg/kg) was administered IP once every 3 days (Q3D) for 3 weeks.
[0005] FIG. 5 shows the anticancer effects of compounds A5 and rituximab in a xenograft mouse model for lymphoma (SU-DHL-2 cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD) from Day 0 to Day 9 and then at 5 mg/kg from Day 10 to Day 28; and rituximab (3 mg/kg) was administered IV once a week (QW) for 4 weeks.
[0006] FIG. 6 shows the anticancer effects of compounds A5 and cyclophosphamide in a xenograft mouse model for lymphoma (DOHH2 cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD); and cyclophosphamide (100 mg/kg) was administered IP once a day (QD).
[0007] FIG. 7 shows the anticancer effects of compounds A5 and cyclophosphamide in a xenograft mouse model for lymphoma (Daudi cells), where compound A5 was administered IP at 25 or 50 mg/kg once a day (QD); and cyclophosphamide (100 mg/kg) was administered IP once a day (QD).
DETAILED DESCRIPTION
[0012] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0013] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0014] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human. [0015] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0016] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
[0017] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
[0018] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
[0019] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0020] The term “ICso” or “ECso” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response.
[0021] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015.
[0022] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0023] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g, //-propyl and isopropyl), butyl (including all isomeric forms, e.g., //-butyl, isobutyl, ec-butyl, and /-butyl), pentyl (including all isomeric forms, e.g., //-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g, //-hexyl, isohexyl, and sec-hexyl).
[0024] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCEE, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.
[0025] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “c/ ” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen- 1-yl, propen-2 -yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
[0026] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-OCCEE) and propargyl (-CH2OCH)), butynyl (including all isomeric forms, e.g., 1-butyn-l-yl and 2-butyn- 1 -yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-l-yl and l-methyl-2-butyn-l-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-l-yl and 2-hexyn-l-yl).
[0027] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]- octyl, decalinyl, and adamantyl.
[0028] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane-l,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1,1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclo- pentane- 1,2-diyl, and cyclopentane-l,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane- 1,1 -diyl, cyclohexane- 1,2-diyl, cyclohexane-l,3-diyl, and cyclohex-l,4-diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane- 1,1 -diyl, cycloheptane- 1,2- diyl, cycloheptane-l,3-diyl, and cycloheptane-l,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline- 1,1 -diyl, decaline- 1,2-diyl, and decaline- 1,8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant- 1,2-diyl, adamant- 1,3 -diyl, and adamant- 1,8-diyl).
[0029] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (Ce-is), or from 6 to 10 (Ce-io) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein. [0030] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1 -phenylethyl and 2-phenyl- ethyl), and phenylpropyl (including all isomeric forms, e.g., 1 -phenylpropyl, 2-phenylpropyl, and 3 -phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.
[0031] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-Z>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-Z>]-pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-Z>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-a]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,l-Z>]-thiazolyl and imidazo[4,5- ]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5- Z>]pyridinyl, oxazolo[4,5-c]-pyridinyl, oxazolo[5,4-Z>]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- Z>]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-Z>]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-J]-pyrimidinyl and [l,2,3]thiadiazolo[4,5-J]pyrimidinyl), and thieno- pyridyl (including all isomeric forms, e.g., thieno[2,3-Z>]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-Z>]pyridinyl, and thieno-[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzo-furanyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phen- anthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.
[0032] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic nonaromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodi oxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[ ][l,3]oxazinyl, 3,4- dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydro- pyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.
[0033] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. If a heterocyclylene group containing a nonaromatic heterocyclic ring also contains a heteroaromatic ring, the heterocyclylene group does not have a linkage to the rest of a molecule via its heteroaromatic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., l,4-dihydrobenzo[ ][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[d][l,2]oxazindiyl), dihydrobenzo- thiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydro- isoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrrol diyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydro- isoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.
[0034] The term “halogen”, “halide,” or “halo” refers to fluoro, chloro, bromo, and/or iodo.
[0035] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2), and oxo (=0); (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”
[0036] In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0037] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
[0038] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S. [0039] The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon- 11 (UC), carbon- 12 (12C), carbon- 13 (13C), carbon- 14 (14C), nitrogen- 13 (13N), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 14 (14O), oxygen- 15 (15O), oxygen- 16 (16O), oxygen- 17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon- 12 (12C), carbon- 13 (13C), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur- 33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon- 11 (nC), carbon- 14 (14C), nitrogen- 13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine- 131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, as example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as example, or any oxygen can be 18O, as example, where feasible according to the judgment of one of ordinary skill in the art.
[0040] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope e.g., 4H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.
[0041] The term “isotopic enrichment factor” refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
[0042] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
[0043] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
[0044] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 (12C) and carbon- 13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
[0045] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon. For example, carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon- 13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
[0046] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.
[0047] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, ^-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate. [0048] For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.
[0049] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a diastereomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein.”
Ketoamide Compounds
[0050] In one embodiment, described herein is a compound of Formula (I):
Figure imgf000021_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4)=; or Z1 is a bond, one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4)= or -S-;
R1 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R2a and R2b is independently hydrogen, deuterium, halo, Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R2a and R2b together with the carbon atom to which they are attached form C3-10 cycloalkylene or heterocyclylene;
R3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl; or -NRlbRlc;
RE1 is hydrogen, deuterium, halo, or C1-6 alkyl;
RE2 is hydrogen or C1-6 alkyl; each RE4 is independently hydrogen or RE5; each RE5 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -0C(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(0)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, or 2; p is an integer of 0, 1, 2, 3, 4, or 5; and q is an integer of 0, 1, 2, or 3; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rb, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRb)NRfRg, -NReC(S)Rb, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rb, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rb is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0051] In certain embodiments, one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4)=; wherein RE4 is as defined herein. In certain embodiments, Z1 is -C=, and Z2, Z3, and Z4 are each independently -C(RE4)=; wherein RE4 is as defined herein. In certain embodiments, Z2 is -C=, and Z1, Z3, and Z4 are each independently - C(RE4)=; wherein RE4 is as defined herein. In certain embodiments, Z3 is -C=, and Z1, Z2, and Z4 are each independently -C(RE4)=; wherein RE4 is as defined herein. In certain embodiments, Z4 is -C=, and Z1, Z2, and Z3 are each independently -C(RE4)=; wherein RE4 is as defined herein.
[0052] In certain embodiments, Z1 is a bond, one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4)= or -S-; wherein RE4 is as defined herein. In certain embodiments, Z1 is a bond, Z2 is -C=, and Z3 and Z4 are each independently -C(RE4)= or -S-; wherein RE4 is as defined herein. In certain embodiments, Z1 is a bond, Z3 is -C=, and Z2 and Z4 are each independently -C(RE4)= or -S-; wherein RE4 is as defined herein. In certain embodiments, Z1 is a bond, Z4 is -C=, and Z2 and Z3 are each independently -C(RE4)= or -S-; wherein RE4 is as defined herein.
[0053] In another embodiment, described herein is a compound of Formula (II):
Figure imgf000024_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein n is an integer of 0, 1, 2, or 3; and R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, p, and q are each as defined herein.
[0054] In yet another embodiment, described herein is a compound of Formula (III):
Figure imgf000024_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0055] In yet another embodiment, described herein is a compound of Formula (IV):
Figure imgf000025_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0056] In yet another embodiment, described herein is a compound of Formula (V):
Figure imgf000025_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0057] In yet another embodiment, described herein is a compound of Formula (VI):
Figure imgf000025_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0058] In yet another embodiment, described herein is a compound of Formula (VII):
Figure imgf000025_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0059] In yet another embodiment, described herein is a compound of Formula (VIII):
Figure imgf000026_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0060] In yet another embodiment, described herein is a compound of Formula (IX):
Figure imgf000026_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0061] In yet another embodiment, described herein is a compound of Formula (X):
Figure imgf000026_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0062] In yet another embodiment, described herein is a compound of Formula (XI):
Figure imgf000027_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0063] In yet another embodiment, described herein is a compound of Formula (XII):
Figure imgf000027_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0064] In still another embodiment, described herein is a compound of Formula (XIII):
Figure imgf000027_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein R1, R2a, R2b, R3, RE1, RE2, RE5, Z, m, n, p, and q are each as defined herein.
[0065] In one embodiment, in any one of Formulae (II) to (XIII),
Z is CH2 or C(=O);
R1 is H or methyl; each R2a and R2b is H;
R3 is dimethylamino, phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or cyclohexyl, each of which is optionally substituted with one, two, or three substituents RA, wherein each substituent RA is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl, morpholinylmethyl, isopropyl, ec-butyl, tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido;
RE1 is H;
RE2 is H or D-valyloxymethyl;
RE5 is fluoro or methyl; m is an integer of 0, 1, or 2; n is an integer of 0, 1, or 2; p is an integer of 0, 1, or 2; and q is an integer of 0, 1, 2, or 3.
[0066] In another embodiment, in any one of Formulae (II) to (XIII),
Z is CH2 or C(=O);
R1 is H or methyl; each R2a and R2b is H;
R3 is dimethylamino, phenyl, cyanophenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, (l-trifluoromethylethyl)phenyl, trifluoromethylphenyl, dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl, tert-butylphenyl, (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl, (l-methylcyclopropyl)phenyl, (1-trifluoro- methylcyclopropyl)-phenyl, phenylphenyl, (l-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl, dimethylaminophenyl, acetamidophenyl, difluorophenyl, dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl, dimethylphenyl, trimethylphenyl, trimethoxyphenyl, dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl, thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl, piperidinyl, or te/7-butylpiperidinyl;
RE1 is H;
RE2 is H or D-valyloxymethyl;
RE5 is fluoro or methyl; m is an integer of 1 or 2; n is an integer of 0 or 1; p is an integer of 0, 1, or 2; and q is an integer of 0, 1, or 2. [0067] In yet another embodiment, in any one of Formulae (II) to (XIII),
Z is CH2 or C(=O);
R1 is H or methyl; each R2a and R2b is H;
R3 is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(l-trifluoro- methylethyl)phenyl, 4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl, 4-morpholin-4- ylmethylphenyl, 4-isopropylphenyl, 4- ec-butylphenyl, 3 -tert-butyl phenyl, 4-tert-butyl phenyl, 4- (hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl, 4-(l-methylcyclopropyl)phenyl, 4-(l- trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl, 4-(l-methylpiperidin-4-yl)phenyl, 4- hydroxylphenyl, 3 -methoxyphenyl, 4-m ethoxyphenyl, 4-dimethylaminophenyl, 4-acetamido- phenyl, 3,4-difluorophenyl, 3, 4-di chlorophenyl, 3-chloro-4-methylphenyl, 3 -methyl -4-/C 7- butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl- 4-tert-butyl phenyl, 3 -dimethylamino-4-m ethylphenyl, 2-naphthyl, thien-2-yl, 5-isopropylthien-2- yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-l-yl;
RE1 is H;
RE2 is H or D-valyloxymethyl;
RE5 is fluoro or methyl; m is an integer of 1 or 2; n is an integer of 0 or 1; p is an integer of 1 or 2; and q is an integer of 0, 1, or 2.
[0068] In one embodiment, described herein is:
2-(4-(tert-butyl)phenyl)-A-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-47/- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide Al;
Figure imgf000029_0001
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A2;
Figure imgf000030_0001
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-oxo-2-(4-(l-(trifluoromethyl)cyclopropyl)phenyl)acetamide A3;
Figure imgf000030_0002
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(5-isopropylthiophen-2-yl)-2-oxoacetamide A4;
Figure imgf000030_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)acetamide A5;
Figure imgf000030_0004
2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A6;
Figure imgf000030_0005
2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A7;
Figure imgf000031_0001
2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l- yl)methyl)-2-oxoacetamide A8;
Figure imgf000031_0002
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l- yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide A9;
Figure imgf000031_0003
(5)-2-(4-(ter/-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A10;
Figure imgf000031_0004
2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide All;
Figure imgf000031_0005
2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A12;
Figure imgf000032_0001
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A13;
Figure imgf000032_0002
2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A14;
Figure imgf000032_0003
2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A15;
Figure imgf000032_0004
2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A16;
Figure imgf000032_0005
2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol- 1 -yl)methyl)-2-oxoacetamide A17;
Figure imgf000033_0001
2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol-l-yl)methyl)-2-oxoacetamide A18;
Figure imgf000033_0002
2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A19;
Figure imgf000033_0003
2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A20;
Figure imgf000033_0004
2-([1, 1'-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A21;
Figure imgf000033_0005
2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-
Figure imgf000034_0001
2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A23;
Figure imgf000034_0002
2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A24;
Figure imgf000034_0003
2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6- dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A25;
Figure imgf000034_0004
2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A26;
Figure imgf000034_0005
2-(3-methyl-4-(ter/-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A27;
Figure imgf000035_0001
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A28;
Figure imgf000035_0002
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A29;
Figure imgf000035_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)acetamide A30;
Figure imgf000035_0004
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-methylpiperidin-4-yl)phenyl)-2-oxoacetamide A31;
Figure imgf000036_0001
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)methyl)-2-oxoacetamide A32;
Figure imgf000036_0002
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A33;
Figure imgf000036_0003
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-N- methyl-2-oxoacetamide A34;
Figure imgf000036_0004
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4JH- thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide A35;
Figure imgf000036_0005
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-oxo-2-(4-( 1,1,1 -trifluoropropan-2-yl)phenyl)acetamide A36;
Figure imgf000037_0001
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2- yl)-2-oxoacetamide A37;
Figure imgf000037_0002
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A38;
Figure imgf000037_0003
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4JH- thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamide A39;
Figure imgf000037_0004
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A40;
Figure imgf000037_0005
2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)ethyl)-2-oxoacetamide A41;
Figure imgf000038_0001
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-methylcyclopropyl)phenyl)-2-oxoacetamide A42;
Figure imgf000038_0002
A-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamide A43;
Figure imgf000038_0003
2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6- dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A44;
Figure imgf000038_0004
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno [2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide A45;
Figure imgf000039_0001
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A46;
Figure imgf000039_0002
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-N-
Figure imgf000039_0003
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)methyl)-2-oxoacetamide A48;
Figure imgf000039_0004
(27?)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-l-oxoisoindolin-2-yl)-2,6- di oxopiperi din- l-yl)m ethyl 2-amino-3-methylbutanoate A49;
Figure imgf000040_0001
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A50;
Figure imgf000040_0002
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A51;
Figure imgf000040_0003
N-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)ethyl)-2-oxo-2-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)acetamide A52;
Figure imgf000040_0004
2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A53;
Figure imgf000041_0001
2-(3-methyl-4-(terZ-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A54;
Figure imgf000041_0002
2-(3-methyl-4-(terZ-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A55;
Figure imgf000041_0003
2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2- oxoacetamide A56;
Figure imgf000041_0004
N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2-oxo-2-(4-(l-(trifluoromethyl)- cyclopropyl)phenyl)acetamide A57;
Figure imgf000042_0001
N-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)acetamide A58;
Figure imgf000042_0002
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2- yl)-2-oxoacetamide A59;
Figure imgf000042_0003
N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A60;
Figure imgf000042_0004
2-(4-(tert-butyl)piperidin-l-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A61;
Figure imgf000043_0001
2-(4-(tert-butyl)piperidin-l-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A62;
Figure imgf000043_0002
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)propanamide A63;
Figure imgf000043_0003
(2,6-dioxo-3-(l-oxo-4-((2-oxo-2-(4-(l-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)- methyl)isoindolin-2-yl)piperidin-l-yl)methyl D-valinate A64;
Figure imgf000043_0004
N-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(l-
(trifluoromethyl)cyclopropyl)phenyl)acetamide A65;
Figure imgf000044_0001
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4-
Figure imgf000044_0002
2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A67;
Figure imgf000044_0003
2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A68;
Figure imgf000044_0004
N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)- 2-oxo-4-phenylbutanamide A69;
Figure imgf000045_0001
A1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-
Figure imgf000045_0002
A1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)- N2,N2-dimethyloxalamide A71;
Figure imgf000045_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(/?-tolyl)acetamide
A72;
Figure imgf000045_0004
2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A73;
Figure imgf000045_0005
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamide
A74;
Figure imgf000046_0001
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4- (trifluoromethyl)phenyl)acetamide A75;
Figure imgf000046_0002
2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A76;
Figure imgf000046_0003
2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A77;
Figure imgf000046_0004
2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A78;
Figure imgf000047_0001
2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A79;
Figure imgf000047_0002
2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)- 2-oxoacetamide A80;
Figure imgf000047_0003
2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A81;
Figure imgf000047_0004
2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A82;
Figure imgf000048_0001
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamide
A83;
Figure imgf000048_0002
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6- trimethoxyphenyl)acetamide A84;
Figure imgf000048_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6- trimethylphenyl)acetamide A85;
Figure imgf000048_0004
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2- fluorophenyl)acetamide A86;
Figure imgf000048_0005
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4- trifluoromethylphenyl)acetamide A87;
Figure imgf000049_0001
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A88;
Figure imgf000049_0002
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2- oxoacetamide A89;
Figure imgf000049_0003
2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A90;
Figure imgf000049_0004
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A91;
Figure imgf000049_0005
2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A92;
Figure imgf000050_0001
2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A93;
Figure imgf000050_0002
2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A94;
Figure imgf000050_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2- oxoacetamide A95;
Figure imgf000050_0004
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2- oxoacetamide A96;
Figure imgf000050_0005
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2- oxoacetamide A97;
Figure imgf000051_0001
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A98;
Figure imgf000051_0002
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A99;
Figure imgf000051_0003
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2- oxoacetamide A100;
Figure imgf000051_0004
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A101;
Figure imgf000052_0001
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A102;
Figure imgf000052_0002
N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(pyri din-4- yl)acetamide A103;
Figure imgf000052_0003
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A104;
Figure imgf000052_0004
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A105; or
Figure imgf000052_0005
2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A106;
Figure imgf000053_0001
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0069] In one embodiment, described herein is compound Al, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A2, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A3, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A4, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A5, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A6, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A7, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A8, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A9, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A10, or a pharmaceutically acceptable salt thereof.
[0070] In one embodiment, described herein is compound All, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound All, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A13, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A14, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A15, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A16, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A17, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A18, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A19, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A20, or a pharmaceutically acceptable salt thereof.
[0071] In one embodiment, described herein is compound All, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A22, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A23, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A24, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A25, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A26, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A27, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A28, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A29, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A30, or a pharmaceutically acceptable salt thereof.
[0072] In one embodiment, described herein is compound A31, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A32, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A33, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A34, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A35, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A36, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A37, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A38, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A39, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A40, or a pharmaceutically acceptable salt thereof.
[0073] In one embodiment, described herein is compound A51, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A52, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A53, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A54, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A55, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A56, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A57, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A58, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A59, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A60, or a pharmaceutically acceptable salt thereof.
[0074] In one embodiment, described herein is compound A61, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A62, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A63, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A64, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A65, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A66, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A67, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A68, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A69, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A70, or a pharmaceutically acceptable salt thereof.
[0075] In one embodiment, described herein is compound A71, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A72, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A73, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A74, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A75, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A76, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A77, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A78, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A79, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A80, or a pharmaceutically acceptable salt thereof.
[0076] In one embodiment, described herein is compound A91, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A92, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A93, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A94, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A95, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A96, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A97, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A98, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A99, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A100, or a pharmaceutically acceptable salt thereof.
[0077] In one embodiment, described herein is compound A101, or a pharmaceutically acceptable salt thereof. In another embodiment, described herein is compound A102, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A103, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A104, or a pharmaceutically acceptable salt thereof. In yet another embodiment, described herein is compound A105, or a pharmaceutically acceptable salt thereof. In still another embodiment, described herein is compound A106, or a pharmaceutically acceptable salt thereof.
[0078] In certain embodiments, a compound described herein is deuterium-enriched. In certain embodiments, a compound described herein is carbon-13 enriched. In certain embodiments, a compound described herein is carbon-14 enriched. In certain embodiments, a compound described herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15N for nitrogen; 17O or 18O for oxygen, and 33S, 34S, or 36S for sulfur.
[0079] In certain embodiments, a compound described herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 30, no less than about 40, no less than about 50, no less than about 60, no less than about 70, no less than about 80, no less than about 90, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6410 for deuterium and 90 for carbon-13.
[0080] In certain embodiments, a compound described herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
[0081] In certain embodiments, a compound described herein has a carbon- 13 enrichment factor of no less than about 1.8 (about 2% carbon-13 enrichment), no less than about 4.5 (about 5% carbon- 13 enrichment), no less than about 9 (about 10% carbon- 13 enrichment), no less than about 18 (about 20% carbon-13 enrichment), no less than about 45 (about 50% carbon-13 enrichment), no less than about 68 (about 75% carbon- 13 enrichment), no less than about 72 (about 80% carbon- 13 enrichment), no less than about 77 (about 85% carbon- 13 enrichment), no less than about 81 (about 90% carbon- 13 enrichment), no less than about 86 (about 95% carbon- 13 enrichment), no less than about 87 (about 97% carbon- 13 enrichment), no less than about 88 (about 98% carbon- 13 enrichment), no less than about 89 (about 99% carbon- 13 enrichment), or no less than about 90 (about 99.5% carbon-13 enrichment). The carbon-13 enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
[0082] In certain embodiments, at least one of the atoms of a compound described herein, as specified as isotopically enriched, has isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound described herein, as specified as isotopically enriched, have isotopic enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In any events, the isotopic enrichment of the isotopically enriched atom of a compound described herein is no less than the natural abundance of the isotope specified.
[0083] In certain embodiments, at least one of the atoms of a compound described herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound described herein, as specified as deuterium-enriched, have deuterium enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
[0084] In certain embodiments, at least one of the atoms of a compound described herein, as specified as 13C-enriched, has carbon- 13 enrichment of no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. In certain embodiments, the atoms of a compound described herein, as specified as 13C-enriched, have carbon- 13 enrichment of no less than about 1%, no less than about 2%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
[0085] In certain embodiments, a compound described herein is isolated or purified. In certain embodiments, a compound described herein has a purity of at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
[0086] The compounds described herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound described herein contains an alkenyl group, the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[0087] A compound described herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. [0088] When a compound described herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Set. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; Wiley-VCH and VHCA, Zurich, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound described herein is a hydrate.
[0089] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid. In certain embodiments, a compound described herein is a hydrochloride salt. In certain embodiments, a compound described herein is a -toluenesulfonate salt. In certain embodiments, a compound described herein is a di- - toluenesulfonate salt.
[0090] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A-methyl-glucamine, hydrabamine, UT-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, A-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)- 1,3 -propanediol, and tromethamine.
[0091] A compound described herein may also be provided as a prodrug, which is a functional derivative of a compound, for example, of Formula I and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
[0092] The compounds described herein can be prepared, isolated, or obtained by any method known to one of ordinary skill in the art, for example, by following the procedures described in US 2020/0369679 Al and WO 2020/242960 Al, the disclosure of each of which is incorporated herein by reference in its entirety.
Pharmaceutical Compositions
[0093] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
[0094] In another embodiment, provided herein is a pharmaceutical composition, comprising any one of compounds Al to A106, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
[0095] A pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
[0096] In one embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, a pharmaceutical composition provided herein is formulated in a dosage form for topical administration.
[0097] A pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[0098] A pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.
[0099] In one embodiment, a pharmaceutical composition provided herein comprises a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and sugar beads, talc, and povidone.
[00100] In another embodiment, a pharmaceutical composition provided herein comprises any one of compounds Al to A106, or a pharmaceutically acceptable salt thereof; and sugar beads, talc, and povidone. In one embodiment, the pharmaceutical composition provided herein is formulated as a capsule.
[00101] In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.1 to about 100, from about 0.2 to about 50, from about 0.5 to about 20, or from about 0.5 to about 10 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.1 to about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.2 to about 50 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.5 to about 20 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount ranging from about 0.5 to about 10 mg per capsule. [00102] In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount of about 0.1, about 0.2, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 10, about 15, about 20, about 25, about 50, about 75, or about 100 mg per capsule. In certain embodiments, a pharmaceutical composition provided herein comprises a compound provided herein or a pharmaceutically acceptable salt in an amount of about 0.1, about 0.2, about 0.5, about 1, about 2, about 2.5, about 5, about 10, about 20, or about 50 mg per capsule.
[00103] In certain embodiments, a pharmaceutical composition provided herein is formulated as an immediate-release capsule with a size of, e.g., size 1 or size 000.
Methods of Treatment
[00104] In one embodiment, provided herein is method of treating a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00105] In certain embodiments, the malignancy is advanced. In certain embodiments, the malignancy is incurable. In certain embodiments, the malignancy is metastatic. In certain embodiments, the malignancy is recurrent. In certain embodiments, the malignancy is relapsed. In certain embodiments, the malignancy is refractory. In certain embodiments, the malignancy is refractory to a standard therapy. In certain embodiments, the malignancy is intolerant of a standard therapy. In certain embodiments, the malignancy is drug-resistant.
[00106] In certain embodiments, the malignancy is MYC dependent. In certain embodiments, the malignancy harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the malignancy harbors MYC gene translocation. In certain embodiments, the malignancy harbors MYC gene amplification. In certain embodiments, the malignancy harbors MYC mRNA overexpression. In certain embodiments, the malignancy harbors MYC protein overexpression.
[00107] In certain embodiments, the malignancy is c-MYC dependent. In certain embodiments, the malignancy harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the malignancy harbors c-MYC gene translocation. In certain embodiments, the malignancy harbors c-MYC gene amplification. In certain embodiments, the malignancy harbors c-MYC mRNA overexpression. In certain embodiments, the malignancy harbors c-MYC protein overexpression.
[00108] In certain embodiments, the malignancy is 1-MYC dependent. In certain embodiments, the malignancy harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the malignancy harbors 1-MYC gene translocation. In certain embodiments, the malignancy harbors 1-MYC gene amplification. In certain embodiments, the malignancy harbors 1-MYC mRNA overexpression. In certain embodiments, the malignancy harbors 1-MYC protein overexpression.
[00109] In certain embodiments, the malignancy is n-MYC dependent. In certain embodiments, the malignancy harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the malignancy harbors n-MYC gene translocation. In certain embodiments, the malignancy harbors n-MYC gene amplification. In certain embodiments, the malignancy harbors n-MYC mRNA overexpression. In certain embodiments, the malignancy harbors n-MYC protein overexpression.
[00110] In certain embodiments, the malignancy is a hematological malignancy. In certain embodiments, the hematological malignancy is advanced. In certain embodiments, the hematological malignancy is incurable. In certain embodiments, the hematological malignancy is metastatic. In certain embodiments, the hematological malignancy is recurrent. In certain embodiments, the hematological malignancy is relapsed. In certain embodiments, the hematological malignancy is refractory. In certain embodiments, the hematological malignancy is refractory to a standard therapy. In certain embodiments, the hematological malignancy is intolerant of a standard therapy. In certain embodiments, the hematological malignancy is drugresistant.
[00111] In certain embodiments, the hematological malignancy is MYC dependent. In certain embodiments, the hematological malignancy harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the hematological malignancy harbors MYC gene translocation. In certain embodiments, the hematological malignancy harbors MYC gene amplification. In certain embodiments, the hematological malignancy harbors MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors MYC protein overexpression.
[00112] In certain embodiments, the hematological malignancy is c-MYC dependent. In certain embodiments, the hematological malignancy harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the hematological malignancy harbors c-MYC gene translocation. In certain embodiments, the hematological malignancy harbors c-MYC gene amplification. In certain embodiments, the hematological malignancy harbors c-MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors c-MYC protein overexpression.
[00113] In certain embodiments, the hematological malignancy is 1-MYC dependent. In certain embodiments, the hematological malignancy harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the hematological malignancy harbors 1-MYC gene translocation. In certain embodiments, the hematological malignancy harbors 1-MYC gene amplification. In certain embodiments, the hematological malignancy harbors 1-MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors 1-MYC protein overexpression.
[00114] In certain embodiments, the hematological malignancy is n-MYC dependent. In certain embodiments, the hematological malignancy harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the hematological malignancy harbors n-MYC gene translocation. In certain embodiments, the hematological malignancy harbors n-MYC gene amplification. In certain embodiments, the hematological malignancy harbors n-MYC mRNA overexpression. In certain embodiments, the hematological malignancy harbors n-MYC protein overexpression.
[00115] In certain embodiments, the malignancy is a leukemia. In certain embodiments, the leukemia is advanced. In certain embodiments, the leukemia is incurable. In certain embodiments, the leukemia is metastatic. In certain embodiments, the leukemia is recurrent. In certain embodiments, the leukemia is relapsed. In certain embodiments, the leukemia is refractory. In certain embodiments, the leukemia is refractory to a standard therapy. In certain embodiments, the leukemia is intolerant of a standard therapy. In certain embodiments, the leukemia is drug-resistant.
[00116] In certain embodiments, the leukemia is MYC dependent. In certain embodiments, the leukemia harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the leukemia harbors MYC gene translocation. In certain embodiments, the leukemia harbors MYC gene amplification. In certain embodiments, the leukemia harbors MYC mRNA overexpression. In certain embodiments, the leukemia harbors MYC protein overexpression.
[00117] In certain embodiments, the leukemia is c-MYC dependent. In certain embodiments, the leukemia harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the leukemia harbors c-MYC gene translocation. In certain embodiments, the leukemia harbors c-MYC gene amplification. In certain embodiments, the leukemia harbors c- MYC mRNA overexpression. In certain embodiments, the leukemia harbors c-MYC protein overexpression.
[00118] In certain embodiments, the leukemia is 1-MYC dependent. In certain embodiments, the leukemia harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the leukemia harbors 1-MYC gene translocation. In certain embodiments, the leukemia harbors 1-MYC gene amplification. In certain embodiments, the leukemia harbors 1- MYC mRNA overexpression. In certain embodiments, the leukemia harbors 1-MYC protein overexpression.
[00119] In certain embodiments, the leukemia is n-MYC dependent. In certain embodiments, the leukemia harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the leukemia harbors n-MYC gene translocation. In certain embodiments, the leukemia harbors n-MYC gene amplification. In certain embodiments, the leukemia harbors n-MYC mRNA overexpression. In certain embodiments, the leukemia harbors n-MYC protein overexpression.
[00120] In certain embodiments, the malignancy is acute myeloid leukemia (AML). In certain embodiments, the AML is MYC dependent. In certain embodiments, the AML harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the AML harbors MYC gene translocation. In certain embodiments, the AML harbors MYC gene amplification. In certain embodiments, the AML harbors MYC mRNA overexpression. In certain embodiments, the AML harbors MYC protein overexpression.
[00121] In certain embodiments, the AML is c-MYC dependent. In certain embodiments, the AML harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the AML harbors c-MYC gene translocation. In certain embodiments, the AML harbors c-MYC gene amplification. In certain embodiments, the AML harbors c-MYC mRNA overexpression. In certain embodiments, the AML harbors c-MYC protein overexpression.
[00122] In certain embodiments, the AML is 1-MYC dependent. In certain embodiments, the AML harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1- MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the AML harbors 1-MYC gene translocation. In certain embodiments, the AML harbors 1-MYC gene amplification. In certain embodiments, the AML harbors 1-MYC mRNA overexpression.
In certain embodiments, the AML harbors 1-MYC protein overexpression.
[00123] In certain embodiments, the AML is n-MYC dependent. In certain embodiments, the AML harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the AML harbors n-MYC gene translocation. In certain embodiments, the AML harbors n-MYC gene amplification. In certain embodiments, the AML harbors n-MYC mRNA overexpression. In certain embodiments, the AML harbors n-MYC protein overexpression.
[00124] In certain embodiments, the AML is advanced. In certain embodiments, the AML is metastatic. In certain embodiments, the AML is recurrent. In certain embodiments, the AML is relapsed or refractory. In certain embodiments, the AML is relapsed. In certain embodiments, the AML is refractory. In certain embodiments, the AML is refractory to a standard therapy. In certain embodiments, the AML is intolerant of a standard therapy. In certain embodiments, the AML is del(5q) AML. In certain embodiments, the AML harbors a cytogenetic abnormality. In certain embodiments, the AML harbors del(5q).
[00125] In certain embodiments, the AML is drug-resistant. In certain embodiments, the AML is resistant to arsenic trioxide, cyclophosphamide, cytarabine, daunorubicin, dexamethasone, doxorubicin, enasidenib, gemtuzumab ozogamicin, gilteritinib, glasdegib, idamycin, idarubicin, ivosidenib, midostaurin, mitoxantrone, thioguanine, venetoclax, and/or vincristine.
[00126] In certain embodiments, the AML is AML with a translocation between chromosomes 8 and 21 [t(8;21 )] . In certain embodiments, the AML is AML with a translocation or inversion in chromosome 16 [t(l 6; 16) or inv(16)]. In certain embodiments, the AML is APL with the PML-RARA fusion gene. In certain embodiments, the AML is AML with a translocation between chromosomes 9 and 11 [t(9; 11)]. In certain embodiments, the AML is AML with a translocation between chromosomes 6 and 9 [t(6:9)]. In certain embodiments, the AML is AML with a translocation or inversion in chromosome 3 [t(3 ;3) or inv(3)]. In certain embodiments, the AML is AML (megakaryoblastic) with a translocation between chromosomes 1 and 22 [t(l :22)]. In certain embodiments, the AML is AML with the BCR-ABL1 (BCR-ABL) fusion gene. In certain embodiments, the AML is AML with mutated NPM1 gene. AML with biallelic mutations of the CEBPA gene (that is, mutations in both copies of the gene). In certain embodiments, the AML is AML with mutated RUNX1 gene.
[00127] In certain embodiments, the AML is AML with myelodysplasia-related changes. In certain embodiments, the AML is AML related to previous chemotherapy or radiation. In certain embodiments, the AML is AML with minimal differentiation (FAB M0). In certain embodiments, the AML is AML without maturation (FAB Ml). In certain embodiments, the AML is AML with maturation (FAB M2). In certain embodiments, the AML is AML (FAB M4). In certain embodiments, the AML is acute monoblastic/monocytic leukemia (FAB M5). In certain embodiments, the AML is pure erythroid leukemia (FAB M6). In certain embodiments, the AML is acute megakaryoblastic leukemia (FAB M7). In certain embodiments, the AML is acute basophilic leukemia. In certain embodiments, the AML is acute panmyelosis with fibrosis.
[00128] In certain embodiments, the AML is relapsed or refractory, and ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit.
[00129] In certain embodiments, the malignancy is a solid tumor. In certain embodiments, the solid tumor is advanced. In certain embodiments, the solid tumor is unresectable. In certain embodiments, the solid tumor is inoperable. In certain embodiments, the solid tumor is incurable. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is recurrent. In certain embodiments, the solid tumor is relapsed. In certain embodiments, the solid tumor is refractory. In certain embodiments, the solid tumor is refractory to a standard therapy. In certain embodiments, the solid tumor is intolerant of a standard therapy. In certain embodiments, the solid tumor is drug-resistant.
[00130] In certain embodiments, the solid tumor is MYC dependent. In certain embodiments, the solid tumor harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the solid tumor harbors MYC gene translocation. In certain embodiments, the solid tumor harbors MYC gene amplification. In certain embodiments, the solid tumor harbors MYC mRNA overexpression. In certain embodiments, the solid tumor harbors MYC protein overexpression.
[00131] In certain embodiments, the solid tumor is c-MYC dependent. In certain embodiments, the solid tumor harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the solid tumor harbors c-MYC gene translocation. In certain embodiments, the solid tumor harbors c-MYC gene amplification. In certain embodiments, the solid tumor harbors c-MYC mRNA overexpression. In certain embodiments, the solid tumor harbors c-MYC protein overexpression.
[00132] In certain embodiments, the solid tumor is 1-MYC dependent. In certain embodiments, the solid tumor harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the solid tumor harbors 1-MYC gene translocation. In certain embodiments, the solid tumor harbors 1-MYC gene amplification. In certain embodiments, the solid tumor harbors 1-MYC mRNA overexpression. In certain embodiments, the solid tumor harbors 1-MYC protein overexpression.
[00133] In certain embodiments, the solid tumor is n-MYC dependent. In certain embodiments, the solid tumor harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the solid tumor harbors n-MYC gene translocation. In certain embodiments, the solid tumor harbors n-MYC gene amplification. In certain embodiments, the solid tumor harbors n-MYC mRNA overexpression. In certain embodiments, the solid tumor harbors n-MYC protein overexpression.
[00134] In certain embodiments, the solid tumor is a histologically or cytologically documented, incurable or metastatic solid tumor. In certain embodiments, the solid tumor is a histologically or cytologically documented, incurable or metastatic solid tumor with MYC genomic amplification/overexpression by tumor- or blood-based analysis. [00135] In certain embodiments, the solid tumor is stage I. In certain embodiments, the solid tumor is stage II. In certain embodiments, the solid tumor is stage III. In certain embodiments, the solid tumor is stage IV. In certain embodiments, the solid tumor is stage II, III, or IV. In certain embodiments, the solid tumor is stage III or IV.
[00136] In certain embodiments, the solid tumor is bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioblastoma, head or neck cancer, hepatic cancer, lymphoma, lung cancer, melanoma, mesothelioma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), nonmelanoma skin cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, skin cancer, small cell lung cancer (SCLC), thyroid cancer, or uterine cancer. In certain embodiments, the solid tumor is bladder cancer, breast cancer, colorectal cancer, lung cancer, melanoma, non-Hodgkin’s lymphoma, oral cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, or uterine cancer. In certain embodiments, the solid tumor is breast cancer, glioma, lung cancer, lymphoma, or ovarian cancer.
[00137] In certain embodiments, the solid tumor is bladder cancer. In certain embodiments, the solid tumor is brain cancer. In certain embodiments, the solid tumor is breast cancer. In certain embodiments, the solid tumor is colorectal cancer. In certain embodiments, the solid tumor is lung cancer. In certain embodiments, the solid tumor is melanoma. In certain embodiments, the solid tumor is oral cancer. In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the solid tumor is pancreatic cancer. In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is renal cancer. In certain embodiments, the solid tumor is thyroid cancer. In certain embodiments, the solid tumor is uterine cancer.
[00138] In certain embodiments, the solid tumor is glioma. In certain embodiments, the glioma is advanced. In certain embodiments, the glioma is unresectable. In certain embodiments, the glioma is inoperable. In certain embodiments, the glioma is incurable. In certain embodiments, the glioma is metastatic. In certain embodiments, the glioma is recurrent. In certain embodiments, the glioma is relapsed. In certain embodiments, the glioma is refractory. In certain embodiments, the glioma is refractory to a standard therapy. In certain embodiments, the glioma is intolerant of a standard therapy. In certain embodiments, the glioma is drugresistant.
[00139] In certain embodiments, the glioma is MYC dependent. In certain embodiments, the glioma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the glioma harbors MYC gene translocation. In certain embodiments, the glioma harbors MYC gene amplification. In certain embodiments, the glioma harbors MYC mRNA overexpression. In certain embodiments, the glioma harbors MYC protein overexpression.
[00140] In certain embodiments, the glioma is c-MYC dependent. In certain embodiments, the glioma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the glioma harbors c-MYC gene translocation. In certain embodiments, the glioma harbors c-MYC gene amplification. In certain embodiments, the glioma harbors c-MYC mRNA overexpression. In certain embodiments, the glioma harbors c-MYC protein overexpression.
[00141] In certain embodiments, the glioma is 1-MYC dependent. In certain embodiments, the glioma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the glioma harbors 1-MYC gene translocation. In certain embodiments, the glioma harbors 1-MYC gene amplification. In certain embodiments, the glioma harbors 1-MYC mRNA overexpression. In certain embodiments, the glioma harbors 1-MYC protein overexpression.
[00142] In certain embodiments, the glioma is n-MYC dependent. In certain embodiments, the glioma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the glioma harbors n-MYC gene translocation. In certain embodiments, the glioma harbors n-MYC gene amplification. In certain embodiments, the glioma harbors n- MYC mRNA overexpression. In certain embodiments, the glioma harbors n-MYC protein overexpression. [00143] In certain embodiments, the solid tumor is lung cancer. In certain embodiments, the lung cancer is advanced. In certain embodiments, the lung cancer is unresectable. In certain embodiments, the lung cancer is inoperable. In certain embodiments, the lung cancer is incurable. In certain embodiments, the lung cancer is metastatic. In certain embodiments, the lung cancer is recurrent. In certain embodiments, the lung cancer is relapsed. In certain embodiments, the lung cancer is refractory. In certain embodiments, the lung cancer is refractory to a standard therapy. In certain embodiments, the lung cancer is intolerant of a standard therapy. In certain embodiments, the lung cancer is drug-resistant.
[00144] In certain embodiments, the lung cancer is MYC dependent. In certain embodiments, the lung cancer harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the lung cancer harbors MYC gene translocation. In certain embodiments, the lung cancer harbors MYC gene amplification. In certain embodiments, the lung cancer harbors MYC mRNA overexpression. In certain embodiments, the lung cancer harbors MYC protein overexpression.
[00145] In certain embodiments, the lung cancer is c-MYC dependent. In certain embodiments, the lung cancer harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the lung cancer harbors c-MYC gene translocation. In certain embodiments, the lung cancer harbors c-MYC gene amplification. In certain embodiments, the lung cancer harbors c-MYC mRNA overexpression. In certain embodiments, the lung cancer harbors c-MYC protein overexpression.
[00146] In certain embodiments, the lung cancer is 1-MYC dependent. In certain embodiments, the lung cancer harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the lung cancer harbors 1-MYC gene translocation. In certain embodiments, the lung cancer harbors 1-MYC gene amplification. In certain embodiments, the lung cancer harbors 1-MYC mRNA overexpression. In certain embodiments, the lung cancer harbors 1-MYC protein overexpression. [00147] In certain embodiments, the lung cancer is n-MYC dependent. In certain embodiments, the lung cancer harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the lung cancer harbors n-MYC gene translocation. In certain embodiments, the lung cancer harbors n-MYC gene amplification. In certain embodiments, the lung cancer harbors n-MYC mRNA overexpression. In certain embodiments, the lung cancer harbors n-MYC protein overexpression.
[00148] In certain embodiments, the lung cancer is a histologically or cytologically documented, incurable or metastatic lung cancer. In certain embodiments, the lung cancer is a histologically or cytologically documented, incurable or metastatic lung cancer with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
[00149] In certain embodiments, the lung cancer is stage I. In certain embodiments, the lung cancer is stage II. In certain embodiments, the lung cancer is stage III. In certain embodiments, the lung cancer is stage IV. In certain embodiments, the lung cancer is stage II, III, or IV. In certain embodiments, the lung cancer is stage III or IV.
[00150] In certain embodiments, the solid tumor is NSCLC. In certain embodiments, the NSCLC is advanced. In certain embodiments, the NSCLC is unresectable. In certain embodiments, the NSCLC is inoperable. In certain embodiments, the NSCLC is incurable. In certain embodiments, the NSCLC is metastatic. In certain embodiments, the NSCLC is recurrent. In certain embodiments, the NSCLC is relapsed. In certain embodiments, the NSCLC is refractory. In certain embodiments, the NSCLC is refractory to a standard therapy. In certain embodiments, the NSCLC is intolerant of a standard therapy. In certain embodiments, the NSCLC is drug-resistant.
[00151] In certain embodiments, the NSCLC is MYC dependent. In certain embodiments, the NSCLC harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the NSCLC harbors MYC gene translocation. In certain embodiments, the NSCLC harbors MYC gene amplification. In certain embodiments, the NSCLC harbors MYC mRNA overexpression. In certain embodiments, the NSCLC harbors MYC protein overexpression. [00152] In certain embodiments, the NSCLC is c-MYC dependent. In certain embodiments, the NSCLC harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the NSCLC harbors c-MYC gene translocation. In certain embodiments, the NSCLC harbors c-MYC gene amplification. In certain embodiments, the NSCLC harbors c- MYC mRNA overexpression. In certain embodiments, the NSCLC harbors c-MYC protein overexpression.
[00153] In certain embodiments, the NSCLC is 1-MYC dependent. In certain embodiments, the NSCLC harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the NSCLC harbors 1-MYC gene translocation. In certain embodiments, the NSCLC harbors 1-MYC gene amplification. In certain embodiments, the NSCLC harbors 1- MYC mRNA overexpression. In certain embodiments, the NSCLC harbors 1-MYC protein overexpression.
[00154] In certain embodiments, the NSCLC is n-MYC dependent. In certain embodiments, the NSCLC harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the NSCLC harbors n-MYC gene translocation. In certain embodiments, the NSCLC harbors n-MYC gene amplification. In certain embodiments, the NSCLC harbors n- MYC mRNA overexpression. In certain embodiments, the NSCLC harbors n-MYC protein overexpression.
[00155] In certain embodiments, the NSCLC is a histologically or cytologically documented, incurable or metastatic NSCLC. In certain embodiments, the NSCLC is a histologically or cytologically documented, incurable or metastatic NSCLC with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
[00156] In certain embodiments, the NSCLC is stage I. In certain embodiments, the NSCLC is stage II. In certain embodiments, the NSCLC is stage III. In certain embodiments, the NSCLC is stage IV. In certain embodiments, the NSCLC is stage II, III, or IV. In certain embodiments, the NSCLC is stage III or IV. [00157] In certain embodiments, the solid tumor is SCLC. In certain embodiments, the SCLC is advanced. In certain embodiments, the SCLC is unresectable. In certain embodiments, the SCLC is inoperable. In certain embodiments, the SCLC is incurable. In certain embodiments, the SCLC is metastatic. In certain embodiments, the SCLC is recurrent. In certain embodiments, the SCLC is relapsed. In certain embodiments, the SCLC is refractory. In certain embodiments, the SCLC is refractory to a standard therapy. In certain embodiments, the SCLC is intolerant of a standard therapy. In certain embodiments, the SCLC is drug-resistant.
[00158] In certain embodiments, the SCLC is MYC dependent. In certain embodiments, the SCLC harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the SCLC harbors MYC gene translocation. In certain embodiments, the SCLC harbors MYC gene amplification. In certain embodiments, the SCLC harbors MYC mRNA overexpression. In certain embodiments, the SCLC harbors MYC protein overexpression.
[00159] In certain embodiments, the SCLC is c-MYC dependent. In certain embodiments, the SCLC harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the SCLC harbors c-MYC gene translocation. In certain embodiments, the SCLC harbors c-MYC gene amplification. In certain embodiments, the SCLC harbors c-MYC mRNA overexpression. In certain embodiments, the SCLC harbors c-MYC protein overexpression.
[00160] In certain embodiments, the SCLC is 1-MYC dependent. In certain embodiments, the SCLC harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the SCLC harbors 1-MYC gene translocation. In certain embodiments, the SCLC harbors 1-MYC gene amplification. In certain embodiments, the SCLC harbors 1-MYC mRNA overexpression. In certain embodiments, the SCLC harbors 1-MYC protein overexpression.
[00161] In certain embodiments, the SCLC is n-MYC dependent. In certain embodiments, the SCLC harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the SCLC harbors n-MYC gene translocation. In certain embodiments, the SCLC harbors n-MYC gene amplification. In certain embodiments, the SCLC harbors n-MYC mRNA overexpression. In certain embodiments, the SCLC harbors n-MYC protein overexpression.
[00162] In certain embodiments, the SCLC is a histologically or cytologically documented, incurable or metastatic SCLC. In certain embodiments, the SCLC is a histologically or cytologically documented, incurable or metastatic SCLC with MYC genomic amplification/overexpression by tumor- or blood-based analysis.
[00163] In certain embodiments, the SCLC is stage I. In certain embodiments, the SCLC is stage II. In certain embodiments, the SCLC is stage III. In certain embodiments, the SCLC is stage IV. In certain embodiments, the SCLC is stage II, III, or IV. In certain embodiments, the SCLC is stage III or IV.
[00164] In certain embodiments, the malignancy is lymphoma. In certain embodiments, the lymphoma is advanced. In certain embodiments, the lymphoma is unresectable. In certain embodiments, the lymphoma is inoperable. In certain embodiments, the lymphoma is incurable In certain embodiments, the lymphoma is metastatic. In certain embodiments, the lymphoma is recurrent. In certain embodiments, the lymphoma is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the lymphoma is refractory to a standard therapy. In certain embodiments, the lymphoma is intolerant of a standard therapy. In certain embodiments, the lymphoma is drug-resistant.
[00165] In certain embodiments, the lymphoma is MYC dependent. In certain embodiments, the lymphoma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the lymphoma harbors MYC gene translocation. In certain embodiments, the lymphoma harbors MYC gene amplification. In certain embodiments, the lymphoma harbors MYC mRNA overexpression. In certain embodiments, the lymphoma harbors MYC protein overexpression.
[00166] In certain embodiments, the lymphoma is c-MYC dependent. In certain embodiments, the lymphoma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the lymphoma harbors c-MYC gene translocation. In certain embodiments, the lymphoma harbors c-MYC gene amplification. In certain embodiments, the lymphoma harbors c-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors c-MYC protein overexpression.
[00167] In certain embodiments, the lymphoma is 1-MYC dependent. In certain embodiments, the lymphoma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the lymphoma harbors 1-MYC gene translocation. In certain embodiments, the lymphoma harbors 1-MYC gene amplification. In certain embodiments, the lymphoma harbors 1-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors 1-MYC protein overexpression.
[00168] In certain embodiments, the lymphoma is n-MYC dependent. In certain embodiments, the lymphoma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the lymphoma harbors n-MYC gene translocation. In certain embodiments, the lymphoma harbors n-MYC gene amplification. In certain embodiments, the lymphoma harbors n-MYC mRNA overexpression. In certain embodiments, the lymphoma harbors n-MYC protein overexpression.
[00169] In certain embodiments, the lymphoma is stage I. In certain embodiments, the lymphoma is stage II. In certain embodiments, the lymphoma is stage III. In certain embodiments, the lymphoma is stage IV. In certain embodiments, the lymphoma is stage II, III, or IV. In certain embodiments, the lymphoma is stage III or IV.
[00170] In certain embodiments, the malignancy is non-Hodgkin’s lymphoma (NHL). In certain embodiments, the NHL is advanced. In certain embodiments, the NHL is unresectable. In certain embodiments, the NHL is inoperable. In certain embodiments, the NHL is incurable. In certain embodiments, the NHL is metastatic. In certain embodiments, the NHL is recurrent. In certain embodiments, the NHL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the NHL is refractory to a standard therapy. In certain embodiments, the NHL is intolerant of a standard therapy. In certain embodiments, the NHL is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
[00171] In certain embodiments, the NHL is MYC dependent. In certain embodiments, the NHL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the NHL harbors MYC gene translocation. In certain embodiments, the NHL harbors MYC gene amplification. In certain embodiments, the NHL harbors MYC mRNA overexpression. In certain embodiments, the NHL harbors MYC protein overexpression.
[00172] In certain embodiments, the NHL is c-MYC dependent. In certain embodiments, the NHL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the NHL harbors c-MYC gene translocation. In certain embodiments, the NHL harbors c-MYC gene amplification. In certain embodiments, the NHL harbors c-MYC mRNA overexpression. In certain embodiments, the NHL harbors c-MYC protein overexpression.
[00173] In certain embodiments, the NHL is LMYC dependent. In certain embodiments, the NHL harbors a l-MYC aberration (e.g., l-MYC gene translocation, LMYC gene amplification, 1- MYC mRNA overexpression, and/or l-MYC protein overexpression). In certain embodiments, the NHL harbors l-MYC gene translocation. In certain embodiments, the NHL harbors l-MYC gene amplification. In certain embodiments, the NHL harbors l-MYC mRNA overexpression. In certain embodiments, the NHL harbors l-MYC protein overexpression.
[00174] In certain embodiments, the NHL is n-MYC dependent. In certain embodiments, the NHL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the NHL harbors n-MYC gene translocation. In certain embodiments, the NHL harbors n-MYC gene amplification. In certain embodiments, the NHL harbors n-MYC mRNA overexpression. In certain embodiments, the NHL harbors n-MYC protein overexpression.
[00175] In certain embodiments, the NHL is stage I. In certain embodiments, the NHL is stage II. In certain embodiments, the NHL is stage III. In certain embodiments, the NHL is stage IV. In certain embodiments, the NHL is stage II, III, or IV. In certain embodiments, the NHL is stage III or IV.
[00176] In certain embodiments, the NHL is B-cell NHL. In certain embodiments, the B-cell NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, or Burkitt lymphoma. In certain embodiments, the NHL is T-cell NHL. In certain embodiments, the NHL is NK-cell NHL.
[00177] In certain embodiments, the malignancy is B-cell NHL. In certain embodiments, the B-cell NHL is advanced. In certain embodiments, the B-cell NHL is unresectable. In certain embodiments, the B-cell NHL is inoperable. In certain embodiments, the B-cell NHL is incurable. In certain embodiments, the B-cell NHL is metastatic. In certain embodiments, the B-cell NHL is recurrent. In certain embodiments, the B-cell NHL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the B-cell NHL is refractory to a standard therapy. In certain embodiments, the B-cell NHL is intolerant of a standard therapy. In certain embodiments, the B-cell NHL is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
[00178] In certain embodiments, the B-cell NHL is MYC dependent. In certain embodiments, the B-cell NHL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the B-cell NHL harbors MYC gene translocation. In certain embodiments, the B- cell NHL harbors MYC gene amplification. In certain embodiments, the B-cell NHL harbors MYC mRNA overexpression. In certain embodiments, the B-cell NHL harbors MYC protein overexpression.
[00179] In certain embodiments, the B-cell NHL is c-MYC dependent. In certain embodiments, the B-cell NHL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the B-cell NHL harbors c-MYC gene translocation. In certain embodiments, the B-cell NHL harbors c-MYC gene amplification. In certain embodiments, the B-cell NHL harbors c-MYC mRNA overexpression. In certain embodiments, the B-cell NHL harbors c-MYC protein overexpression. [00180] In certain embodiments, the B-cell NHL is 1-MYC dependent. In certain embodiments, the B-cell NHL harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1- MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the B-cell NHL harbors 1-MYC gene translocation. In certain embodiments, the B-cell NHL harbors 1-MYC gene amplification. In certain embodiments, the B-cell NHL harbors 1-MYC mRNA overexpression. In certain embodiments, the B-cell NHL harbors 1-MYC protein overexpression.
[00181] In certain embodiments, the B-cell NHL is n-MYC dependent. In certain embodiments, the B-cell NHL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c- MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the B-cell NHL harbors n-MYC gene translocation. In certain embodiments, the B-cell NHL harbors n-MYC gene amplification. In certain embodiments, the B-cell NHL harbors n-MYC mRNA overexpression. In certain embodiments, the B-cell NHL harbors n-MYC protein overexpression.
[00182] In certain embodiments, the B-cell NHL is stage I. In certain embodiments, the B- cell NHL is stage II. In certain embodiments, the B-cell NHL is stage III. In certain embodiments, the B-cell NHL is stage IV. In certain embodiments, the B-cell NHL is stage II, III, or IV. In certain embodiments, the B-cell NHL is stage III or IV.
[00183] In certain embodiments, the B-cell NHL is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
[00184] In certain embodiments, the malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is advanced. In certain embodiments, the DLBCL is unresectable. In certain embodiments, the DLBCL is inoperable. In certain embodiments, the DLBCL is incurable. In certain embodiments, the DLBCL is metastatic. In certain embodiments, the DLBCL is recurrent. In certain embodiments, the DLBCL is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the DLBCL is refractory to a standard therapy. In certain embodiments, the DLBCL is intolerant of a standard therapy. In certain embodiments, the DLBCL is drug-resistant. In certain embodiments, the lymphoma is drug-resistant. [00185] In certain embodiments, the DLBCL is MYC dependent. In certain embodiments, the DLBCL harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the DLBCL harbors MYC gene translocation. In certain embodiments, the DLBCL harbors MYC gene amplification. In certain embodiments, the DLBCL harbors MYC mRNA overexpression. In certain embodiments, the DLBCL harbors MYC protein overexpression.
[00186] In certain embodiments, the DLBCL is c-MYC dependent. In certain embodiments, the DLBCL harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the DLBCL harbors c-MYC gene translocation. In certain embodiments, the DLBCL harbors c-MYC gene amplification. In certain embodiments, the DLBCL harbors c- MYC mRNA overexpression. In certain embodiments, the DLBCL harbors c-MYC protein overexpression.
[00187] In certain embodiments, the DLBCL is 1-MYC dependent. In certain embodiments, the DLBCL harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the DLBCL harbors 1-MYC gene translocation. In certain embodiments, the DLBCL harbors 1-MYC gene amplification. In certain embodiments, the DLBCL harbors 1- MYC mRNA overexpression. In certain embodiments, the DLBCL harbors 1-MYC protein overexpression.
[00188] In certain embodiments, the DLBCL is n-MYC dependent. In certain embodiments, the DLBCL harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the DLBCL harbors n-MYC gene translocation. In certain embodiments, the DLBCL harbors n-MYC gene amplification. In certain embodiments, the DLBCL harbors n- MYC mRNA overexpression. In certain embodiments, the DLBCL harbors n-MYC protein overexpression.
[00189] In certain embodiments, the DLBCL is stage I. In certain embodiments, the DLBCL is stage II. In certain embodiments, the DLBCL is stage III. In certain embodiments, the DLBCL is stage IV. In certain embodiments, the DLBCL is stage II, III, or IV. In certain embodiments, the DLBCL is stage III or IV.
[00190] In certain embodiments, the DLBCL is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
[00191] In certain embodiments, the malignancy is Burkitt lymphoma. In certain embodiments, the Burkitt lymphoma is advanced. In certain embodiments, the Burkitt lymphoma is unresectable. In certain embodiments, the Burkitt lymphoma is inoperable. In certain embodiments, the Burkitt lymphoma is incurable. In certain embodiments, the Burkitt lymphoma is metastatic. In certain embodiments, the Burkitt lymphoma is recurrent. In certain embodiments, the Burkitt lymphoma is relapsed. In certain embodiments, the lymphoma is refractory. In certain embodiments, the Burkitt lymphoma is refractory to a standard therapy. In certain embodiments, the Burkitt lymphoma is intolerant of a standard therapy. In certain embodiments, the Burkitt lymphoma is drug-resistant. In certain embodiments, the lymphoma is drug-resistant.
[00192] In certain embodiments, the Burkitt lymphoma is MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a MYC aberration (e.g., MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, and/or MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors MYC protein overexpression.
[00193] In certain embodiments, the Burkitt lymphoma is c-MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a c-MYC aberration (e.g., c-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or c-MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors c-MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors c-MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors c-MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors c-MYC protein overexpression. [00194] In certain embodiments, the Burkitt lymphoma is 1-MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a 1-MYC aberration (e.g., 1-MYC gene translocation, 1-MYC gene amplification, 1-MYC mRNA overexpression, and/or 1-MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors 1-MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors 1-MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors 1-MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors 1-MYC protein overexpression.
[00195] In certain embodiments, the Burkitt lymphoma is n-MYC dependent. In certain embodiments, the Burkitt lymphoma harbors a n-MYC aberration (e.g., n-MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, and/or n-MYC protein overexpression). In certain embodiments, the Burkitt lymphoma harbors n-MYC gene translocation. In certain embodiments, the Burkitt lymphoma harbors n-MYC gene amplification. In certain embodiments, the Burkitt lymphoma harbors n-MYC mRNA overexpression. In certain embodiments, the Burkitt lymphoma harbors n-MYC protein overexpression.
[00196] In certain embodiments, the Burkitt lymphoma is stage I. In certain embodiments, the Burkitt lymphoma is stage II. In certain embodiments, the Burkitt lymphoma is stage III. In certain embodiments, the Burkitt lymphoma is stage IV. In certain embodiments, the Burkitt lymphoma is stage II, III, or IV. In certain embodiments, the Burkitt lymphoma is stage III or IV.
[00197] In certain embodiments, the Burkitt lymphoma is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
[00198] In certain embodiments, the subject has failed a prior therapy. In certain embodiments, the subject has failed more than one prior therapy.
[00199] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. [00200] A method provided herein encompasses treating a subject regardless of patient’s age, although some diseases are more common in certain age groups.
[00201] In certain embodiments, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.01 to about 10 mg/kg per day, from about 0.02 to about 5 mg/kg per day, from about 0.05 to about 2 mg/kg per day, or from about 0.1 to about 1 mg/kg per day. In one embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.01 to about 10 mg/kg per day. In another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.02 to about 5 mg/kg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.05 to about 2 mg/kg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 0.1 to about 1 mg/kg per day. In still another embodiment, the therapeutically effective amount of a ketoamide described herein is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg/kg per day.
[00202] In certain embodiments, the therapeutically effective amount of a ketoamide described herein is ranging from about 1 to about 500 mg per day, from about 2 to about 200 mg per day, from about 5 to about 100 mg per day, or from about 10 mg to about 100 mg per day. In one embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 1 to about 500 mg per day. In another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 2 to about 200 mg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 5 to about 100 mg per day. In yet another embodiment, the therapeutically effective amount of a ketoamide described herein is ranging from about 10 to about 100 mg per day. In still another embodiment, the therapeutically effective amount of a ketoamide described herein is about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, or about 200 mg per day.
[00203] It is understood that the administered dose of a ketoamide described herein can also be expressed in units other than mg/kg every other day. For example, doses for parenteral administration can be expressed as mg/m2 per day. One of ordinary skill in the art would readily know how to convert doses from mg/kg per day to mg/m2 per day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m2 per day for a 65 kg human is approximately equal to 58 mg/kg per day.
[00204] Depending on the disease to be treated and the subject’s condition, a ketoamide described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
[00205] In one embodiment, a ketoamide described herein is administered orally. In another embodiment, a ketoamide described herein is administered parenterally. In yet another embodiment, a ketoamide described herein is administered intravenously. In yet another embodiment, a ketoamide described herein is administered intramuscularly. In yet another embodiment, a ketoamide described herein is administered subcutaneously. In still another embodiment, a ketoamide described herein is administered topically.
[00206] A ketoamide described herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A ketoamide described herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by a method known in the art such as evaluation of subject’s symptoms, physical examination, visualization of the cancer that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
[00207] A ketoamide described herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). In addition, the administration can be continuous, /.< ., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a ketoamide described herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
[00208] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[00209] In certain embodiments, a ketoamide described herein is cyclically administered to a subject to be treated. Cycling therapy involves the administration of the compound for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
[00210] Consequently, in one embodiment, a ketoamide described herein is administered for a cycle of about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, or about ten weeks, with a rest period of about 1 day to about four weeks. In one embodiment, a ketoamide described herein is administered for a cycle of three weeks, four weeks, five weeks, or six weeks with a rest period of 1, 3, 5, 7, 9, 12, or 14. In certain embodiments, the rest period is 7 days. In certain embodiments, the rest period is 14 days. In certain embodiments, the rest period is a period that is sufficient for bone marrow recovery. The frequency, number, and length of dosing cycles can be increased or decreased.
[00211] In one embodiment, a ketoamide described herein is administered for three weeks in a 28-day cycle with a 7-day rest period. In one embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered every day for five days of a week. In another embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered on Days 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15, 16, 17, 18, and 19. In one embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered every day for three days of a week. In another embodiment, in a 28-day cycle with a 7-day rest period, a ketoamide described herein is administered on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19. [00212] In certain embodiments, the subject is treated with a ketoamide described herein from about 1 to about 50, from about 2 to about 20, from about 2 to 10, or from about 4 to about 8 cycles. In certain embodiments, the subject is treated with a ketoamide described herein from about 1 to about 50 cycles. In certain embodiments, the subject is treated with a ketoamide described herein from about 2 to about 20 cycles. In certain embodiments, the subject is treated with a ketoamide described herein from about 2 to 10 cycles. In certain embodiments, the subject is treated with a ketoamide described herein from about 4 to about 8 cycles.
[00213] In one embodiment, provided herein is a method of inhibiting the growth of a malignant cell, comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00214] In another embodiment, provided herein is a method of inducing apoptosis in a malignant cell, comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00215] In yet another embodiment, provided herein is a method of inducing degradation of a GSPT1 in a malignant cell, comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00216] In still another embodiment, provided herein is a method of downregulating a MYC in a malignant cell, comprising contacting the cell with an effective amount of a compound described herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00217] In certain embodiments, the malignant cell is a cell of a malignancy described herein.
[00218] A compound described herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
[00219] In certain embodiments, provided herein is a kit which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein.
[00220] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
[00221] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [00222] The disclosure will be further understood by the following non-limiting examples.
EXAMPLES
[00223] As used herein, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: mg (milligrams); mL (milliliters); h (hour or hours); and min (minute or minutes).
Example 1
An Open-Label, Escalating Multiple-Dose Study to Evaluate the Safety, Toxicity, Pharmacokinetics, and Efficacy of a Ketoamide in Subjects with an Advanced Malignancy
[00224] This is a multicenter, open label, nonrandomized, sequential dose escalation/cohort expansion, multiple dose study, evaluating the safety, toxicity, pharmacokinetics (PK), and efficacy of a ketoamide in subjects with an advanced malignancy. The study is conducted in two phases: Phases la and lb.
[00225] Phase la is a dose escalation phase, determining the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the ketoamide in the subjects with advanced AML, solid tumor, or NHL. The ketoamide is administered 3 days per week (Monday /Wednesday /Friday (M/W/F)) orally for a 28-day treatment cycle of 4 weeks. The starting dose of the ketoamide for Cohort 1 is 0.1 mg based on nonclinical pharmacology, toxicology, and pharmacokinetic data. The seven dosing levels in Phase la are summarized in Table 1.
[00226] For single-subject cohorts, a single subject is treated at each dose level. If the subject treated at a given dose level does not experience DLT or two adverse events of Grade 2 or higher that cannot be clearly attributed to disease progression, intercurrent illness, preexisting condition, or concomitant medications, the dose is escalated. If the subject treated at a given dose level experiences DLT, then the dose cohort is expanded to 3 subjects and a standard 3+3 design is utilized to further evaluate the dose level at which the DLT occurred and to evaluate all subsequent cohorts.
TABLE 1 : Dosing Levels in Phase la
Figure imgf000092_0001
a. De-escalation in dose, if required in response to DLT, is a mid-dose between the current dose and the previous lower dose with DLT subject incidence of < 33%. b. Dose level increases are 2-fold or less. c. Cohort size(s) is increased to 3 patients if a DLT or two Grade 2 adverse event(s) occur that are not clearly attributable to disease progression, intercurrent illness, preexisting condition, or concomitant medications. d. Dosing interval may be reduced in response to toxicity (either for a given patient or for a cohort).
[00227] For standard 3+3 cohorts, 3 to 6 subjects are initially exposed to the ketoamide at each dose level. To account for early drop out, up to 6 subjects may be enrolled. If 0 of the 3 initial subjects treated at a given dose level experiences DLT, the dose is escalated, and 3 subjects are enrolled at the next higher dose level. In the event more than 3 subjects are enrolled, all subjects are evaluated for DLT before escalation to the next dose level cohort. If 1 of the 3 initial subjects treated at a given dose level experiences DLT, then 3 additional subjects are enrolled at the same dose level (for a total of 6 subjects). In the event more than 3 subjects are enrolled, if 1 DLT is observed, the dose cohort is expanded to 6. If 0 of the additional subjects experiences DLT (z.e., DLT observed in 1 of the 6 subjects enrolled in the level), then the dose is escalated, and 3 subjects are enrolled at the next higher dose level. If 1 or more of the additional subjects experiences DLT (z.e., DLT observed in 2 or more of the 6 subjects enrolled in the level), it is concluded that the MTD has been exceeded. If 1 or more of the additional subjects experiences DLT (z.e., DLT observed in 2 or more of the 6 subjects enrolled in the level), it is concluded that the MTD has been exceeded. If 2 or more of the initial subjects treated at a given dose level experience DLT, then it is concluded that the MTD has been exceeded. If the MTD has been exceeded, then up to 6 subjects are enrolled at the next lower dose if fewer than 6 subjects are evaluated at the lower dose. The MTD is the highest dose level of the ketoamide at which no more than 1 of 6 subjects experiences DLT.
[00228] A DLT is a severe or clinically significant adverse event (AE) or abnormal laboratory value (Grade 3 or greater, unless otherwise specified), unless it is clearly related to disease progression, intercurrent illness, preexisting condition, or concomitant medications. Toxicity severity is graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. For purposes of dose escalation, the totality of accrued safety information across all cycles completed at the time of data review by a Dose Escalation Committee (DEC) is taken into consideration.
[00229] Criteria for potential DLT are summarized in Table 2. Since the ketoamide may be associated with other toxicities, as yet unknown, all AEs that cannot clearly be determined to be unrelated to the ketoamide are considered relevant to determining DLTs and are reviewed by DEC.
[00230] In considering other clinically significant events of > Grade 3, the following would not be considered to be a DLT: (i) Grade 3 electrolyte abnormalities that are asymptomatic and reversible with treatment within 72 h; (ii) Grade 4 tumor lysis syndrome (TLS) if it is successfully managed clinically and resolves within 7 days without end-organ damage; (iii) Grade 3 fatigue, which resolves to < Grade 2 within 7 days; and (iv) Grade 3 hypertension that can be controlled with medical therapy within 48 h. The DEC also reviews any other emergent toxicities that are not explicitly defined by the DLT criteria to determine if any warrant a DLT designation. The recommended Phase 2 dose (RP2D) is determined based on a comprehensive analysis of safety, tolerability, PK/PD, and efficacy as well as the MTD from Phase la.
[00231] Phase lb is a cohort expansion phase, which starts when the RP2D is determined. Up to 41 additional subjects are enrolled in each of two disease cohorts: subjects with AML and subjects with documented MYC genomic amplified/overexpressed tumors. Each subject in this phase is treated for a 28-day treatment cycle of 4 weeks. The DEC reviews cumulative safety and available PK data in subjects treated in Phase lb for DLTs, with DEC reviews scheduled after the 6th, 12th, 21st (interim analysis), 32nd, and 41st subjects of each disease cohort complete a treatment cycle with the ketoamide.
TABLE 2: Criteria for Potential DLT
Figure imgf000094_0001
[00232] Subjects who complete one treatment cycle with the ketoamide in either Phase la or Phase lb are offered continued access to the ketoamide until disease progression or unacceptable toxicity. Dosing continues at the assigned dose or may be increased up to the dose determined to be tolerated in the current study. The DEC continues to review accruing safety /PK data, inclusive of all cycles, for subjects who continue with treatment.
[00233] Once treatment has completed, subjects are contacted by telephone every 3 months for survival status and anticancer therapy; and the cause of death is documented. Individual subjects are considered to have completed the study 2 years after their last treatment or upon death, whichever occurs first. The study ends after a minimum of 70% of subjects have died or 2 years after the last subject is enrolled, whichever occurs first.
[00234] The Dose Escalation Phase (Phase la) enrolls up to 84 subjects, depending on the dose at which the MTD is determined; additional subjects may be enrolled in the event that a given subject either does not receive the ketoamide or discontinues early for reasons other than safety and is not evaluable for toxicity. The Expansion Phase (Phase lb) includes two diseasespecific cohorts: subjects with AML and subjects with MYC-amplified solid tumors, each with advanced malignancies and documented MYC genomic amplification/overexpression to further characterize the safety, tolerability, and efficacy when administered at the recommended dose identified in the Dose-Escalation Phase (Phase la). Each cohort enrolls up to approximately 41 subjects in two stages (Nl=21 for stage 1).
[00235] Eligible subjects for the Dose-Escalation Phase (Phase la) are > 18 years of age with documented diagnosis of (i) relapsed or refractory AML, according to the World Health Organization (WHO) classification, ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit; (ii) B cell NHL that is refractory to or intolerant of all standard therapy or for which no standard therapy is available; or (iii) histologically or cytologically documented, incurable or metastatic solid tumor.
[00236] Eligible subjects for the Expansion Phase (Phase lb) are > 18 years of age with documented diagnosis of (i) relapsed or refractory AML, according to the World Health Organization (WHO) classification, ineligible for or having exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit; or (ii) histologically or cytologically documented, incurable or metastatic solid tumor with MYC genomic amplification/overexpression by tumor- or blood-based analysis. [00237] For a solid tumor, each eligible subject must have a measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST vl.l). For NHL, each eligible subject must have bi-dimensionally measurable disease on cross sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by the Lugano criteria.
[00238] Additional inclusion criteria for the eligible subjects include: (i) an Eastern Cooperative Oncology Group (ECOG) performance status of < 2; (ii) serum AST and serum ALT < 3.0 x LLN (< 5.0 x LLN in subjects with documented liver involvement); (iii) alkaline phosphatase < 2.5 x LLN (< 5.0 x L N in subjects with documented liver involvement or bone metastases); (iv) direct serum bilirubin < 1.5 x LLN; (v) creatinine clearance of > 50 mL/min; and (vi) international normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 x LLN (subjects on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days); if receiving warfarin, the subject must have an INR < 3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study drug); subjects on low molecular weight heparin are allowed).
[00239] The eligible subjects with a solid tumor or NHL must have: (i) absolute neutrophil count (ANC) > 1000 cells/pL; (ii) white blood cell (WBC) count > 1500/pL; (iii) platelet count > 100,000/pL; and (iv) hemoglobin > 9.0 g/dL. The eligible subjects with AML must have white blood cell (WBC) count < 25 x 109L at the time of screening (hydroxyurea may be used to bring the WBC count below the threshold; subjects may be retested within the 28-day screening period following treatment).
[00240] The study excludes those with (i) life expectancy < 3 months as determined by an investigator; (ii) diagnosis of acute promyelocytic leukemia; (iii) treatment with any local or systemic antineoplastic therapy (including chemotherapy, hormonal therapy, or radiation) within 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of the ketoamide, except (a) hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer; (b) hormone-replacement therapy or oral contraceptives; (c) herbal therapy intended as anti-cancer > 1 week prior to first dose of the ketoamide; (d) palliative radiotherapy for bone metastases > 2 weeks prior to first dose of the ketoamide; and (e) hydroxyurea to treat leukocytosis; (iv) those who have undergone autologous or allogeneic stem cell transplantation, (a) transplantation within the 3 months prior to the screening; (b) active graft-versus-host disease requiring anything other than topical corticosteroids and budesonide; and (c) treatment with systemic immunosuppressive medications including high-dose steroids (> 20 mg prednisolone or equivalent per day), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), sirolimus, mycophenylate mofetil, azathioprine, or ruxolitinib for at least 1 week prior to the screening; with the exception that use of topical steroids and oral budesonide is permitted as systemic steroid use as premedication for transfusions or treatment of any anaphylactic event; (v) immediate life threatening severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation; (vi) chronic use of corticosteroids in excess of 10 mg daily of prednisone or equivalent within 4 weeks prior to first dose of the ketoamide, except replacement doses of corticosteroids, e.g., prednisone 5-7.5 mg daily; (vii) major trauma or major surgery within 4 weeks prior to first dose of the ketoamide; (viii) adverse events from prior anti-cancer therapy that have not resolved to Grade < 1 except for alopecia or Grade < 2 immunotherapy-related thyroid toxicity; (ix) active central nervous system (CNS) disease involvement, or prior history of NCI CTCAE Grade > 3 drug- related CNS toxicity, except that subjects with known CNS metastases that are treated and stable (without evidence of CNS toxicity) and are not requiring systemic steroids are allowed to be enrolled; (x) a clinically significant cardiac disease; (xi) active uncontrolled systemic fungal, bacterial, mycobacterial, or viral infection; (xii) known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS); (xiii) active hepatitis C virus (HCV) or hepatitis B virus (HBV) (subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment; those who are PCR positive are excluded); (xiv) second primary malignancy that has not been in remission for greater than 3 years, except non-melanoma skin cancer, cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on Papanicolaou (PAP) smear, localized prostate cancer (Gleason score < 6), or resected melanoma in situ, other localized, solid tumors in situ or other low risk cancers; and (xv) any serious underlying medical (e.g., pulmonary, renal, hepatic, gastrointestinal, or neurological) or psychiatric condition (c.g, alcohol or drug abuse, dementia or altered mental status) or any issue that would limit compliance with study requirements, impair the ability of the subject to understand informed consent, or that in the opinion of the investigator would contraindicate the subject’s participation in the study or confound the results of the study.
[00241] Screening commences with obtaining the subject’s signed informed consent and occurs up to 28 days prior to the first dosing of the ketoamide. Screening procedures include medical history review; physical exam; vital signs; 12 lead electrocardiogram (ECG); ECOG performance status; prior/concomitant medication review; blood collection for pregnancy test (females of childbearing potential); chemistry, hematology, and coagulation; AE assessment; and archival or recent biopsy formalin-fixed paraffin-embedded (FFPE) tissue block collection. Baseline tumor lesions are measured and characterized prior to Cycle 1 Day 1 to assess the subject disease status prior to beginning treatment via bone marrow biopsy/aspirate, PB sample and/or CT/MRI/positron emission tomography-computed tomography (PET-CT) (scans that meet protocol requirements that are obtained as part of standard medical practice up to 6 weeks prior to Cycle 1 Day 1 are acceptable).
[00242] The ketoamide is supplied as orally administered, immediate-release capsules of 0.1 mg, 0.5 mg, and 2.5 mg each. Subjects who meet eligibility criteria receive the ketoamide orally 3 days per week (M/W/F) for a 28-day treatment cycle of 4 weeks.
[00243] All subjects are hospitalized for the first 3 days of Cycle 1, at a minimum, for safety monitoring and prophylaxis for tumor lysis syndrome (TLS) as appropriate. Thereafter, safety and efficacy assessments occur on an outpatient basis including assessment of tumor response, physical exam, vitals, ECG, collection of blood samples (for routine safety labs, the study drug PK, pharmacodynamic markers, and other biomarkers at applicable visits), urine pregnancy test (every 4 weeks while receiving the study drug in females of childbearing potential), and assessment of AEs. In addition, subjects undergo post-baseline BM biopsy/aspirate (patients with AML and non-FDG avid lymphomas), CT/MRI, or PET-CT (as appropriate for FDG-avid lymphomas) scans for tumor response assessment. A subject who does not show evidence of disease progression by clinical assessment or by biopsy/aspirate, CT/MRI, or applicable scan may continue receiving study treatment until disease progression (clinical or radiographic), unacceptable toxicity, withdrawal of consent, or other reasons. An end of treatment (EOT) visit is conducted within 14 to 28 days after the last dose of the ketoamide is administered, regardless of the reason for discontinuation. In addition, a safety follow-up is done by phone 30 days after last dose of the ketoamide. Adverse events > Grade 2 ongoing at the 30-day safety follow-up are followed until the event resolves to < Grade 1, stabilizes, subject starts alternate therapy, returns to a status that is clinically acceptable, is lost to follow-up, or terminates with the subject’s death.
[00244] The safety of the ketoamide is evaluated by (i) adverse events (NCI CTCAE Version 5.0); (ii) clinical laboratory testing (hematology, chemistry, and coagulation); (iii) physical examinations; (iv) vital signs (blood pressure, pulse, respiratory rate, body temperature, and weight); and (v) 12 lead ECGs. Dose limiting toxi cities are evaluated for determination of the MTD and/or RP2D. Throughout the study, safety is evaluated by a Dose Escalation Committee (DEC) that includes principal investigator(s), the sponsor’s physician (in consultation with the sponsor’s pharmacologist/pharmacokineticist as needed), and/or independent experts. The DEC reviews all cumulative available data and authorizes plans for the dosing of each subsequent cohort.
[00245] In evaluating the preliminary efficacy of the ketoamide, responses are evaluated every cycle for subjects with AML and every 8 weeks for subjects with NHL or solid tumors at the beginning of each odd numbered cycle (i.e., Cycle 3, 5, 7, etc.). Responses are evaluated based on BM biopsy/aspirate, peripheral blood (PB), CT, MRI, and/or PET-CT as appropriate for the corresponding malignancy.
[00246] For AML subjects, responses are evaluated using the European LeukemiaNet (ELN) panel 2017 guidelines. Response categories include complete response (CR), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), stable disease, and progressive disease. For NHL subjects, responses are evaluated using the Lugano response criteria. Response categories include CR, PR, stable disease, or progressive disease. For subjects with solid tumors, responses are evaluated using RECIST vl.l. Response categories include CR, PR, stable disease, or progressive disease. A response based on imaging is confirmed by the same imaging technique no less than 4 weeks after the criteria for response are first met.
[00247] The preliminary efficacy of the ketoamide is evaluated by the following measures and endpoints: (i) objective response rate (ORR); (ii) best response; (iii) disease control rate (DCR); (iv) duration of response (DOR); (v) progression-free survival (PFS), defined as the time from first enrollment into the study to the earlier of the first documentation of definitive disease progression or death due to any cause (summarized descriptively using the Kaplan Meier method); and (vi) overall survival (OS), defined as the time from first enrollment into the study to death due to any cause (summarized descriptively using the Kaplan Meier method).
[00248] The PK parameters of the ketoamide are determined, including (i) maximum observed plasma concentration (Cmax); (ii) observed time of peak concentration (Tmax); (iii) overall exposure (area under the plasma concentration curve, AUC); and (iv) elimination halflife.
[00249] Peripheral blood mononuclear cells (PBMC) and PB samples are collected to evaluate markers of pharmacodynamic activity, including GSPT1 levels in CD3+ T cells. Samples are also collected and stored for analysis for possible exploratory association with response or biomarker analyses, including, but not limited to, gene sequencing and gene expression profiling. Cytogenetics and mutation panel include (i) gene expression levels of MYC by digital droplet polymerase chain reaction (PCR); (ii) MYC protein expression levels; and (iii) gene mutation analysis by next generation sequencing.
[00250] Blood samples are obtained for biomarker evaluation from all eligible subjects. Archival tumor tissue samples obtained outside of this study for other purposes are collected from all subjects and used for biomarker evaluation.
Example 2 Cell Viability Assays
[00251] ABC-1 cells were cultured in EMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. Daudi, DOHH-2, Namalwa, SU-DHL-2, SU-DHL-6, and WSU-DLCL-2 cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. All other cell lines were cultured as per a standard protocol. ABC-1, DOHH-2, and WSU-DLCL-2 cells were seeded at 4,000 cells per well; and Daudi, Namalwa, SU-DHL-2, and SU-DHL-6 cells were seeded at 5,000 cells per well in white walled 96-well plates. All other cell lines were seeded at similar low densities. The cells were incubated in the presence of DMSO (control) or a compound for 3 days at 37 °C under 5% CO2. A CELLTITER-GLO® reagent (100 pL) was added to each well. After incubation for 2 min with and 10 min without shaking, luminescence is measured using a VICTOR WALLAC luminometer or a PERKINELMER ENVISION® 2105 multimode plate reader. The results are summarized in Tables 3 to 5.
Table 3. Effects of Compound A5 and CC-90009 on the Viability of AML Cells
Figure imgf000101_0001
Table 4. Effects of Compound A5 on the Viability of Solid Tumor Cells
Figure imgf000101_0002
Figure imgf000102_0001
Table 5. Effects of Compound A5 on the Viability of MYC-Driven Malignant Cells
Figure imgf000102_0002
Example 3
Protein Degradation Assay
[00252] ABC-1 cells were cultured in EMEM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. Daudi and SU-DHL-2 cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin.
[00253] ABC-1 cells were plated at 1.75 million cells per well in a 12 well plate. Daudi and SU-DHL-2 cells were cultured at approximately 3 x 106 cells per well in a 24 well plate and incubated in the presence of DMSO or a compound for 6 h. Whole cell extracts were prepared using an IP lysis buffer according to the manufacturer’s protocol (Pierce). Briefly, 4 x 106 cells were washed once in PBS. The cell pellets were then resuspended in the IP lysis buffer and incubated for 15 min on ice. Cells debris was removed by centrifugation and the cleared whole cell lysates were transferred to new tubes for further analysis.
[00254] For Western blot analysis, the whole cell protein extracts were separated on 4-12% SDS-polyacrylamide gels, transferred to nitrocellulose, and probed with primary antibodies. Membranes were subsequently washed and probed with IRDYE® secondary antibodies (LL COR). The signal was detected using an ODYSSET® imaging system (LLCOR). Whole cell protein extracts were also analyzed using JESS according to JESS user manual. The following antibodies were used: anti-eRF3/GSPTl antibody (Abeam), c-MYC rabbit monoclonal antibody (Cell Signaling Technology), n-MYC rabbit monoclonal antibody (Cell Signaling Technology), P-actin mouse monoclonal antibody (Cell Signaling Technology), IRDYE® goat anti-rabbit antibody (LI-COR), and IRDYE® goat anti-mouse antibody (LI-COR). The results are summarized in Table 6.
Table 6. Effects of Compound A5 on the Viability of MYC-Driven Malignant Cells
Figure imgf000103_0001
NI: No impact.
Example 4
Xenograft Mouse Models - Intraperitoneal Administration
[00255] BALB/c nude mice were inoculated subcutaneously at the flank with A2780 (ovarian cancer), NCI-H526 (SCLC), NCI-H1155 (NSCLC), or T47D (breast cancer) cells in PBS for tumor development. Female CB.17 SCID mice were inoculated subcutaneously at the flank with DOHH-2 (B-cell lymphoma), SU-DHL-2 (large cell lymphoma), or Daudi (Burkitt’s lymphoma) cells in PBS for tumor development. The treatments started when the average tumor volume reached approximately 100-150 mm3. Each compound was administered IP daily. The results are shown in FIGS. 1 to 7. Example 5
Xenograft Mouse Models - Oral Administration
[00256] BALB/c nude mice are inoculated subcutaneously at the flank with NCI-H526 or NCI-H1155 cells in PBS for tumor development. Female CB.17 SCID mice are inoculated subcutaneously at the flank with SU-DHL-2 or Daudi cells in PBS for tumor development. The treatments start when the average tumor volume reaches approximately 100-150 mm3. Compound A5 is administered orally daily.
[00257] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A method of treating, preventing, or ameliorating one or more symptoms of a malignancy in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):
Figure imgf000105_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(RE4)=; or Z1 is a bond, one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4)= or -S-;
R1 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla,
Figure imgf000105_0002
each R2a and R2b is independently hydrogen, deuterium, halo, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R2a and R2b together with the carbon atom to which they are attached form C3-10 cycloalkylene or heterocyclylene;
R3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl;
RE1 is hydrogen, deuterium, halo, or C1-6 alkyl; RE2 is hydrogen or Ci-6 alkyl; each RE4 is independently hydrogen or RE5; each RE5 is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rld is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; m is an integer of 0, 1, or 2; p is an integer of 0, 1, 2, 3, 4, or 5; and q is an integer of 0, 1, 2, or 3; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
2. The method of claim 1, wherein the malignancy is MYC dependent.
3. The method of claim 1 or 2, wherein the malignancy is c-MYC dependent.
4. The method of any one of claims 1 to 3, wherein the malignancy is 1-MYC dependent.
5. The method of any one of claims 1 to 4, wherein the malignancy is n-MYC dependent.
6. The method of any one of claims 1 to 5, wherein the malignancy harbors a MYC aberration.
7. The method of any one of claims 1 to 6, wherein the malignancy harbors MYC gene translocation, MYC gene amplification, MYC mRNA overexpression, or MYC protein overexpression.
8. The method of any one of claims 1 to 7, wherein the compound is a compound of
Formula (II):
Figure imgf000108_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
9. The method of any one of claims 1 to 8, wherein the compound is a compound of Formula (III):
Figure imgf000108_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
10. The method of any one of claims 1 to 8, wherein the compound is a compound of Formula (IV):
Figure imgf000108_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
11. The method of any one of claims 1 to 7, wherein Z1 is a bond, one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(RE4)= or -S-.
12. The method of any one of claims 1 to 7 and 11, wherein the compound is a compound of Formula (V):
Figure imgf000109_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
13. The method of any one of claims 1 to 7, 11, and 12, wherein the compound is a compound of Formula (VI):
Figure imgf000109_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
14. The method of any one of claims 1 to 7, 11, and 12, wherein the compound is a compound of Formula (VII):
Figure imgf000109_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
15. The method of any one of claims 1 to 7, and 11, wherein the compound is a compound of Formula (VIII):
Figure imgf000110_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
16. The method of any one of claims 1 to 7, 11, and 15, wherein the compound is a compound of Formula (II):
Figure imgf000110_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
17. The method of any one of claims 1 to 7, 11, and 15, wherein the compound is a compound of Formula (X):
Figure imgf000110_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
18. The method of any one of claims 1 to 7 and 11, wherein the compound is a compound of Formula (XI):
- 109 -
Figure imgf000111_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
19. The method of any one of claims 1 to 7, 11, and 18, wherein the compound is a compound of Formula (XII):
Figure imgf000111_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
20. The method of any one of claims 1 to 7, 11, and 18, wherein the compound is a compound of Formula (XIII):
Figure imgf000111_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
21. The method of any one of claims 1 to 20, wherein R1 is hydrogen or Ci-6 alkyl optionally substituted with one or more substituents Q.
22. The method of any one of claims 1 to 21, wherein R1 is hydrogen or methyl.
- 110 -
23. The method of any one of claims 1 to 22, wherein R1 is hydrogen.
24. The method of any one of claims 1 to 23, wherein each R2a is independently hydrogen or Ci-6 alkyl optionally substituted with one or more substituents Q.
25. The method of any one of claims 1 to 24, wherein each R2a is independently hydrogen or methyl.
26. The method of any one of claims 1 to 25, wherein each R2a is hydrogen.
27. The method of any one of claims 1 to 26, wherein each R2b is independently hydrogen or Ci-6 alkyl optionally substituted with one or more substituents Q.
28. The method of any one of claims 1 to 27, wherein each R2b is independently hydrogen or methyl.
29. The method of any one of claims 1 to 28, wherein each R2b is hydrogen.
30. The method of any one of claims 1 to 29, wherein each R2a and R2b is hydrogen.
31. The method of any one of claims 1 to 30, wherein q is an integer of 0, 1, or 2.
32. The method of any one of claims 1 to 31, wherein q is an integer of 0.
33. The method of any one of claims 1 to 32, wherein R3 is -NRlbRlc.
34. The method of any one of claims 1 to 33, wherein R3 is di(Ci-6 alkyl)amino optionally substituted with one or more substituents Q.
35. The method of any one of claims 1 to 34, wherein R3 is dimethylamino.
36. The method of any one of claims 1 to 32, wherein R3 is C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, or heterocyclyl; each optionally substituted with one or more substituents Q.
37. The method of any one of claims 1 to 32 and 36, wherein R3 is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or cyclohexyl, each of which is optionally substituted with one, two, or three substituents RA, wherein each substituent RA is independently cyano, fluoro, chloro,
- I l l - bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl, morpholinyl- methyl, propyl, butyl, hydroxyl-butyl, cyclopropyl, methylcyclopropyl, trifluoromethylcyclopropyl, phenyl, methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido.
38. The method of any one of claims 1 to 32, 36, and 37, wherein R3 is phenyl, cyanophenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, (1-trifluoromethylethyl)- phenyl, trifluoromethylphenyl, dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl, isopropylphenyl, .scc-butyl phenyl, tert-butylphenyl, (hydroxyl -Zc/V-butyl (phenyl, cyclopropylphenyl, (l-methylcyclopropyl)phenyl, (l-trifluoromethylcyclopropyl)-phenyl, phenylphenyl, (1- methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl, dimethylaminophenyl, acetamidophenyl, difluorophenyl, dichlorophenyl, chloro-methylphenyl, methyl-tert-butyl- phenyl, dimethylphenyl, trimethylphenyl, trimethoxyphenyl, dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl, thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl, piperidinyl, or /c/V-butylpiperidinyl.
39. The method of any one of claims 1 to 32 and 36 to 38, wherein R3 is phenyl, 4- cyanophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(l-trifluoromethylethyl)-phenyl, 4-trifluoromethylphenyl, 4- dimethylaminomethylphenyl, 4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl, 4- ec-butyl- phenyl, 3 -/c/V-butyl phenyl, 4-tert-butyl phenyl, 4-(hydroxyl-tert-butyl (phenyl, 4-cyclopropyl- phenyl, 4-(l-methyl-cyclopropyl)phenyl, 4-(l-trifluoromethylcyclopropyl)phenyl, 4-phenyl- phenyl, 4-(l-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl, 3-methoxyphenyl, 4-methoxy- phenyl, 4-dimethylaminophenyl, 4-acetamidophenyl, 3,4-difluorophenyl, 3, 4-di chlorophenyl, 3- chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl, 3-dimethylamino-4-methylphenyl, 2- naphthyl, thien-2-yl, 5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl, or 4- tert-butyl pi peri di n- 1 -yl .
40. The method of any one of claims 1 to 32 and 36 to 39, wherein R3 is phenyl, 4- cyanophenyl, 2-fluorophenyl, 3 -fluorophenyl, 3 -chlorophenyl, 4-trifluoromethylphenyl, 3-tert- butylphenyl, 4-tert-butylphenyl, 4-(l-trifluoromethylcyclopropyl)phenyl, 3-methoxyphenyl, 4- m ethoxyphenyl, 3,4-difluorophenyl, 3, 4-di chlorophenyl, 3-chloro-4-methylphenyl, 3-methyl-4- tert-butyl phenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6- dimethyl-4-terZ-butylphenyl, 2-naphthyl, 5-isopropylthien-2-yl, 4-pyridyl, 4-tert- butylcyclohexyl, or 4-terZ-butylpiperidin-l-yl.
41. The method of any one of claims 1 to 40, wherein p is an integer of 1 or 2.
42. The method of any one of claims 1 to 41, wherein p is an integer of 1.
43. The method of any one of claims 1 to 42, wherein Z is CH2.
44. The method of any one of claims 1 to 42, wherein Z is C(=O).
45. The method of any one of claims 1 to 44, wherein m is an integer of 1 or 2.
46. The method of any one of claims 1 to 45, wherein m is an integer of 1.
47. The method of any one of claims 1 to 46, wherein RE1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more substituents Q.
48. The method of any one of claims 1 to 47, wherein RE1 is hydrogen, deuterium, or methyl.
49. The method of any one of claims 1 to 48, wherein RE1 is hydrogen or deuterium.
50. The method of any one of claims 1 to 49, wherein RE1 is hydrogen.
51. The method of any one of claims 1 to 50, wherein RE2 is hydrogen or C1-6 alkyl optionally substituted with one or more substituents Q.
52. The method of any one of claims 1 to 51, wherein RE2 is hydrogen or D- valyloxymethyl.
53. The method of any one of claims 1 to 52, wherein RE2 is hydrogen.
54. The method of any one of claims 8 to 53, wherein RE5 is halo or C1-6 alkyl optionally substituted with one or more substituents Q.
55. The method of any one of claims 8 to 54, wherein RE5 is fluoro or methyl.
56. The method of any one of claims 8 to 55, wherein RE5 is fluoro.
57. The method of any one of claims 1 to 56, wherein n is an integer of 0 or 1.
58. The method of any one of claims 1 to 57, wherein n is an integer of 0.
59. The method of any one of claims 8 to 20, wherein:
Z is CH2 or C(=O);
R1 is H or methyl; each R2a and R2b is H;
R3 is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(l-trifluoro- methylethyl)phenyl, 4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl, 4-morpholin-4- ylmethylphenyl, 4-isopropylphenyl, 4- ec-butylphenyl, 3 -Zc/V-butyl phenyl, 4-tert-butyl phenyl, 4- (hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl, 4-(l-methylcyclopropyl)phenyl, 4-(l- trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl, 4-(l-methylpiperidin-4-yl)phenyl, 4- hydroxylphenyl, 3 -methoxyphenyl, 4-m ethoxyphenyl, 4-dimethylaminophenyl, 4-acetamido- phenyl, 3,4-difluorophenyl, 3, 4-di chlorophenyl, 3-chloro-4-methylphenyl, 3 -methyl -4-/C 7- butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl- 4-tert-butyl phenyl, 3 -dimethylamino-4-m ethylphenyl, 2-naphthyl, thien-2-yl, 5-isopropylthien-2- yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-l-yl;
RE1 is H;
RE2 is H or D-valyloxymethyl;
RE5 is fluoro or methyl; m is an integer of 1 or 2; n is an integer of 0 or 1; p is an integer of 1 or 2; and q is an integer of 0, 1, or 2.
60. The method of any one of claims 1 to 7, wherein the compound is: 2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A1; 2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A2; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-oxo-2-(4-(l-(trifluoromethyl)cyclopropyl)phenyl)acetamide A3; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(5-isopropylthiophen-2-yl)-2-oxoacetamide A4; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A5;
2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A6;
2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A7;
2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l- yl)methyl)-2-oxoacetamide A8; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l- yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide A9;
(5)-2-(4-(ter/-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A10;
2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide All;
2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide All;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperi din-3-yl)-4,6-di oxo-5, 6-dihydro-4Z7- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A13;
2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A14;
2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A15;
2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A16; 2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol- 1 -yl)methyl)-2-oxoacetamide A17;
2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol-l-yl)methyl)-2-oxoacetamide A18;
2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A19;
2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A20;
2-([l,r-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A21;
2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol- 1 -yl)methyl)-2-oxoacetamide A22;
2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A23;
2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno [3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A24;
2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6- dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A25;
2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A26;
2-(3-methyl-4-(ter/-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A27;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A28;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A29; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A30; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-methylpiperidin-4-yl)phenyl)-2-oxoacetamide A31; 2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)methyl)-2-oxoacetamide A32;
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A33;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-N- methyl-2-oxoacetamide A34;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4JH- thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide A35; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-oxo-2-(4-( 1,1,1 -trifluoropropan-2-yl)phenyl)acetamide A36; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2- yl)-2-oxoacetamide A37;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A38;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4JH- thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamide A39;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A40;
2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4JH- thieno[3,4-c]pyrrol-l-yl)ethyl)-2-oxoacetamide A41; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-methylcyclopropyl)phenyl)-2-oxoacetamide A42; N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- 2-(4-(l-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamide A43;
2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6- dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)-2-oxoacetamide A44;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4JH- thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide A45;
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A46; 2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-N- methyl-2-oxoacetamide A47;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)methyl)-2-oxoacetamide A48;
(27?)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-l-oxoisoindolin-2-yl)-2,6- di oxopiperi din- l-yl)m ethyl 2-amino-3-methylbutanoate A49;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A50;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A51; N-(2-(2-(2,6-di oxopiperi din-3-yl)- l-oxoisoindolin-5-yl)ethyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A52;
2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A53;
2-(3-methyl-4-(/er/-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A54;
2-(3-methyl-4-(/er/-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A55;
2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2- oxoacetamide A56; N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2-oxo-2-(4-(l-(trifluoromethyl)- cyclopropyl)phenyl)acetamide A57; N-((2-(2,6-di oxopiperi din-3-yl)- 1, 3-di oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A58; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2- yl)-2-oxoacetamide A59; N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A60;
2-(4-(tert-butyl)piperidin-l-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A61; 2-(4-(tert-butyl)piperidin-l-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A62;
A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)propanamide A63;
(2,6-dioxo-3-(l-oxo-4-((2-oxo-2-(4-(l-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)- methyl)isoindolin-2-yl)piperidin-l-yl)methyl D-valinate A64;
A-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(l- (trifluoromethyl)cyclopropyl)phenyl)acetamide A65;
A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4- yl)phenyl)acetamide A66;
2-(4-(tert-butyl)cyclohexyl)-A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A67;
2-(4-(tert-butyl)cyclohexyl)-A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A68;
A-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)- 2-oxo-4-phenylbutanamide A69;
A1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-l-yl)methyl)- N2,N2-dimethyloxalamide A70;
A1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)- N2, N2 -dimethyloxalamide A71;
A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(/?-tolyl)acetamide
A72;
2-(3,4-difluorophenyl)-A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A73;
A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamide
A74;
A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4- (trifluoromethyl)phenyl)acetamide A75;
2-(4-cyanophenyl)-A-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A76; 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A77;
2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A78;
2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A79;
2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)- 2-oxoacetamide A80;
2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A81;
2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A82; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamide
A83; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6- trimethoxyphenyl)acetamide A84; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6- trimethylphenyl)acetamide A85; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2- fluorophenyl)acetamide A86; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4- trifluoromethylphenyl)acetamide A87;
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A88; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2- oxoacetamide A89;
2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A90;
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A91; 2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A92;
2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A93;
2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A94; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2- oxoacetamide A95; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2- oxoacetamide A96; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2- oxoacetamide A97;
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A98;
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A99; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2- oxoacetamide A100;
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A101;
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2- oxoacetamide A102; N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2-oxo-2-(121yridine-4- yl)acetamide A103;
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)methyl)-2-oxoacetamide A104;
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)methyl)-2-oxoacetamide A105; or
2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)methyl)-2- oxoacetamide A106; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
61. The method of any one of claims 1 to 60, wherein the malignancy is acute myeloid leukemia (AML).
62. The method of claim 61, wherein the AML is advanced AML.
63. The method of claim 61 or 62, wherein the AML is metastatic.
64. The method of any one of claims 61 to 63, wherein the AML is relapsed.
65. The method of any one of claims 61 to 64, wherein the AML is refractory.
66. The method of any one of claims 61 to 65, wherein the AML is del(5q) AML.
67. The method of any one of claims 57 to 64, wherein the AML harbors a cytogenetic abnormality.
68. The method of any one of claims 1 to 60, wherein the malignancy is a solid tumor.
69. The method of claim 68, wherein the solid tumor is unresectable.
70. The method of claim 68 or 69, wherein the solid tumor is refractory.
71. The method of any one of claims 68 to 70, wherein the solid tumor is relapsed.
72. The method of any one of claims 68 to 71, wherein the solid tumor is metastatic.
73. The method of any one of claims 68 to 72, wherein the solid tumor is stage II, III, or IV.
74. The method of any one of claims 68 to 73, wherein the solid tumor is stage III or
IV.
75. The method of any one of claims 68 to 74, wherein the solid tumor is c-MYC dependent.
76. The method of any one of claims 68 to 75, wherein the solid tumor harbors a c- MYC aberration.
77. The method of any one of claims 68 to 76, wherein the solid tumor harbors c- MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, or c-MYC protein overexpression.
78. The method of any one of claims 68 to 77, wherein the solid tumor is n-MYC dependent.
79. The method of any one of claims 68 to 78, wherein the solid tumor harbors a n- MYC aberration.
80. The method of any one of claims 68 to 79, wherein the solid tumor harbors n- MYC gene translocation, n-MYC gene amplification, n-MYC mRNA overexpression, or n-MYC protein overexpression.
81. The method of any one of claims 1 to 7 and 68 to 80, wherein the malignancy is lymphoma.
82. The method of claim 81, wherein the lymphoma is non-Hodgkin’s lymphoma.
83. The method of claim 81 or 82, wherein the lymphoma is B-cell non-Hodgkin’s lymphoma.
84. The method of any one of claims 81 to 83, wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, or Burkitt lymphoma.
85. The method of any one of claims 81 to 84, wherein the lymphoma is diffuse large B-cell lymphoma.
86. The method of any one of claims 81 to 84, wherein the lymphoma is Burkitt lymphoma.
87. The method of any one of claims 81 to 86, wherein the lymphoma is advanced lymphoma.
88. The method of any one of claims 81 to 87, wherein the lymphoma is unresectable.
89. The method of any one of claims 81 to 88, wherein the lymphoma is refractory.
90. The method of any one of claims 81 to 89, wherein the lymphoma is relapsed.
91. The method of any one of claims 81 to 90, wherein the lymphoma is metastatic.
92. The method of any one of claims 81 to 91, wherein the lymphoma is stage II, III, or IV.
93. The method of any one of claims 81 to 92, wherein the lymphoma is stage III or IV.
94. The method of any one of claims 81 to 93, wherein the lymphoma is c-MYC dependent.
95. The method of any one of claims 81 to 94, wherein the lymphoma harbors a c- MYC aberration.
96. The method of any one of claims 81 to 95, wherein the lymphoma harbors c- MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, or c-MYC protein overexpression.
97. The method of any one of claims 68 to 80, wherein the solid tumor is breast cancer, lung cancer, or ovarian cancer.
98. The method of any one of claims 68 to 80 and 97, wherein the solid tumor is breast cancer.
99. The method of any one of claims 68 to 80 and 97, wherein the solid tumor is lung cancer.
100. The method of claim 99, wherein the lung cancer is non-small cell lung cancer (NSCLC).
101. The method of claim 99, wherein the lung cancer is small cell lung cancer (SCLC).
102. The method of any one of claims 99 to 101, wherein the lung cancer is c-MYC dependent.
103. The method of any one of claims 99 to 102, wherein the lung cancer harbors a c- MYC aberration.
104. The method of any one of claims 99 to 103, wherein the lung cancer harbors c- MYC gene translocation, c-MYC gene amplification, c-MYC mRNA overexpression, or c-MYC protein overexpression.
105. The method of any one of claims 99 to 104, wherein the lung cancer is n-MYC dependent.
106. The method of any one of claims 99 to 105, wherein the lung cancer harbors a n- MYC aberration.
107. The method of any one of claims 99 to 106, wherein the lung cancer harbors n- MYC gene translocation, n-MYC gene amplification, n-MYC mRNA overexpression, or n-MYC protein overexpression.
108. The method of any one of claims 68 to 80 and 97, wherein the solid tumor is ovarian cancer.
109. The method of any one of claims 1 to 108, wherein the subject has failed a prior therapy.
110. The method of any one of claims 1 to 109, wherein the subject is a human.
111. The method of any one of claims 1 to 110, wherein the compound is administered orally.
112. The method of any one of claims 1 to 111, wherein the compound is administered as a tablet or capsule.
113. The method of any one of claims 1 to 112, wherein the therapeutically effective amount is ranging from about 0.01 to about 10 mg/kg per day.
114. The method of any one of claims 1 to 113, wherein the therapeutically effective amount is ranging from about 1 to about 500 mg per day.
115. The method of any one of claims 1 to 114, wherein the compound is administered in a cycle.
116. The method of any one of claims 1 to 115, wherein one cycle is 28 days.
117. The method of any one of claims 1 to 116, wherein the compound is administered for 3 days per week.
118. The method of any one of claims 1 to 117, wherein the compound is administered on Days 1, 3, and 5 in a week.
119. The method of any one of claims 1 to 118, wherein the compound is administered in a 28-day cycle for 3 days per week for 3 weeks, followed by 1 week of rest.
120. The method of any one of claims 1 to 119, wherein the compound is administered in a 28-day cycle on Days 1, 3, and 5 per week for 3 weeks followed by 1 week of rest.
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Citations (3)

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